OncoTrials - мониторинг клинических исследований

Описание

The goal of this clinical research study is to learn if metal detoxification (with calcium disodium edetate /[Ca-EDTA/] and dimercaptosuccinic acid /[DMSA/]) during standard therapy can help improve outcomes in patients with intermediate-risk, high-risk, or secondary AML compared to standard therapy alone. Researchers think lowering the level of metals found in the blood/bone marrow may help to control the disease and/or improve the response to chemotherapy.

Критерии включения

• 1. Understand and voluntarily sign an informed consent form for participants 18 years or older, unless LAR signs where applicable along with any required verbal assents if patients can provide assent.
• 2. Age 18 years or older at the time of signing the informed consent form.
• 3. Diagnosis of Any of the Following:
• * Newly diagnosed (or untreated) AML or Newly diagnosed Myeloproliferative Neoplasm in Myeloid Blast Phase (MPN-BP) /[including Chronic Myeloid Leukemia in Blast Phase (CML-BP)/], Ph+AML with intermediate-risk or high-risk (by ELN), or any other intermediate or high-risk AML by ELN
• * Secondary AML regardless of ELN risk status, however, may not have CBF /[t(8;21) or inv(16)/]
• Secondary AML types include:
• * Secondary AML evolved from prior untreated MDS, myeloproliferative neoplasm (MPN), or Aplastic Anemia
• * Therapy-related AML (t-AML)
• * AML evolved after prior MDS, MPN, or Aplastic Anemia after prior therapy for those myeloid bone marrow disorders
• * Secondary AML, including blast phase of MPN (MPN-BP) /[also, including CML in blast phase (BP of CML) after prior hematologic myeloid bone marrow disease (MDS, MPN, Aplastic Anemia, CML) (patients may have received treatment for their prior hematologic disorder for their previous bone marrow disorder) . Newly diagnosed (or untreated) myeloid blast phase of MPN (including myeloid blast phase of CML)/Ph+AML.150
• 4. Patients can enroll on this study after start of non-investigational induction therapy but must be within first 2 cycles of front-line therapy, as long as not in a complete remission.
• 5. Transformed and untreated AML transformed from previously treated MDS, myeloproliferative neoplasm (MPN) or other types of secondary AML are allowed. Myeloid-Blast Phase of MPN and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML) are allowed/Ph+ AML are allowed.
• 6. Eastern Cooperative Oncology Group (ECOG) performance status of . 2
• 7. Laboratory test results within these ranges (unless due to leukemia or other hematologic malignancy):
• * Serum creatinine.2.0 mg/dL
• * Total Bilirubin . 2.0 x Upper limit of normal (ULN) unless the patient has Gilbert fs.
• * AST (SGOT) and/or ALT (SGPT) . 2.0 x ULN
• 8. Women of childbearing potential (WCBP) must have a negative urine or serum pregnancy test within 14 days and must either commit to continued abstinence from heterosexual intercourse or adopting at least one highly effective method of contraception. These methods include intra-uterine device, tubal ligation, partners vasectomy, and hormonal birth control pills. Men must agree not to father a child and agree to use a condom if his partner is of childbearing potential.
• 9. Extramedullary disease is allowed if it can be measured and followed for response.

Критерии исключения

• 1. Nursing and pregnant individuals. Should a study participant become pregnant or suspect pregnancy while participating in this study, the study participant should inform their treating physician immediately.
• 2. Uncontrolled inter-current illness including, but not limited to, uncontrolled active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements or which judged by the investigator, places the patient at unacceptable risk.
• 3. Acute Promyelocytic leukemia (APL)
• 4. Prior venetoclax failure

Описание

The main objective of this study is to observe and evaluate the safety and tolerability of the XP-005 personalized tumor mRNA vaccine, either alone or in combination with toripalimab, for the treatment of acute myeloid leukemia patients who are in remission with minimal residual disease (MRD) positive but cannot undergo allogeneic hematopoietic stem cell transplantation.

Критерии включения

• 1. Subject voluntarily signs the written informed consent form and is able to comply with the scheduled visits and related procedures specified in the protocol
• 2. Subject must be ≥ 18 years old, with no gender restrictions
• 3. The expected survival period is ≥3 months
• 4. Conforming to the World Health Organization (WHO) 2022 classification criteria for Acute Myeloid Leukemia (AML).
• 5. Subject has completed induction and consolidation chemotherapy and has achieved complete remission (CR), complete remission with partial hematologic recovery (CRh), or complete remission with incomplete hematologic recovery (CRi) according to the 2022 European LeukemiaNet (ELN) criteria. The patient does not meet the criteria for or has contraindications to stem cell transplantation.
• CR is defined as: bone marrow blasts /<5%, absence of circulating blasts or blasts with Aure rods; absence of extramedullary disease, absolute neutrophil count (ANC) ≥1.0 × 10/^9/L, and platelet count ≥100 × 10/^9/L.
• CRh is defined as: ANC ≥0.5 × 10/^9/L, and platelet count ≥50 × 10/^9/L, otherwise all other CR criteria met CRi is defined as: All CR criteria except for ANC /<1.0 × 10/^9/L or platelet count /<100 × 10/^9/L. If both CRh and CRi are considered, CRi only includes patients who do not meet the criteria for CRh.
• 6. MRD positivity (①when using MFC, MRD is considered positive if the proportion of immunophenotypically abnormal cells among CD45+ cells is ≥0.01%; ② when using qPCR, MRD is considered positive if the NPM1 /<3log10 reduction in BM.
• 7. NPM1 mutation classification as Type A, D, G, H, B, and J
• 8. The peripheral blood HLA typing is HLA-A02:01
• 9. The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score is 0-2
• 10. Subject must be willing to provide existing valid diagnostic evidence prior to treatment or undergo bone marrow aspiration and biopsy, and must also be willing to undergo bone marrow aspiration and biopsy after receiving treatment

Критерии исключения

• 1. Copy number variants (CNVs) or loss of heterozygosity (LOH) in HLA-related genes or chromosomal regions were detected by genetic sequencing
• 2. Received chemotherapy, hormonal therapy, traditional Chinese medicine with anti-tumor indications, or other anti-tumor treatments within 4 weeks before the first dose (for mitomycin and nitrosoureas, within 6 weeks after the last dose), or within 5 half-lives of immunotherapy or molecular targeted therapy
• 3. Received tumor vaccines, cellular therapy, or planned to receive other vaccines within 4 weeks before the first dose
• 4. Subject who has undergone major surgery other than diagnostic or biopsy procedures within 4 weeks before the first dose, or who are expected to undergo major surgery during the study period
• 5. Uncontrolled central nervous system (CNS) lymphoma
• 6. Patients with extramedullary disease, or those deemed unsuitable for enrollment by the investigator
• 7. Eligible for allogeneic bone marrow or allogeneic stem cell transplantation at the time of Screening
• 8. Subject has previously undergone allogeneic hematopoietic stem cell transplantation or organ transplantation, or who is planned to undergo organ transplantation during this study
• 9. Within 7 days before treatment, laboratory tests show:
• 1. AST (SGOT) / ALT (SGPT) /> 3 ULN
• 2. Total bilirubin /> 2 ULN
• 3. eGFR /< 45 mL/min
• 4. SpO2 /< 95% without supplemental oxygen
• 10. DIC (Disseminated Intravascular Coagulation)
• 11. Active malignancy
• 12. A history of interstitial lung disease (ILD), pulmonary interstitial fibrosis, or stage III or higher chronic obstructive pulmonary disease (COPD)
• 13. A history of severe cardiovascular and cerebrovascular diseases, including but not limited to:
• 1. Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, second- or third-degree atrioventricular block; corrected QTc interval /> 450 milliseconds for males and /> 470 milliseconds for females,
• 2. Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events within 6 months before the first dose,
• 3. New York Heart Association (NYHA) functional class ≥ III heart failure or left ventricular ejection fraction (LVEF) /< 50%
• 14. Other severe and/or uncontrollable diseases, as determined by the investigator, that possibly affect the subject to participate in this study, including but not limited to:
• 1. A history of severe drug allergy, or known allergy to any component of the tumor vaccine or toripalimab injection formulation; or a history of severe allergic reactions to other monoclonal antibodies,
• 2. A history of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases,
• 3. Evidence of severe or uncontrollable liver or kidney disease,
• 4. Poorly controlled hypertension, diabetes, etc.,
• 5. Patients with active ulcers or gastrointestinal bleeding,
• 6. Presence of severe infections requiring intravenous antibiotics or hospitalization; or uncontrolled active infections within 4 weeks before the first dose,
• 7. Active syphilis infection
• 15. Hepatitis B surface antigen (HBsAg) positive with peripheral blood hepatitis B virus deoxyribonucleic acid (HBV DNA) levels above the upper limit of normal; hepatitis C virus antibody (HCV Ab) positive with HCV RNA levels above the upper limit of normal
• 16. Pregnant or breastfeeding women
• 17. Subject who has taken part in other clinical trials within 4 weeks before the first dose (excluding those who failed screening) or whom the investigator deems unsuitable for participation in the clinical trial for other reasons
• 18. Received systemic immunosuppressive therapy (excluding topical glucocorticoids) within 1 month before enrollment (e.g., />10 mg/d prednisone or equivalent)
• 19. Men and women of childbearing potential should agree to use non-pharmacological contraceptive measures from the time of signing the informed consent form until 3 months after the last dose

Описание

Abstract:

This clinical study is designed to evaluate the efficacy and safety of a thiotepa, busulfan, and fludarabine (TBF) conditioning regimen for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in elderly patients (≥55 years) with high-risk acute myeloid leukemia (AML). A total of 56 eligible patients will be enrolled in this prospective, single-arm, multicenter trial.

Study Design:

This is a multicenter, single-arm, prospective clinical trial. Eligible patients will receive the following conditioning regimen: thiotepa 5 mg/kg/day on Days -10 to -9; busulfan 3.2 mg/kg/day on Days -8 to -6; fludarabine 30 mg/m²/day on Days -6 to -2; and rabbit anti-thymocyte globulin (rATG) 1.5-2.5 mg/kg/day on Days -5 to -2. Hematopoietic stem cell infusion will be performed on Day 0. Graft-versus-host disease (GVHD) prophylaxis will include cyclosporine A (CsA), mycophenolate mofetil (MMF), and methotrexate (MTX). The primary endpoint of this study is 1-year relapse-free survival (RFS).

Inclusion Criteria:

Age 55-70 years (inclusive). Diagnosis of high-risk AML , include relapsed/refractory AML or CR MRD+ or ELN22 adverse risk group .Relapsed/refractory AML defined as at least one of the following: recurrence of leukemia cells in peripheral blood or bone marrow blasts />5% after complete remission (CR), failure to achieve remission after two courses of standard induction therapy, relapse within 12 months after consolidation therapy, relapse after 12 months that is refractory to conventional chemotherapy, multiple relapses, or persistent extramedullary leukemia）.

Scheduled to undergo haploidentical hematopoietic stem cell transplantation (haplo-HSCT).

Adequate organ function. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Written informed consent obtained.

Exclusion Criteria:

Unwillingness or refusal to accept the study treatment protocol. Presence of donor-specific anti-HLA antibodies. Known human immunodeficiency virus (HIV) infection. Active hepatitis B or C, or chronic active hepatitis. Uncontrolled active infection at the time of enrollment. Any other condition deemed by the investigator as unsuitable for study inclusion.

Критерии включения

• 1. Age 55-70 years (inclusive).
• 2. Diagnosis of high-risk AML , include relapsed/refractory AML or CR MRD+ or ELN22 adverse risk group . Relapsed/refractory AML defined as at least one of the following: recurrence of leukemia cells in peripheral blood or bone marrow blasts />5% after complete remission (CR), failure to achieve remission after two courses of standard induction therapy, relapse within 12 months after consolidation therapy, relapse after 12 months that is refractory to conventional chemotherapy, multiple relapses, or persistent extramedullary leukemia .
• 3. Scheduled to undergo haploidentical hematopoietic stem cell transplantation (haplo-HSCT).
• 4. Adequate organ function.
• 5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• 6. Written informed consent obtained.

Критерии исключения

• 1. Unwillingness or refusal to accept the study treatment protocol.
• 2. Presence of donor-specific anti-HLA antibodies.
• 3. Known human immunodeficiency virus (HIV) infection.
• 4. Active hepatitis B or C, or chronic active hepatitis.
• 5. Uncontrolled active infection at the time of enrollment.
• 6. Any other condition deemed by the investigator as unsuitable for study inclusion.

Описание

This is a Phase 1b open-label, multicenter, dose-escalation and dose-optimization study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor efficacy of eganelisib as monotherapy and in combination with cytarabine in patients with relapsed/refractory (r/r) acute myeloid leukemia (AML) or r/r higher-risk myelodysplastic syndromes (HR-MDS).

The study consists of 2 parts:

* Part 1: Dose Escalation (DE) in both monotherapy and in combination.
* Part 2: Dose Optimization

Критерии включения

• * Pathological diagnosis of either: AML according to World Health Organization (WHO) 2022 revised criteria per the local pathology report and with ≥10% bone marrow blasts (acute promyelocytic leukemia is excluded but secondary AML and treatment-related AML can be included); Higher-risk (IPSS-R Intermediate, High or Very High Risk at time of study entry) myelodysplastic syndromes (HR-MDS) according to WHO 2022 revised criteria per the local pathology report and with ≥10% bone marrow blasts.
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• * Adequate hepatic and renal function measured within 7 days prior to the first dose of eganelisib.

Критерии исключения

• * Autologous or allogeneic stem cell transplant within 6 months prior to Cycle 1 Day 1.
• * Receiving immunosuppressants (eg, cyclosporin) or systemic steroids (except for steroid use as cortisol replacement therapy in documented adrenal insufficiency).
• * Active fungal disease or uncontrolled infection of any kind; patients receiving antibiotic, antifungal or antiviral treatment must be afebrile and hemodynamically stable for />72 hours prior to treatment
• * WBC count />25 × 10/^9/L measured within 7 days prior to the first dose of eganelisib (hydroxyurea is permitted to decrease the WBC count).
• * Presence of a clinically significant non-hematologic toxicity of prior therapy that has not resolved to Grade ≤1 or Baseline, whichever is worst, as determined by NCI CTCAE v 5.0, except alopecia or skin pigmentation. Fatigue and neuropathy must have resolved to Grade ≤2.

Описание

This study is a prospective, multicenter, open-label umbrella clinical study planned to enroll 126 subjects with acute myeloid leukemia/myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplantation. Subjects eligible for enrollment were grouped based on the results of the initial myeloid genomic second-generation sequencing, and were given different regimens of maintenance therapy, with the aim of evaluating the efficacy and safety of the maintenance regimen.

Критерии включения

• * 1) Age 14-75 years and gender; (2) Initial diagnosis, pre-transplant myelogenetic second-generation sequencing data refinement; 3)ARM1: TP53 mutation (VAF ≥ 2%, excluding germline mutations), and/or AML-MR (SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, STAG2) by second-generation sequencing of the initial bone marrow gene; ARM2 Initial bone marrow gene II sequencing showed FLT3-ITD mutation with or without NPM1 mutation, no TP53 mutation, and no AML/MR. ARM3 Initial bone marrow gene II sequencing showed KIT mutations (loci: D816, N822, exon 8, VAF ≥2%, excluding germline mutations); no TP53 mutations, AML/MR, FLT3-ITD; ARM4 MDS in the intermediate/high/very high risk group as assessed by IPSS-M or AML in the intermediate/high risk group as assessed by ELN2022 without ARM1, 2, or 3 related mutations/fusions; 4) Subjects receive their first allogeneic hematopoietic stem cell transplantation within 30-60 days and STR-PCR shows complete donor chimerism; 5) Evaluation of the primary disease prior to maintenance therapy as complete remission and negative bone marrow flow MRD; 6) No active infection and no acute graft-versus-host disease requiring systemic treatment 7) Have appropriate organ function and laboratory results within 7 days prior to the start of treatment need to meet the following criteria:
• * Aspartate aminotransferase (AST) ≤ 3 times ULN (upper limit of normal, ULN);
• * Alanine aminotransferase (ALT) ≤ 3x ULN;
• * Total serum bilirubin ≤ 1.5 times the upper limit of normal ULN unless the patient has documented Gilbert`s syndrome; patients with Gilbert`s syndrome with bilirubin ≤ 3.0 times the upper limit of normal and direct bilirubin ≤ 1.5 times the upper limit of normal may be included;
• * Hemoglobin ≥ 70 g/L (had not received a red blood cell transfusion within 1 week prior to administration); Absolute neutrophil count (ANC) ≥ 0.8 x 10/^9/L (had not received long-acting colony-stimulating factor (LACSF) within 1 week prior to administration and short-acting colony-stimulating factor (SACSF) within 3 days prior to administration); and Platelet count ≥ 20 x 10/^9/L (1 week prior to administration) have not received a platelet transfusion);
• * Serum creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60 mL/min;
• * Coagulation function: International Normalized Ratio (INR) ≤1.5×ULN, Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN;
• * Left ventricular ejection fraction (LVEF) ≥45%; 8) Women of childbearing potential must have a negative serum pregnancy study within 7 days prior to the first dose. Female subjects of childbearing potential and male subjects whose partner is a woman of childbearing potential must agree to use a highly effective method of contraception from the time of signing the informed consent form until 180 days after the last dose of study drug is given (9) Voluntarily signing the informed consent, understanding and complying with the requirements of the study, good compliance, and cooperating with the follow-up visits.

Критерии исключения

• Patients were not enrolled if they met any of the following criteria:
• 1. Bone marrow or peripheral blood MRD changes from negative to positive;
• 2. Presence of acute or chronic GVHD, active infection requiring systemic immunosuppressive therapy prior to maintenance therapy;
• 3. Have clinically significant active cardiovascular disease such as uncontrolled arrhythmias, uncontrolled hypertension, congestive heart failure, any grade 3 or 4 heart disease as determined by the New York Heart Association (NYHA) functional class, or a history of myocardial infarction within the 6 months prior to screening;
• 4. Other serious medical conditions that may limit the patient`s participation in this trial (e.g., uncontrolled diabetes, active autoimmune disease, etc.);
• 5. Known human immunodeficiency virus (HIV) infection, or chronic infection with hepatitis B virus (HBsAg-positive) or hepatitis C virus (anti-HCV-positive) that is uncontrolled by drugs;
• 6. Patients with neurological or psychiatric disorders;
• 7. Those who are unable to understand or comply with the study protocol or are unable to sign the informed consent form;
• 8. The researcher does not consider it appropriate to participate in this study.

Описание

This is a single-arm pilot clinical trial evaluating dalbavancin-based prophylaxis in children and adolescents with acute myeloid leukemia or relapsed lymphoblastic leukemia receiving myelosuppressive chemotherapy.

Primary objective:

- To estimate the rate of bacterial bloodstream infection in pediatric patients with AML or relapsed ALL undergoing chemotherapy receiving dalbavancin-based prophylaxis

Secondary objectives:

* To describe the population pharmacokinetics of every 28 days dalbavancin up to 12 weeks in pediatric patients with AML or relapsed ALL undergoing chemotherapy
* To describe the tolerability of every 28 days dalbavancin prophylaxis in pediatric patients with AML or relapsed ALL undergoing chemotherapy
* To describe the acceptability of every 28 days dalbavancin prophylaxis in pediatric patients with AML or relapsed ALL undergoing chemotherapy
* To estimate the rates of likely bacterial infections, Clostridioides difficile infection, and febrile neutropenia in pediatric patients receiving dalbavancin-based prophylaxis

Критерии включения

• * Aged less than or equal to 25 years at enrollment
• * Receiving treatment for AML or relapsed ALL at St. Jude and treatment is expected to cause prolonged (/> 7 days) severe neutropenia (ANC /< 500/ml)
• * Expected to receive care at St. Jude for at least 56 days following enrollment on the protocol
• * Female participant, greater than or equal to 9 years old, has a documented negative pregnancy test prior to receipt of study drug.

Критерии исключения

• * Allergy to vancomycin, dalbavancin, teicoplanin, levofloxacin or ciprofloxacin (Not including non-anaphylactic vancomycin infusion reaction)
• * Documented past or current infection or colonization with pathogenic bacteria resistant to vancomycin plus either ciprofloxacin or levofloxacin
• * Diagnosed with long QT syndrome
• * Any condition judged by the investigator to put the participant at high risk from participation
• * Suspected or proven active bacterial infection
• * Inability to complete requirements of participation in the study (in the opinion of the investigator)
• * Expected survival /<28 days
• * Alkaline phosphatase, alanine transferase or total bilirubin ≥ 3x upper limit of normal for age
• * Estimated glomerular filtration rate (EGFR) /<30 mL/minute/1.73 m2
• * Other absolute contraindication to administration of fluoroquinolone antibiotics or dalbavancin
• * Participant is pregnant or breastfeeding a child

Описание

This is a phase I/2, interventional, open-label, multicenter study to assess the safety and efficacy of ARD103 in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome.

Критерии включения

• * Documented diagnosis of AML with either refractory or relapsed disease or diagnosis of MDS and ≥ 5% BM blasts
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• * Adequate hematologic status:
• * Absolute lymphocyte count (ALC) /> 100/mm3
• * Adequate renal, hepatic, cardiac and pulmonary function:
• * ALT and AST /< 3.0 × the ULN
• * Creatinine clearance ≥ 45.0 mL/min as estimated by Cockcroft-Gault and independent dialysis
• * Total bilirubin ≤ 2.0 mg/dL
• * Pregnancy testing: females of childbearing potential must have a negative serum or urine pregnancy test
• * Contraception: males and females of childbearing potential must agree to use an effective method of contraception
• * Participant is capable of giving signed informed consent

Критерии исключения

• * Participants with acute promyelocytic leukemia
• * Presence of active and clinically relevant central nervous system (CNS) disorder
• * Autoimmune disease requiring immunosuppressive treatment
• * Participants with known hepatic bridging cirrhosis
• * Currently active infection with hepatitis B or C
• * Previous treatment with investigational gene or cell therapy (including CAR therapy)
• * Any active acute GvHD or systemic treatment of more than 10 mg prednisone daily (or equivalent)
• * Previous chemotherapy including biologic/targeted therapy or immunological agents directed to the pathology within 14 days prior to screening and all along the study duration

Описание

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are serious, life changing blood cancers. Patients with MDS and AML commonly experience complications related to bleeding, which affect patient quality-of-life and can sometimes lead to hospitalization or death. The investigators will conduct a randomized controlled trial to evaluate the effectiveness and safety of tranexamic acid (TXA; a medication that prevents clots from dissolving) to prevent bleeding. In this study, 50% of patients will be randomized (like the flip of a coin) to receive TXA; the other 50% of patients will receive placebo. The investigators will monitor both groups of patients to see if the medication improves the risk and/or severity of bleeding. If tranexamic acid were to safely reduced the frequency of bleeding, this would broadly influence how doctors provide care for patients with MDS and AML around the world.

Критерии включения

• Master platform inclusion criteria:
• 1. Age ≥ 18 years
• 2. Diagnosis of myelodysplastic syndromes or acute myeloid leukemia
• MYELO-CAN TXA inclusion criteria:
• 1. Receipt of less-intensive chemotherapy (includes both frontline and relapsed/refractory setting)
• 2. Severe thrombocytopenia (platelets ≤ 30x10/^9/L or platelets ≤ 50x10/^9/L prior to chemotherapy initiation)

Критерии исключения

• Master platform exclusion criteria:
• 1. Participant is deemed unlikely to survive />30 days (as determined by clinical team)
• 2. Participant unable to provide informed consent
• MYELO-CAN TXA exclusion criteria:
• 1. Known allergy to tranexamic acid
• 2. Active thromboembolic disease
• 3. Active ischemic heart disease
• 4. Gross hematuria
• 5. Stage V chronic kidney disease
• 6. Clinically suspected disseminated intravascular coagulation (DIC)
• 7. Pregnancy and/or breastfeeding

Описание

The study is designed as a collection of biological samples of newly diagnosed acute myeloid leukemia (AML) patients treated in the clinical units involved. Samples of peripheral blood (PB) and bone marrow (BM) will be analyzed to determine the Inflammasome profile before and after a first-line chemotherapy treatment.

Критерии включения

• * Any gender,
• * Adults (/>18 years old),
• * New suspect diagnosis of acute myeloid leukemia (ELN2022 Criteria)
• * Capable of comprehend the study and the consent form,
• * Willing to sign the informed consent for the study.
• For the retrospective population we will select:
• biological samples (BM Biopsies, BM Aspirates and PB) already banked upon research purpose informed consent and collected from the 01/06/2006 up to 01/06/2024 from adults patients with diagnosis of acute myeloid leukemia according to ELN2017 Criteria.

Критерии исключения

• * Pediatric patients (/<18 years old),
• * Patients unable or unwilling to sign the informed consent.

Описание

This is a first in human, multi center, open label, phase 1/1b study to evaluate the safety and preliminary efficacy of CER-1236 in patients with relapsed/refractory (R/R), measurable residual disease (MRD) positive acute myeloid leukemia (AML), or TP53mut disease.

Критерии включения

• * Patients need to have a confirmed diagnosis of de novo or secondary AML, or myelodysplastic syndrome (MDS)/AML with 10% to 19% blasts, per the International Consensus Classification 2022 or the WHO 2022 classification.
• * Absolute lymphocyte count />0.3 x 109/L prior to apheresis.
• * Eastern cooperative oncology group (ECOG) performance status 0 to 1.

Критерии исключения

• * Prior therapy with a permanently integrated, genetically modified cell product.
• * No measurable leukemia on the screening bone marrow evaluation prior to any bridging therapy.
• * Active autoimmune disease or history of autoimmune disease requiring treatment within the prior 2 years. Patients with history of autoimmune thyroiditis or type 1 diabetes well controlled on replacement regimen are eligible.
• * A known hypersensitivity or severe allergy to fludarabine, cyclophosphamide, or study drug components or diluents.
• * Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the physician.
• * Primary immunodeficiency disorder.

Описание

This is a first-in-human, multicenter, open-label, phase 1 study to evaluate the safety, PK, PD and preliminary efficacy of STX-0712 in patients with advanced CMML and AML for whom there are no further treatment options known to confer clinical benefit.

Критерии включения

• * Refractory/resistant CMML, defined as: Diagnosis of CMML 1 or 2; and has not responded to at least 4 cycles of hypomethylating agents (HMAs)(for myeloproliferative CMML - HMAs or hydroxyurea) or discontinued prior to 4 cycles due to toxicity or has progressive disease OR
• * Relapsed/refractory monocytic or monocytic predominant AML. Monocytic predominant AML is defined as ≥50% monocytes and/or monocytic precursors (promonocytes/monoblasts) and expressing at least two monocytic markers including CD4, CD11c, CD14, CD36, or CD64; and peripheral blood white blood cell (WBC) /<30,000/µL (microliters) and /<20% circulating blasts.
• * Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.
• * Life expectancy of />2 months and stable enough to complete two cycles of STX-0712, in the opinion of the Investigator.
• * Adequate organ function.
• * Both females of child-bearing potential and males must agree to use acceptable contraceptive methods for the duration of time in the study and to continue to use acceptable contraceptive methods for 90 days after last STX-0712 infusion.
• * Able to understand and willing to sign a written informed consent form.
• * Willing and able to comply with study procedures and follow-up examinations.

Критерии исключения

• * Has any of the following disease-specific conditions: For CMML: Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes other than CMML. For AML: Acute Promyelocytic Leukemia (APL) or Isolated extramedullary disease.
• * Eligible for an immediate allogenic stem cell transplant (alloSCT).
• * Current active use of nicotine products including tobacco, nicotine patches or vaping products.
• * Prior bone marrow transplant (BMT) within 6 months of date of consent; or transplanted patients who received the last dose of immunosuppressive therapies within 3 months of date of consent.
• * Has active autoimmune condition requiring immunosuppressive treatment or is receiving immunosuppressive therapy for the treatment of autoimmune disorders, allergies, or other clinical symptoms. Systemic steroids /<10 mg (milligrams) daily of prednisone equivalent are allowed; and intermittent use of bronchodilators or inhaled steroids, local steroid injections, topical steroids are allowed.
• * Received treatment with chemotherapy, biologic therapy, or wide-field radiation within 14 days of consent. Exceptions for hydroxyurea: For CMML and AML participants, hydroxyurea may be continued up to 72 hours prior to first dose of STX-0712. Hydroxyurea will also be permitted for first cycle of STX-0712 treatment for participants with proliferative CMML or AML with high white blood count (WBC ≥25,000/µL).
• * Received an investigational treatment within 30 days prior to dosing with STX-0712.
• * Received Granulocyte Colony Stimulating Factor /[G-CSF/], Granulocyte Macrophage Colony Stimulating Factor /[GM-CSF/], erythropoietin, romiplostim, or other growth factors within 2 weeks prior to first dose of STX- 0712.
• * Received a live or live attenuated vaccine within 30 days before the first dose of STX-0712.
• * Clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled or unstable chest pain, history of heart attack(s), or stroke within 6 months prior to consent, uncontrolled high blood pressure, or clinically significant arrhythmias not controlled by medication).
• * QT interval corrected by Fridericia`s formula (QTcF) />470 msec for both men and women on Screening electrocardiogram(s) (ECG). Patients with a bundle branch block must have QT interval corrected for bundle branch block.
• * Other than AML or CMML, active malignancy and/or cancer history that requires active therapy. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia, or organ-confined prostate cancer with no evidence of progressive disease.
• * Active, uncontrolled bacterial, fungal, or viral infection.
• * Known human immunodeficiency virus (HIV).
• * Active or chronic hepatitis B or hepatitis C infection.
• * Evidence of any other severe or uncontrolled systemic diseases, any other serious and/or unstable pre-existing medical conditions, psychiatric disorder, or other conditions that could interfere with participant`s safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.

Описание

The objective of this study to evaluate the safety, tolerability, pharmacokinetic profile, and preliminary efficacy of BL-M11D1 in patients with relapsed/refractory acute myeloid leukemia.

Критерии включения

• 1. Signed the informed consent
• 2. Age ≥18 years
• 3. Has a life expectancy of ≥3 months
• 4. Relapsed and/or refractory CD33-positive AML as determined by local pathology review that has failed initial standard of care therapy. Diagnosis of primary AML or AML secondary to myelodysplastic syndromes. Relapsed or refractory status. CD33-positive as confirmed by local flow cytometry or cytology
• 5. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2
• 6. Toxicity of previous anticancer therapy has returned to Grade ≤1 as defined by NCI CTCAE V5.0, except for alopecia and endocrinopathies controlled by replacement therapy that must be Grade ≤2
• 7. Has adequate liver and renal function before registration, defined as: a. Hepatic function: Total bilirubin (TBIL) ≤1.5×ULN (≤3×ULN for subjects with Gilbert`s syndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN b. Renal function: Creatinine clearance ≥50 mL/min (Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration /[CKD-Epi/], or Modification of Diet in Renal Disease Study /[MDRD/] equations)
• 8. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception during the course of the study and for 7 months after the last dose of study treatment. An additional contraceptive method, such as a barrier method (eg, condom), is recommended
• 9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must be nonlactating

Критерии исключения

• 1. Subjects with acute promyelocytic leukemia (APL) or chronic myelogenous leukemia in blast crisis (CML)
• 2. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, major surgery, targeted therapy (including small molecule inhibitor of tyrosine kinase), and other anticancer therapy within 2 weeks) prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration, or palliative radiotherapy within 2 weeks prior to the first administration
• 3. Subjects with history of severe heart disease, such as symptomatic congestive heart failure (CHF) ≥ Grade 2 (CTCAE 5.0), New York Heart Association (NYHA) ≥ Grade 2 heart failure, history of transmural myocardial infarction, unstable cardiac arrhythmias or angina pectoris within 6 months before screening
• 4. Subjects with prolonged QT interval (QTcF />470 msec), complete left bundle branch block, Grade 3 atrioventricular block or a history of additional risk factors for Torsades de Pointes (TdP; eg, heart failure as defined in Exclusion Criterion 3, chronic or recurrent hypokalemia that requires medical intervention, congenital long QT syndrome, family history of long QT syndrome) or any current concomitant medication known to prolong the QT/QTc interval or cause TdP
• 5. Active autoimmune diseases and inflammatory diseases, such as: systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease and Hashimoto`s thyroiditis, etc., except for Type I diabetes, hypothyroidism that can be controlled only by standard of care treatment, and skin diseases that do not require systemic treatment (such as vitiligo, psoriasis)
• 6. Subjects with other prior or concurrent malignancies except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or carcinoma in situ after adequate resection, or other malignancy treated with curative intent with as disease-free interval of at least 1 year
• 7. Subjects with poorly controlled hypertension or uncontrolled hypertension by two or more antihypertensive drugs (systolic blood pressure />150 mmHg or diastolic blood pressure />100 mmHg)
• 8. Subjects with active acute or chronic graft vs. host disease (aGVHD or cGVHD) should be excluded from this study. Subjects with GVHD who are receiving treatment with systemic glucocorticoids />10 mg/day equivalent of prednisone should also be excluded from the study; however, treatment with low-dose glucocorticoids (≤10 mg/day equivalent of prednisone) is permitted
• 9. Subjects currently receiving immunosuppressive therapy should be excluded from this study.
• 10. Clinical evidence of disseminated intravascular coagulation (DIC). Smoldering low grade DIC is allowed after discussion with the sponsor
• 11. Subjects with stroke or transient ischemic attack (TIA) within 6 months before screening
• 12. Subjects with a thromboembolic event (eg, deep vein thrombosis /[DVT/] or pulmonary embolism /[PE/]) within 6 months before screening except for those who are clinically stable and receiving treatment with adequate anticoagulant therapy for at least 3 weeks before screening
• 13. Subjects with active central nervous system (CNS) AML will be excluded. A lumbar puncture does not need to be performed unless there is clinical suspicion of CNS involvement per investigator judgment. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS AML is allowed with the approval of the sponsor
• 14. Subjects with pre-existing ≥Grade 2 peripheral neuropathy
• 15. Subjects with advanced/ clinically significant lung diseases, such as poorly controlled COPD and asthma, restrictive lung disease, pulmonary hypertension etc.
• 16. Subjects who have a history of noninfectious interstitial lung disease (ILD)/ pneumonitis that required treatment with steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• 17. Subjects who have a history of anaphylaxis or severe hypersensitivity to recombinant humanized antibodies or human-mouse chimeric antibodies or any of the components of BL-M11D1
• 18. Subjects with known human immunodeficiency virus infection (HIV Ab positive) Subjects are allowed to participate if all of the following criteria are met: (1) Undetectable HIV RNA and CD4 count ≥350 cells/μL at screening, (2) No AIDS defining opportunistic infection within 12 months prior to screening, (3) On stable antiretroviral therapy (ART) for at least 4 weeks prior to screening with projected continuation of ART as clinically indicated while on the study
• 19. Subjects with active Hepatitis B virus (HBV) infection (positive HBsAg test). Subjects with chronic inactive HBV infection are eligible if they meet all of the following criteria:
• 1. Have a HBV DNA viral load ≤ 500 IU/mL
• 2. Have normal AST and ALT, OR if liver involvement is present, has AST and ALT /<3 × ULN which are not attributed to HBV infection
• 3. on antiviral treatment, as clinically indicated
• 20. Subjects with active Hepatitis C virus (HCV) infection (HCV antibody positive and HCV-RNA /> the lower limit of detection). Subjects with a positive anti-HCV antibody are eligible only if PCR is negative for HCV RNA
• 21. Subjects with active or latent tuberculosis
• 22. Subjects with active and uncontrolled infections requiring IV antibiotic, antiviral, or antifungal treatment, such as severe pneumonia, bacteremia, sepsis, etc., within 1 week prior to first dose of study treatment. Subjects on stable oral antimicrobials with no clinical or laboratory evidence of active infection are eligible
• 23. Received an investigational drug within 2 weeks prior to first dose of study treatment.
• 24. Subjects who are pregnant, breastfeeding, or planning to become pregnant during the study

Описание

The VERDI study is an investigator-initiated, multicenter, multicohort, phase II trial with combination of venetoclax + azacitidine for patients treated for AML under according to an intensive chemotherapy protocol (CETLAM-20) failing to achieve or maintain MRD negativity at pre-established time-points: at chemotherapy completion for ELN favorable subtypes, and prior to alloHCT for non-favorable European LeukemiaNet (ELN) AML patients.

The primary objective is to determine Ven/Aza treatment activity in MRD clearance in patients diagnosed with AML with persistent MRD or MRD reappearance after frontline chemotherapy, or prior to alloHCT.

Критерии включения

• 1. Patients must have confirmation of with acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) or MRD reappearance after frontline intensive chemotherapy (including at least one cycle of cytarabine and anthracycline), and prior to allogeneic hematopoietic cell transplantation (allo-HCT).
• 1. In patients with NPM1 mutation, qRT-PCR of NPM1 will be the method used to establish a molecular failure, defined as failure to achieve molecular response after consolidation therapy (NPM1mut/ABL1·100 /> 0.01) or MRD reappearance after molecular response. All cases of molecular failure must be confirmed with a second MRD assessment in 2 to 4 weeks.
• 2. In patients with core-binding factor AML, qRT-BCR of RUNX1-RUNX1T1 and CBFb-MYH11 transcripts will be used. Patients failing to achieve a major MRD reduction after consolidation therapy (i.e., RUNX1-RUNX1T1/ABL1·100/>0.1 or CBFb-MYH11/ABL1·100/>0.1), a log increase in MRD between two positive samples or confirmed MRD reappearance after molecular response will be considered as molecular failures and could be included in the trial.
• 3. In the remaining cases, an appropriate leukemia-associated immunophenotype (LAIP) measured by multiparameter flow cytometry will be used for MRD surveillance. A cutoff of 0.1% will be used to define MRD positivity.
• 2. Age ≥18 years.
• 3. Without clinical signs of active central nervous system disease.
• 4. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2 or Karnofsky performance status (KPS) equivalent.
• 5. Patients must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
• 6. Patients must have adequate liver function as demonstrated by:
• 1. aspartate aminotransferase (AST) ≤ 3.0 × upper limit normal (ULN)
• 2. alanine aminotransferase (ALT) ≤ 3.0 × ULN
• 3. bilirubin ≤ 1.5 × ULN, unless due to Gilbert/'s syndrome
• 7. Non-sterile male patients must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 3 months after the last dose of study drug. Male patients must agree to refrain from sperm donation from initial study drug administration until 3 months after the last dose of study drug.
• 8. WOCBP must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting therapy; 2) throughout the entire duration of treatment; 3) during dose interruptions; and 4) for at least 6 months after discontinuation of therapy (last dose of study drug).
• 9. Patients must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed screening procedures.

Критерии исключения

• 1. Patient has received other prior rescue treatment for MRD.
• 2. Patient is known to be positive for Human immunodeficiency virus (HIV). Note: HIV testing is not required.
• 3. Patient is known to be positive for hepatitis B (HBV) or C (HCV) infection with the exception of those with an undetectable viral load.
• Note: Hepatitis B or C testing is not required and patients with serologic evidence of prior vaccination to HBV (i.e., HBsAg-, anti-HBs+ and anti-HBc-) may participate.
• 4. Patient has known active central nervous system (CNS) involvement from AML.
• 5. Patient has received within 7 days prior to the first dose of study drug: steroid therapy ≥ 20 mg/day (prednisone or equivalent) for antineoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers.
• 6. Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
• 7. Patient has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:
• 1. New York Heart Association heart failure /> class 2.
• 2. Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.
• 8. Patient has a malabsorption syndrome or other condition that precludes the enteral route of administration.
• 9. Patient exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).
• 10. Patient has a history of other malignancies within the prior year to study entry, except for:
• 1. Adequately treated in situ carcinoma of the breast or cervix uteri.
• 2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.
• 3. Prostate cancer with no plans for therapy of any kind.
• 4. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
• 11. Pregnant and breastfeeding females.

Описание

This pilot study aims to gather preliminary evidence on how different hemoglobin levels impact blood biomarkers related to bleeding. The feasibility of conducting a future larger clinical trial will also be assessed. Red blood cell transfusions are part of the standard of care for patients with leukemia. This study evaluates two transfusion strategies: one that maintains hemoglobin levels above the standard-of-care threshold, reflecting current routine practice; and another that maintains hemoglobin levels above 110 g/L, which is closer to the normal hemoglobin range. The normal hemoglobin range is 120-160 g/L for females and 140-180 g/L for males. Raising hemoglobin levels closer to normal values may reduce bleeding risk.

Критерии включения

• 1. ≥18 years old.
• 2. Inpatient
• 3. Diagnosis of acute myeloid leukemia or acute lymphocytic leukemia.
• 4. Less than 5 days have elapsed since the start of induction chemotherapy treatment.
• 5. Hemoglobin at enrolment is under 130 g/L.

Критерии исключения

• 1. Failure to provide informed consent.
• 2. Unwilling to receive blood transfusions.
• 3. Life expectancy /<72 hours.
• 4. Undergoing palliative chemotherapy.
• 5. Requires specialized blood products (e.g., antigen-matched, irradiation, etc.).
• 6. Diagnosis of acute promyelocytic leukemia.
• 7. Diagnosis of hyperleukocytosis (a white blood cell count exceeding 100 × 10/^9/L).
• 8. Diagnosed with coagulopathies or ongoing treatment with therapeutic anticoagulants, aspirin or nonsteroidal anti-inflammatory drugs (history of inherited or acquired coagulation disorder, known hemolytic disease, INR /> 1.5)
• 9. Evidence of iron overload (ferritin />800 ng/mL, transferrin saturation />80%) .

Описание

The purpose of this study is as follows:

1. Determine whether people receiving the combination treatment of olutasidenib, venetoclax, and azacitidine have the same, more, or fewer side effects compared to the usual chemotherapy treatment that people with this condition receive.
2. Determine how well the combination treatment of olutasidenib, venetoclax, and azacitidine works compared to the usual chemotherapy treatment that people with this condition receive.

Критерии включения

• 1. Participant is an adult male or female participant aged 18-75 years considered eligible to undergo intensive induction chemotherapy at the time of signing the informed consent form (ICF).
• 2. Eastern Cooperative Oncology Group (ECOG) performance status ≤2
• 3. Confirmed diagnosis of:
• 1. Newly diagnosed AML Isocitrate dehydrogenase 1 (IDH1) R132 mutated disease as assessed locally. Note: historical results from within 30 days of informed consent will be accepted if the participant did not receive systemic treatment after collection.
• 2. Secondary AML, including prior hypomethylating agents (HMA) exposure for myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), or MDS/MPN is allowed.
• 4. Participant must have adequate organ function, defined by the following:
• 1. Aspartate transaminase (AST) and alanine aminotransferase (ALT) values ≤3 × upper limit of normal (ULN) or ≤5 × ULN for participants with leukemic involvement.
• 2. Bilirubin ≤2 ULN (≤3 × ULN in participants with Gilbert Syndrome) or ≤3 × ULN for participants with leukemic involvement.
• 3. Creatinine clearance ≥30 mL/min (using Cockcroft-Gault), or serum creatinine ≤1.5 × ULN.
• 5. The interval from prior treatment for an antecedent hematologic disorder to the first dose of study treatment (C1D1) will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents. In addition, the following will be allowed:
• 1. Intrathecal chemotherapy for prophylactic use or for controlled central nervous system (CNS) leukemia.
• 2. Use of hydroxyurea for participants with rapidly proliferative disease is allowed before the start of study therapy and for the first 4 weeks on study treatment.
• 6. Recovery from non-hematologic toxic effects of prior treatment to Grade ≤1, or baseline value according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 classification (excluding infertility, alopecia, or Grade 1 neuropathy).
• 7. Baseline QT interval corrected using the Fridericia equation (QTcF) ≤ 480 msec. Note: This criterion does not apply to participants with a bundle branch block (BBB); for participants with BBB, a cardiology consult is recommended to ensure that QTcF is not prolonged.
• 8. Female participants who are women of childbearing potential (WOCBP) must have a negative serum or urine (beta-human chorionic gonadotropin (βhCG)) pregnancy test at screening and negative serum or urine test documented within the 24-hour period prior to the first dose of study drug. WOCBP are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression (Section 4.8.1).
• 9. Sexually active female participants who are WOCBP and male participants who are sexually active partners of WOCBP must agree to use a highly effective method of contraception during the course of the study from the date of informed consent and for at least 3 months after their last dose of study drug. Effective birth control methods include the following:
• 1. Intrauterine device (IUD) plus one barrier method.
• 2. Stable doses of hormonal contraception for at least 3 months (eg, oral, injectable, implant, transdermal).
• 3. 2 barrier methods; effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).
• 4. A vasectomized partner (where vasectomy was done at least 4 months prior to first dose of study treatment).
• 5. True abstinence (ie, abstinence that is in line with the preferred and usual lifestyle of the participant).
• 10. Female and male participants must agree to refrain from egg/ova retrieval either for their own use or donation or from sperm donation, respectively, from the date of informed consent until 3 months after the last dose of study treatment.
• 11. Participant is willing and able to participate and comply with all study requirements and to provide signed and dated written informed consent prior to initiation of any study procedures.

Критерии исключения

• 1. Relapsed/Refractory AML.
• 2. ELN (2022) favorable risk AML, except for nucleophosmin 1 (NPM1) mutated AML, which is allowed.
• 3. Acute promyelocytic leukemia (APL).
• 4. Positive Fms related receptor tyrosine kinase 3-Internal tandem duplication (FLT3-ITD) mutation.
• 5. Active CNS involvement by leukemia (other extramedullary disease is allowed).
• 6. Participants /<18 years or />75 years of age.
• 7. Female participant who is pregnant or breastfeeding.
• 8. Participant plans to become pregnant or father a child (including ova or sperm donation) while enrolled in this study or within 3 months after last dose of study treatment (Section 4.8).
• 9. Participant has a known allergy or history of hypersensitivity to study drugs or their excipients.
• 10. Previous therapy with olutasidenib (or ivosidenib or other IDH1 inhibitor) or venetoclax (or another B cell lymphoma 2 (BCL-2) inhibitor).
• 11. Participant has active evidence of clinically significant unstable medical condition such as uncontrolled infection, severe metabolic abnormality, poorly controlled psychiatric illness, or symptomatic coronary artery disease (other than stable angina), which could place the participant at unacceptable risk of study treatment, per the Investigator`s judgement.
• 12. Participants receiving treatment with strong Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors within 7 to 14 days or 5 half-lives (whichever is longer) prior to the first dose of study medication. Azoles are allowed with appropriate venetoclax dose reductions. Please note that participants receiving these medications would qualify for this study after undergoing a washout period of 7 to 14 days or 5 half-lives, whatever is longer for the inhibitor/inducer.
• 13. Participants receiving treatment with strong CYP3A inducers within 7 to 14 days or 5 half-lives (whichever is longer) prior to the first dose of study medication. Please note that participants receiving these medications would qualify for this study after undergoing a washout period of 7 to 14 days or 5 half-lives, whatever is longer for the inhibitor/inducer.
• 14. History of allogeneic hematopoietic stem cell transplant (HSCT) for a diagnosis other than AML if there is clinically significant active graft-versus-host disease (GVHD) or ongoing immunosuppressive therapy is required beyond prednisone 10 mg daily or equivalent. Otherwise, prior allogeneic HSCT is allowed.
• 15. Participants with a concurrent active malignancy under treatment.
• 16. Known history of active hepatitis B (HBV) or hepatitis C (HCV) infection or human immunodeficiency virus (HIV) infection (clinically detectable viral load).
• 17. Major surgery within 28 days prior to the first dose. Participants must have recovered from surgery and be without current complications.
• 18. Participants with impaired decision-making capacity.

Описание

In resource-constrained settings such as Malawi, survival rates for pediatric acute myeloid leukemia (AML) are dismally low compared to high-resource environments. This disparity highlights the urgent need for feasible treatment protocols tailored to the realities of these regions where most children with cancer are treated. In 2023, after reviewing favorable clinical trials results in other resource-limited settings, the Kamuzu Central Hospital (KCH) pediatric cancer unit adopted an evidence-based intensity-adapted clinical practice guideline (CPG) developed by the International Society of Paediatric Oncology (SIOP) as its standard of care for the treatment of pediatric AML, aiming to balance curative intent with manageable toxicity. The current study is a prospective evaluation of outcomes of standard of care in Malawi using the SIOP CPG in a real-world setting.

The LEAP study aims to assess the implementation of the SIOP AML guidelines at KCH in an effort to continually improve outcomes in Malawi. The study is an observational-implementation design with a composite effectiveness-implementation outcome called Implementation Success. Implementation Success combines feasibility, the ability of patients to complete all aspects of the CPG, with effectiveness, the ability to maintain historical rates of complete remission of 40% at the treatment center.

This prospective cohort study will enroll children under 18 years diagnosed with de novo AML at KCH. Implementation Success will be the primary endpoint, with secondary endpoints including CPG fidelity, long-term survival, adverse events, and hematologic recovery times. Patient-reported outcomes will also be collected to assess the impact of treatment on quality of life.

This will be the first prospective study of pediatric AML in sub-Saharan Africa, providing critical data on the management of AML in low-resource settings. By assessing the implementation of a context-adapted CPG, the study will contribute to the global effort to improve pediatric AML outcomes in resource-constrained environments. The findings will serve to guide practitioners in Malawi and similar settings, and the data generated will be invaluable for future clinical decisions and CPG development.

Критерии включения

• 1. Age Patients must be /<18 years of age at time of study enrollment.
• 2. Diagnosis
• Patients must be diagnosed with de novo AML according to 2022 WHO 5th Edition classification with or without extramedullary disease. Patients must have one of the following:
• * Bone marrow myeloblasts ≥20%. In cases of dry taps due to fibrosis, myeloblast percentage can be estimated from a bone marrow biopsy core specimen. Due to unavailable molecular/cytogenetic diagnostics in Malawi, patients with /<20% bone marrow myeloblasts can be included in the study at the discretion of the treating oncologist with rationale documented.
• * In cases where a bone marrow evaluation is not safe/feasible, a peripheral blood sample may be used with a documented absolute myeloblast percentage of ≥1000/μL calculated based on a total white blood cell count and percentage circulating blasts.
• 3. Therapy Patients must begin treatment according to the 2023 KCH AML therapy CPG.

Критерии исключения

• 1. Patients with any of the following conditions or criteria will be excluded from the study:
• * Juvenile myelomonocytic leukemia
• * Transient myeloproliferative disorder
• * Acute promyelocytic leukemia
• * Mixed phenotype acute leukemia
• * Trisomy 21
• * Current pregnancy
• * Previous or concurrent malignancy
• * Isolated myeloid sarcoma
• 2. Patients previously treated with antineoplastic therapy with the following exceptions:
• * Hydroxyurea
• * Corticosteroids
• * Intrathecal chemotherapy at diagnosis

Описание

This Phase 1, multicenter, open-label, dose escalation and dose optimization study is designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of AUTX-703 administered orally in subjects with advanced hematologic malignancies.

Критерии включения

• 1. Participant must be ≥18 years of age
• 2. Participant must have confirmed diagnosis as follows:
• R/R AML and has not achieved adequate response to, cannot tolerate, or refused all approved therapies known to be active for treatment of their disease OR R/R MDS with over 10% blasts in the bone marrow and has not achieved an adequate response to at least 4 cycles of a hypomethylating agent (HMA)- containing regimen or other treatment known to be active for their disease OR R/R AML or R/R MDS that has relapsed after a hematopoietic stem cell transplant (HSCT)
• 3. Participant must be willing and able to comply with scheduled study visits and treatment plans.
• 4. Participant must be willing to undergo all study procedures unless contraindicated due to medical risk.
• 5. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
• 6. Participant must have adequate hepatic function
• 7. Participant must have adequate renal function
• 8. Participant must have adequate cardiovascular function
• 9. Participant must have a white blood cell (WBC) count ≤20 × 10⁹/L (with stable hydroxyurea use allowed)
• 10. Participant must meet timing requirements with respect to prior therapy and surgery
• 11. Participant must agree to use effective contraception during the study and for the required post-treatment period: Males: Use condoms (even if vasectomized) during the study and for 90 days post-treatment. Females of childbearing potential: Use a combination of 1 highly effective and 1 effective method of contraception during the study and for 180 days post-treatment.

Критерии исключения

• 1. Participant is unable to provide informed consent and/or to follow protocol requirements.
• 2. Participant has undergone chimeric antigen receptor T cell therapy or HSCT within 60 days of the first dose of study treatment or has active clinically significant graft-versus-host disease (GVHD)
• 3. Participant has another malignancy that may interfere with diagnosis and treatment of R/R AML or R/R MDS.
• 4. Participant has an active severe infection that requires anti-infective therapy or has an unexplained temperature of />38.5°C during screening visits or on their first day of study treatment.
• 5. Participant has a known sensitivity to AUTX-703 or any of its components.
• 6. Participant is taking systemic strong CYP3A4 inhibitors or inducers within 14 days of the first dose of study treatment.
• 7. Participant who are taking proton pump inhibitors should be switched to another acid-reducing agent such as an antacid or H2 blocker
• 8. Participant is taking P-gp and breast cancer resistance protein (BCRP) inhibitors or inducers within 14 days of first dose of study treatment.
• 9. Participant has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections with detectable viral load
• 10. Participant has experienced AIDS related illness within the past 6 months or have detectable HIV viral load.
• 11. Participant has an uncontrolled intercurrent illness
• 12. Participant has active Class III or IV cardiovascular disease within 6 months prior to the start of study treatment
• 13. Participant is unable to tolerate the administration of oral medication or has GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of an oral medication
• 14. Participant is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment

Описание

This phase II MyeloMATCH treatment trial studies how well ASTX727 and venetoclax plus enasidenib works compared to ASTX727 and venetoclax alone for the treatment of older patients with newly diagnosed acute myeloid leukemia (AML) or younger patients who are considered unfit for standard treatment, and who have an abnormal change (mutation) in the IDH2 gene. This gene mutation can cause AML to grow and spread. This trial is being done to see if adding enasidenib to the usual treatment can help more patients with the IDH2 gene get rid of AML. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Enasidenib works by stopping the growth and spread of tumor cells that have the IDH2 mutation. Giving ASTX727 and venetoclax plus enasidenib may work better in treating AML patients with the IDH2 mutation.

Критерии включения

• * Participants must have been registered to the MYELOMATCH Master Screening and Reassessment Protocol prior to consenting to this study. Participants must have disease with a detectable IDH2 mutation based on central testing through the MYELOMATCH and be assigned to this clinical trial via MATCHBox prior to registration to this study
• * Note: Pre-enrollment/diagnosis labs must have already been performed under MYELOMATCH
• * Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) defined by having ≥ 20% blasts in the bone marrow and/or peripheral blood, excluding acute promyelocytic leukemia (APL) with PML-RARA
• * Participants must not be receiving or planning to receive any other investigational agents while on protocol therapy
• * Participants must not have received prior therapy for AML or myelodysplastic syndrome (MDS) and/or myeloproliferative neoplasm (MPN) with the exception of hydroxyurea, all-trans retinoic acid (ATRA), colony-stimulating factors, erythropoiesis-stimulating agents, immunosuppressive therapy, intrathecal chemotherapy, a single dose of cytarabine for cytoreduction, and/or leukapheresis
• * Participants must not be currently receiving any cytarabine-containing therapy other than up to 1 g/m/^2 of cytarabine, which is allowed for urgent cytoreduction. The use of prior hydroxyurea, all-trans retinoic acid (ATRA), BCR-ABL directed tyrosine kinase inhibitor, erythropoiesis-stimulating agent, thrombopoietin receptor agonist and lenalidomide are allowed. Participants may receive hydroxyurea prior to treatment assignment on this substudy for cytoreduction but must agree to discontinue hydroxyurea prior to beginning treatment on this substudy
• * White blood cell (WBC) must be /< 25 x 10/^9/L. Hydroxyurea, leukapheresis, and cytarabine /< 1 g/m/^2 are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped prior to initiation of protocol therapy
• * Participants must be ≥ 60 years old; OR must be ≥ 18 years old and considered not eligible for cytarabine-based induction therapy
• * Participants must have Zubrod Performance Status of 0-3 as determined by a history and physical (H/&P) exam completed within 14 days prior to registration
• * Participants must have a complete medical history and physical exam within 14 days prior to registration
• * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless history of Gilbert`s syndrome. Participants with history of Gilbert`s syndrome must have total bilirubin ≤ 3 x institutional ULN (within 14 days prior to registration)
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]) ≤ 3 × institutional ULN, unless considered to be elevated due to disease involvement (within 14 days prior to registration)
• * Participants must have adequate kidney function as evidenced by creatinine clearance ≥ 30mL/min (by Cockcroft Gault) within 14 days prior to registration
• * Participants must not have a baseline corrected QT interval ≥ 480 msec using Fridericia correction (QTcF).
• * NOTE: Since older participants are at risk for prolonged QTc and may require supportive care with agents that affect QTc, an electrocardiogram (ECG) is recommended if clinically indicated. If the QTc is prolonged, they should be treated on MYELOMATCH TAP instead of MM1OA-S03
• * Participants must have adequate cardiac function in the assessment of their treating physician. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2 or better
• * Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration
• * Participants with a known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated
• * Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated
• * Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• * Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen
• * Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications
• * Participants must have agreed to have specimens submitted for translational medicine for MRD under MYELOMATCH and specimens must be submitted
• * Enrollment to this treatment study requires prior enrollment into the myeloMATCH Master Protocol (MYELOMATCH). Participants enrolled in MYELOMATCH will submit bone marrow samples, peripheral blood samples, and buccal swabs to the Molecular Diagnostics Network (MDNet), the Clinical Laboratory Improvement Act (CLIA) laboratory network for myeloMATCH
• * In addition to the MYELOMATCH specimens, there will be specimens obtained on treatment for this substudy. These specimens will be derived from procedures performed as part of standard assessments in the clinical care and management of AML with material being sent to the MDNet laboratories as specified. After performing the required tests on the specimens, the MDNet laboratories will send the residual material for biobanking and future research. Therefore, participants must be asked for their consent for the biobanking of specimens for future unspecified research. Participants may refuse this, but it is mandatory for sites to ask participants
• * Participants must be offered the opportunity to participate in specimen banking
• * NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution`s identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• * Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations

Критерии исключения

Описание

The purpose of this research is to see how certain genetic variations relate to side effects and outcomes experienced while receiving treatment with azacitidine and venetoclax.

Критерии включения

• * Written informed consent and HIPAA authorization for release of personal health information.
• * Age ≥ 18 years of age at the time of enrollment
• * Confirmed diagnosis of AML
• * Planned initial treatment with azacitidine and venetoclax
• * Ability to read and understand the English and/or Spanish language
• * As determined by the enrolling investigator, ability of the participant to understand and comply with study procedures for the entire length of the study

Критерии исключения

• * None

Описание

The purpose of Part 1 (Dose Escalation) of the study is to assess the effective dose (recommended Phase 2 dose/[s/] /[RP2Ds/]) that can be safely administered, and dosing regimens of JNJ-90189892 in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) or R/R higher-risk type of myelodysplastic neoplasms (type of cancer of the blood and bone marrow, which does not respond to treatment or comes back after treatment). The purpose of Part 2 (Cohort Expansion) is to further assess the safety, tolerability and efficacy in participants with R/R AML or higher-risk types of MDS.

Критерии включения

• * Have a diagnosis, per the world health organization (WHO) 2022 criteria, of (a) Acute myeloid leukemia (AML) or (b) Moderate high, high, or very high-risk myelodysplastic neoplasms (MDS) per Molecular International Prognostic Scoring System (IPSS-M)
• * Body weight that is greater than or equals to (/>=) 40 kg
• * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• * Have adequate renal function defined as Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Estimated Glomerular Filtration Rate (eGFR) />=40 milligrams per minute (mL/min) computed with the calculator on the CKD-EPI website
• * Participants must have laboratory parameters in the required range

Критерии исключения

• * Has a medical history of clinically significant pulmonary compromise, particularly the current need for supplemental oxygen use to maintain adequate oxygenation
• * Has evidence of uncontrolled systemic viral, bacterial, or fungal infection. Antimicrobial prophylaxis is permitted
• * Has known allergies, hypersensitivity, or intolerance to JNJ-90189892 or its excipients
• * Had major surgery or had significant traumatic injury within 14 days of planned first dose of JNJ-90189892
• * Had a prior or concurrent second malignancy with natural history or treatment likely to interfere with any study endpoints of safety or the efficacy of the study treatment
• * Has known active central nervous system involvement

Описание

Treatment of patients with newly diagnosed AML who are not eligible for intensive chemotherapy has remained an area of high unmet medical need. The combination therapy with two medicines, azacitidine and venetoclax, is the usual plan of action. This has brought significant progress in the treatment, but it nevertheless is not curative and the disease does relapse over time.

Revumenib blocks a specific molecule called menin in the cell nucleus. Some types of AML are reliant on menin working properly. These are leukemia cells with a change in the DNA, i.e. a mutation in the NPM1 or KMT2A gene. Revumenib can prevent the production of these types of leukemia cells by disrupting the production of this menin.

The current study investigates whether adding revumenib to the combination therapy improves the prognosis for AML patients with a mutation in the NPM1 or KMT2A gene.

This is a randomized, double-blind, placebo-controlled clinical study where subjects will be treated until disease progression, or development of side effects or death. From the moment of inclusion of the last patient, there will be a 4-year observational follow-up study in order to register survival duration and follow-up visits.

Approximately 415 previously untreated patients with a mutation in the NPM1 or KMT2A gene and with newly diagnosed AML, who are not eligible for intensive chemotherapy. Patients must be ≥18 years of age.

Критерии включения

• In order to be eligible to participate in this study, a patient must meet all of the following criteria:
• 1. Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts).
• OR Patient with newly diagnosed KMT2A-rearranged AML according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible.
• Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173) and EVOLVE-2 (HO177) are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173)
• 2. Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.
• 3. Age ≥ 18 years, no upper age limit.
• 4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
• * ≥ 75 years of age: ineligible for intensive chemotherapy per physician`s discretion (with an ECOG performance status 0-2) .
• * 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities: o ECOG performance status 2 or 3 .
• * Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina.
• * DLCO ≤ 65% or FEV1 ≤ 65%.
• * Creatinine clearance ≥ 30 mL/min to /<45 ml/min calculated by the Cockcroft Gault formula.
• * Moderate hepatic impairment with total bilirubin /> 1.5 to /< 3.0 x upper limit of normal (ULN).
• * Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy must be reviewed and approved by the Sponsor`s (co-) Principal Investigator (written approval must be sent to HO177@erasmusmc.nl before study enrolment).
• 5. Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
• 6. Patient must have a white cell blood (WBC) count of /< 25 x 109/L. Hydroxyurea can be used prior to study enrolment to reduce the WBC count to meet this criterion.
• 7. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance />30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
• 8. Adequate hepatic function as evidenced by:
• * Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert`s disease, or leukemic involvement following written approval by the sponsor (Co-)Principal Investigator (copy in HO177@erasmusmc.nl).
• * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following written approval by the sponsor (Co-)Principal Investigator (copy in HO177@erasmusmc.nl).
• 9. Female patient must:
• * be of nonchildbearing potential:
• o postmenopausal (defined as at least 1 year without any menses).
• o documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status post hysterectomy (at least 1 month prior to screening).
• * or, if of childbearing potential (not surgically sterile and not postmenopausal) agree to avoid pregnancy during the study and for 6 months after the final study drug administration.
• o and have a negative urine or serum pregnancy test at screening.
• o and, if heterosexually active, agree to consistently apply one highly effective/* method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration.
• /*Highly effective forms of birth control include
• - Consistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birth control, if a combined /[estrogen and progestogen containing/] hormonal contraception or a progestogen-only hormonal contraception - both associated with inhibition of ovulation - is used.
• - Established intrauterine device (IUD) or intrauterine system (IUS)
• - Bilateral tubal occlusion
• * Vasectomy - a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
• * Male is sterile due to a bilateral orchiectomy.
• * Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
• List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.
• * agree not to breastfeed starting at screening and throughout the study period.
• * agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
• 10. Men must use a latex condom during any sexual contact with women of childbearing potential (WOCBP), even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.
• 11. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
• 12. Able to understand and willing to sign an informed consent form (ICF).
• 13. Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).

Критерии исключения

• Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.
• 2. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes. 3. AML with BCR-ABL1; or myeloid blast crisis of CML. 4. Significant active cardiac disease within 3 months prior to the start of study treatment, including:
• * New York Heart Association (NYHA) class III or IV congestive heart failure
• * Myocardial infarction
• * Unstable angina
• * Severe cardiac arrhythmias
• * Congenital long QT syndrome of family member with this condition QTcF />450 msec on screening electrogram for males and />470msec on screening electrogram for females (mean of triplicate recordings; calculated using Fridericia`s correction). 5. Severe obstructive or restrictive ventilation disorder. 6. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
• 7. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening. 8. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by PCR test prior to inclusion in the trial. 9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation. 10. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
• 11. Patient with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at /< 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
• * Basal or squamous cell carcinoma of the skin;
• * Carcinoma in situ of the cervix;
• * Carcinoma in situ of the breast;
• * Incidental histologic finding of prostate cancer. 12. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
• 13. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
• 14. Known or suspected hypersensitivity to any of the anti-leukemic agents used.
• 15. Participation in other prospective studies with anti-leukemic and/or investigational agents.
• 16. Patient taking Dabigatran unless they can be transferred to other medications within ≥5 half-lives prior to dosing. Patients taking other P-gP transporter-sensitive medications (see Appendix H) should be properly monitored during the study if they cannot be transferred to other medications.
• 17. Patient taking known strong cytochrome P450 (CYP) 3A4 inducers , unless they can be transferred to other medications within ≥5 half-lives prior to dosing. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
• 19. Patient who has once been screened and randomized into this HO177 trial but was considered ineligible cannot re-enter this trial at a later date.

Описание

The purpose of this study is to observe the impact leukaemia treatment has on gut health (microbiomes) and how quickly the gut health recovers after leukamia treatment. The gut microbiome has a number of important functions not only in the gut but within the whole body. Changes to your child`s nutritional status throughout treatment may affect how well they recover from treatment. This study will monitor the impact of feeding and nutrition on nutritional status and gut health in young people undergoing treatment for leukaemia. The measurements needed to observe nutritional and gut microbiomes will occur when your child attends their routine medical appointments at Great Ormond Street Hospital.

Medical treatment uses chemicals to kill leukaemia cells. The type of medications used in the treatment of leukaemia can damage the gut resulting in inflammation call mucositis. This stops the gut from working and sometimes nutrition has to be provided via a feeding tube or intravenous. Chemotherapy, mucositis and intravenous nutrition all have an impact on the gut. Little is know how the gut health recovers after treatment for leukaemia. This will be the first study to specifically monitor the impact of feeding and nutritional on gut health in children undergoing treatment for leukaemia.

By understanding what changes are occurring to your child`s nutritional status and gut halth during treatment and during recovery will help to develop guidelines for healthcare professionals to support optimal gut health recovery.

Критерии включения

• * - Consented to partake in the study
• * Aged 0-16 years old
• * Diagnosed with AML/HLH/ Burkits

Критерии исключения

• * 17 years old + (treated at UCL adolescent unit)
• * Inflammatory bowel disease: ulcerative colitis or Crohn`s disease
• * Children who had previously been treated with chemotherapy in another institution age

Описание

This pivotal phase 2/3, multi-center, adaptive design study of L-Annamycin for Injection in combination with Cytarabine Injection as second line therapy for remission induction in adult subjects with refractory/relapsed AML is divided into two parts, Part A and Part B.

Критерии включения

• 1. Has a pathologically confirmed diagnosis of AML per the 2022 International Consensus Classification (ICC) as adopted in the European LeukemiaNet (ELN) 2022 recommendations for the diagnosis and management of AML. The tests and procedures used to establish the diagnosis of AML should be consistent with the ELN`s 2022 recommendations
• 2. Has refractory/relapsed AML after having received only one prior induction therapy. Remission induction followed by consolidation therapy or consolidation therapy and maintenance therapy counts as one prior line of therapy.
• 3. Between 18 and 80 years of age (inclusive) at the time of signing the informed consent form (ICF).
• 4. Has received no chemotherapy, radiation, or major surgery within 2 weeks prior to the first randomized dose of study drug or has recovered from the toxic side effects of that therapy. Hydroxyurea to control white blood cell (WBC) count, supportive measures, and prophylaxes as required under the protocol will be allowed. Treatment of opportunistic or other infections with antibiotics, antifungals, and/or antiviral agents, including therapy for meningeal disease (i.e., intrathecal chemotherapy), per institutional standards of care will be allowed during this period, as long as the symptoms of infection have resolved by 1 week prior to the first dose of randomized study drug.
• 5. Has received no investigational therapy within 4 weeks prior to the first randomized dose of study drug.
• 6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at screening.
• 7. Has a life expectancy of greater than six weeks at screening.
• 8. Has adequate laboratory results at screening including the following:
• 1. Total bilirubin ≤2.0 times the upper limit of normal (ULN); higher levels due to Gilbert Syndrome or leukemic infiltration of the liver will be allowed, if in the opinion of the PI, it does not place the subject at unacceptable risk if they were to participate in the study.
• 2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase /<3.5 times the ULN; higher levels due to organ involvement will be allowed, if in the opinion of the PI, it does not place the subject at unacceptable risk if they were to participate in the study.
• 3. Creatinine clearance ≥60 mL/min (using Cockcroft-Gault equation).
• 9. Can understand and sign the ICF, can communicate with the PI, and can understand and comply with the requirements of the protocol.
• 10. For women of childbearing potential (WCBP): Must have a negative serum beta human chorionic gonadotropin (ß-hCG) pregnancy test within 72 hours prior to the first randomized dose of study drug. See Section 5.9 for definition of WCBP.
• 11. For WCBP: Must agree to use a highly effective method of birth control from the time of informed consent through 6 months after their last randomized dose of study drug. See Section 5.9 for definition of WCBP and examples of highly effective methods of birth control.
• 12. For males with partners who are WCBP: Must agree to use a highly effective method of birth control from the time of informed consent through 6 months after their last randomized dose of study drug. See Section 5.9 for definition of WCBP and examples of highly effective methods of birth control.

Критерии исключения

• 1. Has prior or current diagnosis of acute promyelocytic leukemia (APL) or myelodysplastic syndrome (MDS)/AML
• 2. Received prior mediastinal radiotherapy.
• 3. Has central nervous system involvement.
• 4. Has impaired cardiac function, including any of the following:
• 1. LVEF /<40% at screening.
• 2. Valvular heart disease.
• 3. Severe, uncontrolled hypertension.
• 4. Uncontrolled cardiac arrhythmias.
• 5. Recent (≤6 months prior to screening) myocardial infarction.
• 6. Unstable angina.
• 7. Symptomatic congestive heart failure.
• 8. New York Heart Association (NYHA) classification of 3 or 4.
• 9. QT interval/corrected QT (QTc) interval />480 msec at screening.
• 10. History of additional risk factors for torsade des pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• 11. Use of concomitant medications that significantly prolong the QT/QTc interval.
• 5. Has clinically relevant serious comorbid medical conditions including, but not limited to, active infection, chronic obstructive or chronic restrictive pulmonary disease, known positive status for human immunodeficiency virus (virus detected in serum) and/or active hepatitis B or C, or psychiatric illness/social situations that would limit compliance with study requirements.
• 6. Has evidence of mucositis/stomatitis at screening or baseline, or has history of severe (≥Grade 3) mucositis/stomatitis from prior therapy.
• 7. Has any condition that, in the opinion of the PI, places the subject at unacceptable risk if he/she were to participate in the study.
• 8. Has received prior treatment with L-asparaginase.
• 9. Pregnant or breastfeeding.
• 10. Known hypersensitivity to anthracyclines, cytarabine, the excipients of L Annamycin for Injection or Cytarabine Injection, or contrast media that may be used for the protocol-specified GLS assessments.

Описание

The major morbidities of allogeneic hematopoietic stem cell transplant (HSCT) using donors that are not human leukocyte antigen (HLA) matched siblings are graft vs host disease (GVHD) and life- threatening infections. T cell receptor alpha beta (TCRαβ) T lymphocyte depletion and CD19+ B lymphocyte depletion of alternative donor hematopoietic stem cell (HSC) grafts is effective in preventing GVHD, but immune reconstitution may be delayed, increasing the risk of infections. The central hypothesis of this study is that an addback of CD45RO memory T lymphocytes, derived from a fraction of the original donor peripheral stem cell product depleted of CD45RA naïve T lymphocytes, will accelerate immune reconstitution and help decrease the risk of infections in TCRab/CD19 depleted PSCT.

Критерии включения

• 1. Disease for which allogeneic HSCT may be curative.
• 2. Remission status of hematologic malignancies and additional disease-specific eligibility determinations will be according to standards of practice within the CHOP Cellular Immunotherapy and Transplant Program (CTTS).
• 3. Patients must be 25 years of age and less
• 4. Evaluation for organ and infectious status as per our CTTS standard operating procedure.
• 5. Signed consent by parent/guardian or able to give consent if 18 years of age and older.
• 6. Participants of childbearing potential must have a negative pregnancy test as per institutional SOP.

Критерии исключения

• 1. Patients who have performance score less than 60.
• 2. No suitable donor available for mobilized peripheral stem cells.
• 3. Patients with Hodgkin lymphoma or non-Burkitt, non-lymphoblastic lymphoma.
• 4. Planned receipt of alemtuzumab during conditioning.
• 5. Patients with an available 10/10 HLA matched sibling donor.
• 6. Patients who do not meet institutional disease, organ or infectious criteria.
• Donor selection and eligibility:
• 1. Unrelated donor meets National Marrow Donor Program criteria for donation.
• 2. Related donor (at least haploidentical) willing and able to donate mobilized peripheral stem cells.
• 3. HLA testing/matching
• * HLA testing to be done by molecular methods for A, B, C, DRB1, DQB1
• * Related donor: Must be ≥ 5/10 match
• * Unrelated donor: 10/10 or 9/10 match
• * KIR typing for haploidentical donor for hematologic malignancies
• * Donor specific HLA antibodies (DSA) should be assessed for all subjects receiving an HLA mismatched graft (≤ 9/10).
• 4. Donor must be willing to undergo granulocyte colony stimulating factor (GCSF) mobilization and peripheral blood stem cell collection
• 5. Donors must be willing to sign consent to participate in this study.

Описание

This study aims to determine the impact of massage therapy for pediatric patients receiving intensive chemotherapy or stem cell transplant (SCT).

Критерии включения

• 1. Diagnosis of cancer, such as acute myeloid leukemia (AML) or relapsed acute lymphoblastic leukemia (rALL) OR admitted to receive autologous or allogeneic HSCT for any indication
• 2. Expected to be an inpatient for at least 21 days
• 3. Aged 12 to 21 years at enrollment.
• 4. Inpatient at Children`s National or Children`s Hospital of Philadelphia (CHOP).

Критерии исключения

• 1. Cognitive impairment sufficient to preclude completing questionnaires appropriately
• 2. Insufficient knowledge of English or Spanish that would prohibit completing the study instruments
• 3. Previous enrollment

Описание

Acute myeloid leukemia (AML) is one of the hematologic malignancies, for which patients typically undergo chemotherapy to achieve complete remission. However, approximately 30% of patients fail to respond to initial treatment, and many experience relapse after achieving remission. For patients with relapsed or refractory AML, allogeneic hematopoietic stem cell transplantation (HSCT) offers a potentially curative option. Sibling-matched HSCT has demonstrated a disease-free survival rate of 20-30%, while unrelated donor transplants yield an overall survival rate of approximately 22%. Haploidentical transplantation is a viable alternative for patients lacking a sibling donor. A 2019 study involving 1,693 patients with relapsed/refractory (R/R) AML revealed that haploidentical transplants yielded outcomes comparable to other transplant modalities, including HLA-matched and 9/10 matched unrelated donor transplants, thus supporting haploidentical transplantation as a viable therapeutic option.

The conditioning regimen is a critical component of the transplantation. In China, the modified BU/CY conditioning regimen, which combines busulfan (BU) and cyclophosphamide (CTX), is widely utilized for tumor cytoreduction and immunosuppression. Some centers also employ post-transplant cyclophosphamide (PTCy) to mitigate the risk of graft-versus-host disease (GVHD). Despite advances, relapse remains a significant challenge. Optimizing conditioning regimens to enhance tumor cell targeting and achieve deeper remission is crucial. Additionally, many patients are unfit due to prior chemotherapy, infections, and organ dysfunction, which may make them unable to tolerate high-intensity conditioning.

Recent studies suggest that melphalan (MEL)-based conditioning regimens may offer advantages over CTX-based protocols. While total body irradiation (TBI) has been traditionally used in conditioning for HSCT, it is associated with considerable organ toxicity.

A low-dose TBI regimen combined with BU+MEL represents a promising conditioning regimen for R/R AML. In preliminary studies, 7 patients treated with this regimen successfully achieved hematopoietic stem cell engraftment. Building on these results, a clinical study is planned to evaluate further the safety and efficacy of the TBI+BUMEL (IBM) conditioning regimen in relapsed/refractory AML, with a focus on improving engraftment rates, reducing relapse rates, minimizing GVHD incidence, and enhancing overall survival outcomes.

Критерии включения

• 1. Age between 14 and 70 years (inclusive of the age limits);
• 2. Patients diagnosed with relapsed/refractory (R/R) AML, meeting the World Health Organization (WHO) 2016 AML diagnostic criteria, must meet one of the following definitions:
• Relapsed AML: Leukemic cells reappear in peripheral blood or bone marrow blasts />5% after achieving complete remission (CR, CRi) (excluding other causes such as bone marrow regeneration following consolidation chemotherapy), or extramedullary leukemic infiltration occurs.
• Refractory AML:Initial cases that do not respond to two courses of standard treatment. Relapse within 12 months after consolidation therapy. Relapse after 12 months with no response to conventional chemotherapy. Two or more relapses. Persistent extramedullary leukemia.
• 3. Heart, liver, and kidney function must meet the following criteria:
• Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 3× the upper limit of normal (ULN); Total bilirubin ≤ 3× ULN; Serum creatinine ≤ 2× ULN or creatinine clearance ≥ 40 mL/min; Left ventricular ejection fraction (LVEF), as measured by echocardiography or multi-gated acquisition (MUGA) scan, must be within the normal range (/>50%).
• 4. Availability of a suitable allogeneic donor;
• 5. Life expectancy of ≥3 months;
• 6. Karnofsky Performance Status (KPS) ≥ 60%, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2;
• 7. The patient understands the study protocol and voluntarily signs the informed consent form.

Критерии исключения

• 1. Patients had serious adverse reactions to investigational drugs such as allergies;
• 2. Patients with a history of immunodeficiency, or other acquired or congenital diseases, immunodeficiency diseases, and a history of organ transplantation;
• 3. Patients with hypertension, ventricular arrhythmia requiring clinical intervention, acute coronary syndrome, congestive heart failure, stroke, or other grade III or higher cardiovascular events within 6 months;
• 4. Patients received Class II or higher surgery within 4 weeks prior to enrollment;
• 5. Patient has an active and difficult-to-control infection, including but not limited to active fungal, bacterial, or viral infections that require systemic treatment, such as active HIV, hepatitis B or C;
• 6. Patient has active central nervous system leukemia infiltration;
• 7. Pregnant or lactating patients;
• 8. Patient is currently participating in another clinical studies;
• 9. Other conditions where the investigator deems the patient unsuitable for inclusion.

Описание

This is a multicenter, randomized, open-label, pragmatic low intervention clinical trial comparing high intensity reinduction chemotherapy with low intensity therapies in 1st or 2nd relapse Acute Myeloid Leukemia. The study is funded by European Commission (HORIZON-MISS-2022-CANCER-01-03, Project ID 101104421)

Критерии включения

• * Non-Acute promyelocytic leukemia (APL) AML defined according World Health Organization (WHO) 2022 (or International Consensus Classification (ICC) 2022) criteria
• * 1st or 2nd relapse or refractory according to European leukemia Network (ELN) 2022
• * Patient is clinically candidate to both low intensity therapy and high dose chemotherapy in the opinion of the physician
• * Both low intensity therapy and high dose chemotherapy to which patient is candidate are available and can be provided as per local practice
• * No specific treatment protocol can be rationally considered better suited to patient needs.This specifically include, but is not limited to:
• i) the availability of a drug that is already demonstrated superior to comparator arm and can be considered the only standard of care ii) specific contraindications related to fitness or any medical conditions that deem to avoid one of the two arms of this randomization iii) patient willingness to avoid one of the two arm of this randomization iv) lack of social support that make unfeasible one of the two arm of this randomization
• * Male or Female, aged/>18 years
• * Eastern Cooperative Oncology Group (ECOG) performance status /<4
• * A female participant is eligible to participate if she is not pregnant and not breastfeeding. If Women of childbearing potential (WOCBP), negative serum pregnancy test within 14 days of starting treatment must be obtained. WOCBP must adopt highly effective birth control methods, according to guideline "Recommendation related to contraception and pregnancy testing in clinical trials". Male patient and his female partner who is of childbearing potential must use 2 methods of birth control (a condom as a barrier method of contraception and one of the highly effective birth control methods, according to guideline "Recommendation related to contraception and pregnancy testing in clinical trials". Use of- and compliance to- birth control methods are required beginning at the screening visit and continuing until 6 months following last treatment with study drug.
• * Participant is willing and able to give informed consent for participation in the study

Критерии исключения

• * Known contraindication to the study drug that will be selected by the treating physician within the list of high or low intensity treatment, according to most update version of Summary of Product Characteristics (SmPC) (e.g. hypersensitivity, allergy, organ failure precluding treatment)
• * Participation in another clinical trial with any investigational agents within 14 days or 5 drug half-lives (whatever comes first) prior to randomization
• * Active infections or other clinical conditions that in the opinion of the investigator make the patient ineligible to receive study treatment.

Описание

To find the recommended dose of ziftomenib in combination with gemtuzumab ozogamicin and venetoclax that can be given to pediatric participants who have relapsed or refractory AML or MPAL.

Критерии включения

• 1. Age ≥ 3 year to 21 years
• 2. Karnofsky for children />16yo and Lansky /<16yo.
• 3. Relapsed/refractory AML, or MPAL with a myeloid phenotype.
• 1. Evidence of leukemia (AML, MPAL with a myeloid phenotype) in the bone marrow as detected by morphology or molecular diagnostics.
• 2. Presence of KMT2Ar, NUP98r, NPM1c, UBTF-ITD or other HOX pathway mutation.
• 4. WBC must be below 25,000/ƒÊL at time of enrollment. Participants may receive cytoreduction prior to enrollment.
• 5. Baseline ejection fraction must be /> 40%.
• 6. Adequate hepatic function (direct bilirubin /< 1.5x upper limit of normal (ULN) unless increase is due to Gilbert`s disease or leukemic involvement, and AST and/or ALT /< 3x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT /< 5x ULN will be considered eligible).
• 7. Adequate renal function (creatinine clearance ≥ 30 mL/min) unless related to disease.
• 8. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives of the prior therapy. Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for participants with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the PI. Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
• 9. 3 month washout prior from bone marrow transplantation.
• 10. Unless surgically or biologically sterile: Women of childbearing potential must agree to adequate methods of contraception during the study and at least 3 months for males, and 6 months for females, after the last treatment.

Критерии исключения

• 1. Participants who weigh less than 10kg.
• 2. Participants with any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment.
• 3. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea for patients with rapidly proliferative disease or for control of counts during differentiation syndrome. (3) use of steroids for treatment of differentiation syndrome.
• 4. Participants with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
• 5. Participants with chronic liver disease.
• 6. Participants with a concurrent active malignancy under treatment.
• 7. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.
• 8. Female participants who are pregnant or breast-feeding.
• 9. Participants has an active uncontrolled infection.
• 10. Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
• 11. Mean corrected QT interval by Fredericia`s formula />480 ms on triplicate 12-lead electrocardiograms performed within approximately 5 minutes of each other.
• 12. History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator`s opinion might confound the results of the study, interfere with the participant`s participation for the full duration of the study, or is not in the best interest of the patient to participate.
• 13. Clinically active central nervous system (CNS) leukemia.
• 14. The use of topical steroids for cutaneous graft-versus-host disease (GVHD) or stable systemic steroid doses less than or equal to 20 mg of prednisone daily are permitted.
• 15. Participants with Grade /> 2 active acute GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.

Описание

This is a dose-finding study of oral zelenirstat (PCLX-001) in patients with R/R AML. There are two parts to the study: Dose Escalation and Dose Expansion.

Критерии включения

• -
• The following inclusion criteria apply to ALL (dose escalation and dose expansion) patients:
• 1. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained before any study-specific procedures are performed.
• 2. Male or female patients aged ≥ 18 years
• 3. A diagnosis of AML as per 2016 WHO classification (Arber et al, 2016)
• 4. Patients must have received at least one prior therapy for AML
• 5. Patient must not be eligible for other therapies expected to provide clinical benefit
• 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Appendix A).
• 7. The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions: (1) intrathecal (IT) therapy for patients with controlled CNS leukemia at the discretion of the Investigator. Controlled CNS leukemia is defined by the absence of active clinical signs of CNS disease and no evidence of CNS leukemia on the most recent 2 simultaneous cerebrospinal fluid (CSF) evaluations. (2) Use of hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy. These medications will be recorded in the case-report form.
• 8. Patients must have adequate liver function as assessed by the following laboratory tests to be conducted within 7 (±3) days before the first dose of study drug:
• 1. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) unless increase is due to hemolysis or congenital disorder such as Gilbert`s syndrome
• 2. ALT and AST ≤ 2.5 times ULN or ≤ 5 times ULN for patients with malignant liver involvement
• 9. Patients must have adequate kidney function, as assessed by both:
• 1. the estimated glomerular filtration rate (eGFR) />60 mL/min within 7 (±3) days before the first dose of study drug (eGFR to be calculated by the Cockcroft-Gault formula)
• 2. creatinine ≤ 1.5 times the ULN
• 10. Adequate cardiac function per institutional normal measured by echocardiography or multi-gated acquisition (MUGA) scan (Left ventricular ejection fraction (LVEF) ≥ 50%)
• 11. Ability to take oral medication
• 12. Women of childbearing potential must have a negative serum beta human chorionic gonadotropin (β- human chorionic gonadotropin (HCG)) pregnancy test obtained within 7 (±3) days before the start of administration of study drug.
• a. Note: A woman is of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy.
• 13. Women of childbearing potential and fertile men must agree to use adequate contraception when sexually active from signing of the informed consent form for the full study until at least 6 months after the last study drug administration. Patients must agree to utilize 2 reliable and acceptable methods of contraception simultaneously. A man is considered fertile after puberty unless permanently sterile by bilateral orchiectomy. Men being treated with PCLX-001 are advised not to father a child during and up to 6 months after treatment; prior to treatment, advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment with PCLX-001. Female partners of childbearing potential from male study participants have to use adequate contraception / birth control between signing of the informed consent and 6 months after the last administration of the study drug if the male study participant is not sterilized. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control. Highly effective (failure rate of less than 1% per year) contraception methods, when used consistently and correctly, include:
• 1. Combined (estrogen and progestin containing: oral, intravaginal transdermal and progestin-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation.
• 2. Intra-uterine device (IUD) or intrauterine hormone-releasing system (IUS).
• 3. Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole sexual partner and has received medical assessment of the surgical success).
• 4. Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient).
• 14. Male patients with a female partner of reproductive potential must use a condom and ensure that an additional form of contraception is also used during treatment and until 6 months after last study drug administration. Patients must agree to utilize reliable and acceptable methods of contraception simultaneously.

Критерии исключения

• -
• The following exclusion criteria apply to ALL (dose escalation and dose expansion) patients:
• 1. Acute promyelocytic leukemia.
• 2. Known hypersensitivity to the study drugs or excipients of the preparations or any agent given in association with this study
• 3. History of cardiac disease: congestive heart failure New York Heart Association (NYHA) class /> II, unstable angina (angina symptoms at rest), new-onset angina (within the past 6 months before study entry), myocardial infarction within the past 6 months before study entry, or uncontrolled cardiac arrhythmias
• 4. Uncontrolled arterial hypertension despite optimal medical management (per investigator`s opinion)
• 5. Moderate or severe hepatic impairment, i.e., Child-Pugh class B or C
• 6. Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load, CD4+ counts/levels /> 250, no history of AIDs-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on same anti-HIV retroviral medications.
• 7. Patients who have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Patients with chronic HBV or HCV infection are eligible at the investigator`s discretion provided that the disease is stable and sufficiently controlled under treatment.
• 8. Infections of CTCAE Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade /> 2
• 9. Uncontrolled seizure disorder requiring therapy with strong CYP3A4 inducers such as carbamazepine and phenytoin
• 10. Previous or concurrent cancer that is distinct in primary site or histology from AML, with the exception of the following previous or concurrent cancer types:
• 1. Curative treatment for localized cancer completed without signs of recurrence and treatment-related toxicity and low risk of recurrence as assessed by the investigator,
• 2. In-situ prostate cancer, Gleason Score /<7, prostate-specific antigen /<10 ng/mL (very low risk and low risk, according to therapy guidelines, e.g., the National Comprehensive Cancer Network guideline; active surveillance / observation is a recommended option).
• 11. Inability to swallow oral medications
• 12. Any malabsorption condition that may significantly alter the absorption of PCLX-001.
• 13. Breastfeeding. Female patients must not breastfeed during treatment and until 4 months after last study drug administration.
• 14. Acute toxic effects (CTCAE Grade ≥2) of previous anticancer chemotherapy or immunotherapy that have not yet stabilized or if significant post-treatment toxicities have been observed. (Note however that toxic effects of previous anticancer therapy considered as chronic, such as chemotherapy-induced neuropathy, fatigue, alopecia, or anorexia of CTCAE Grade /<2, for which further resolution is not expected, do not prevent participation in this study.)
• 15. Patients on active radiation therapy or active antineoplastic therapy for a concurrent malignancy at the time of screen. Maintenance therapy, hormonal therapy, or steroid therapy for well-controlled malignancy is allowed.
• 16. Previous assignment to treatment during this study
• 17. Concomitant participation in another clinical study with investigational medicinal product(s)
• 18. Substance abuse, medical, psychological, or social conditions that may interfere with the patient`s participation in the study or evaluation of the study results
• 19. Clinically relevant findings in the ECG such as a second- or third-degree atrioventricular block, prolongation of the QRS complex /> 120 ms (except for bundle branch block pattern), or prolongation of the of the QTc interval (Fridericia) over 450 ms unless agreed otherwise between the investigator and the sponsor`s medically responsible person.

Описание

The purpose of the study is to explore the safety and efficacy of UCMSC-Exo in consolidation chemotherapy-induced myelosuppression in patients with acute myeloid leukemia after achieving complete remission.

Критерии включения

• 1. Aged between 18 and 60 years old;
• 2. Acute myeloid leukemia (AML, AML subtype M3 excluded) diagnosed according to the 2022 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, who have achieved complete remission (CR1) and are going to receive consolidation therapy (cytarabine or cytarabine-based combined regimen, the cycle of consolidation therapy is not limited);
• 3. The participant or his/her legal guardian is adequately informed of the nature and risks of the study, voluntarily participates in the study with signed informed consent;
• 4. Male or female;
• 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 (by the day chemotherapy is initiated)
• 6. Estimated survival of at least 3 months;
• 7. Adequate major organ function:
• 1. Respiratory function: indoor oxygen saturation of at least 95%;
• 2. Cardiac function: ejection fraction of left ventricular of at least 45%;
• 3. Hepatic function: alanine aminotransferase/aspartate aminotransferase of at most 2.5 times/upper limit of normal value and serum total bilirubin of at most 1.5 times/upper limit of normal value;
• 4. Renal function: Serum creatinine of at most 1.5 times/upper limit of normal value;
• 8. Participants who do not receive any type of anti-cancer therapy within 2 weeks before enrollment (radiation therapy, chemotherapy and/or immune therapy, et al.), and treatment-associated toxicities induced by previous therapy has recovered to Grade 1 or below (except for low grade toxicities such as alopecia).
• 9. For female participants, they should be surgical sterilized or post-menopausal, or agree to utilize a medically recognised method of contraception (such as intrauterine device, condom) during treatment period of the study and within 6 months after the end of treatment period of the study; For male participants, they should be surgical sterilized or agree to utilize a medically recognised method of contraception (such as intrauterine device, condom) during treatment period of the study and within 6 months after the end of treatment period of the study

Критерии исключения

• 1. Central nervous system manifestations of acute myeloid leukemia at diagnosis;
• 2. Secondary acute myeloid leukemia;
• 3. Myelosuppression induced by conditions other than anti-cancer therapy;
• 4. Previous radiation therapy performed on sternum or pelvis;
• 5. Specifically diagnosed and uncontrolled infection at enrollment (Uncontrolled is defined as exhibiting ongoing signs and symptoms of infection without improvement despite anti-infective agents) ;
• 6. Uncontrolled active bleeding at enrollment;
• 7. Severe underlying comorbidities affecting survival, including cachexia, severe malnutrition, etc;
• 8. Estimated survival of at most 48 hours;
• 9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection;
• 10. History of or current human immunodeficiency virus (HIV) infection;
• 11. Syphilis infection;
• 12. Continuous usage of immunosuppressants or received organ transplantation in the last 6 months;
• 13. Participation in clinical trials of other drugs within 6 weeks before enrollment;
• 14. Previous participation in clinical stem cell or exosome research;
• 15. Receive any agent concurrently with UCMSC-Exo infusion which inhibits cell division (hydroxyurea, low-dose cytarabine or methotrexate, etc) ;
• 16. Severe allergic constitution, or known or suspected allergy to the study drug and its components;
• 17. Known contraindication to receiving hematopoietic growth factors, transfusion of blood components, anti-infective agents;
• 18. Female participants who are pregnant or breast feeding;
• 19. Participants suffering from mental illness;
• 20. Presence of drug abuse/addiction;
• 21. History of other malignancies other than hematological malignancies within 3 years;
• 22. Participants without signed informed consent;
• 23. Participants with poor compliance and are unable to complete the whole course of the study;
• 24. Participants with circumstances that, in the opinion of the investigator, may increase the risk of the participants or interfere with conduct of the clinical trial and the judgment of results (excessive tension, sensitivity or cognitive impairment, etc) ;
• 25. Participants with other circumstances that are ineligible for enrollment in this study, in the opinion of the investigator.

Описание

The study is a monocentric, interventional study that evaluates the efficacy of allogeneic HLA-matched or haploidentical transplantation consisting of an irradiation-based conditioning regimen coupled with donor Treg/Tcon adoptive immunotherapy for high-risk acute leukemia patients.

Критерии включения

• * AML patients
• * Diagnosis of AML with indication to allogeneic hematopoietic cell transplantation.
• * Diagnosis of adverse genetic risk leukemia or presence of MRD or active disease (bone marrow infiltration 5-30%) at the time of the transplant procedure.
• * Availability of a hematopoietic stem cell donor (family or unrelated HLA-matched or HLA-haploidentical with the patient) suitable to be treated with G-CSF (10 mcg/kg/die) for a maximum of 7 days and able to tolerate 2 or more leukaphereses.
• * Age ≥ 18 and ≤ 65 years
• * ECOG ≤ 2
• * HCT-CI ≤ 4 (51,52)
• * Absence of relevant psychiatric diseases
• * Signature of the informed consent
• ALL patients
• * Diagnosis of ALL, either T or B (Philadelphia negative) or mixed phenotype with indication to allogeneic transplant
• * Presence of MRD or active disease (bone marrow infiltration 5-30%) or patient with ≥ 2nd complete hematologic remission at the time of the transplant procedure.
• * Availability of a hematopoietic stem cell family donor (family or unrelated HLA-matched or HLA-haploidentical with the patient) suitable to be treated with G-CSF (10 mcg/kg/die) for a maximum of 7 days and able to tolerate 2 or more leukaphereses.
• * Age ≥ 18 and ≤ 65 years
• * ECOG ≤ 2
• * HCT-CI ≤ 4
• * Absence of relevant psychiatric diseases
• * Signature of the informed consent

Критерии исключения

• * AML patients
• * AML in CR MRD-
• * AML with /> 5% peripheral blasts or bone marrow infiltration ≥ 30%
• * Age /< 18 years or /> 65 years
• * ECOG /> 2
• * Unacceptable lung, liver, kidney, and/or heart function and presence of relevant psychiatric diseases according to clinical judgment
• * Pregnancy
• * No signature of the informed consent
• * ALL patients
• * ALL with /> 5% peripheral blasts or bone marrow infiltration ≥30%
• * Philadelphia positive ALL
• * Age /< 18 years or /> 65 years
• * ECOG /> 2
• * Unacceptable lung, liver, kidney, and/or heart function and presence of relevant psychiatric diseases according to clinical judgment
• * Pregnancy
• * No signature of the informed consent

Описание

Phase I, open-label study to assess the safety, feasibility, pharmacokinetics, and preliminary efficacy of CART123 cells given in combination with ruxolitinib in patients with relapsed or refractory acute myeloid leukemia (AML). All subjects will receive a single infusion of CART123 cells following ruxolitinib administration and lymphodepletion. Ruxolitinib dosing will begin at initiation of lymphodepleting chemotherapy (Day -6 ±1d) and continue for up to 14 days post CART123 administration.

Критерии включения

• * 1. Signed informed consent form 2. Male or female age ≥ 18 years. 3. Patients with active acute myeloid leukemia (AML) with no available curative treatment options using currently available therapies. This is specifically defined as one of the following:
• 1. AML that has not achieved a complete remission or morphologic leukemia free state by ELN 2022 criteria57 after at least 2 cycles of induction (includes partial remission or refractory/primary refractory disease), OR:
• 2. AML relapsed following allogeneic stem cell transplantation (including MDS evolved to AML post-allogeneic stem cell transplant).
• i. Note: Morphologic relapse is not required; Patient may have persistent/recurrent disease-associated molecular, phenotypic or cytogenetic abnormalities (i.e., MRD) at any time after allogeneic HCT to qualify. Mutations involving DNMT3A, ASXL1 or TET2 should not count as molecular MRD+ disease unless accompanied by other, more specific disease-related molecular or cytogenetic abnormalities.
• 4. Patients with relapsed disease after prior allogeneic SCT must be at least 3 months from transplantation (where receipt of the stem cell product is defined as day 0) and must not require systemic immunosuppression (for prevention or treatment of GVHD).
• 5. Patients must have a suitable stem cell donor identified with projected ability to proceed to transplant within 6-8 weeks of CART123 infusion if clinically indicated. Donor may be matched or mismatched and must be found to be suitable according to the institution`s standard criteria.
• 6. Adequate organ function defined as:
• 1. Estimated creatinine clearance /> 35mL/min using the CKD-EPI equation for Glomerular Filtration Rate (GFR); Patients must not be on dialysis
• 2. ALT/AST ≤ 5x upper limit of normal range
• 3. Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert`s syndrome (≤3.0 mg/dl)
• 4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen /> 92% on room air
• 5. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by transthoracic echocardiography or MUGA scan.
• 7. ECOG Performance Status 0-2.
• Exclusion Criteria:
• * 1. Patients with the JAK2 V617F mutation by PCR or next generation sequencing. 2. Patients with signs or symptoms indicative of active CNS involvement. A CNS evaluation should be performed as clinically appropriate to rule out CNS involvement.
• 3. Patients with relapsed AML with t(15:17). 4. Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.
• 5. Active acute or chronic GVHD requiring systemic therapy. 6. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
• 7. Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
• 8. Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications.
• 9. Planned use of fluconazole within the anticipated study treatment window. For additional details on concomitant medication restrictions.
• 10. Receipt of prior CART123 therapy. 11. Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.
• 12. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
• 13. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).

Критерии исключения

Описание

Evaluation of the safety, tolerability, pharmacokinetics, and preliminary efficacy of XS-04 in patients with relapsed or refractory hematologic malignancies

Критерии включения

• Patients must meet all of the following conditions to be enrolled:
• * Voluntarily participate in the clinical trial and sign the informed consent form (ICF).
• * Age ≥18 years, ≤75 years, regardless of gender.
• * Dose escalation phase: Patients with mature B-cell malignant tumors confirmed by histopathology according to the 2017 World Health Organization (WHO) classification, who have failed existing treatments and have no suitable treatment options and have treatment indications.
• Dose expansion phase: Patients with B-cell lymphoma confirmed by histopathology according to the 2017 WHO classification (cohort 1 includes DLBCL patients, cohort 2 includes other B-cell lymphoma patients), and patients with myeloid tumors confirmed according to the 2016 WHO classification (cohort 3 includes AML, MDS patients).
• Meet the following disease-specific criteria (tumor types not listed below will be discussed by the sponsor and the investigators to decide if they can be enrolled):
• 1. For indolent B-NHL (follicular lymphoma /[FL/], marginal zone lymphoma /[MZL/], and Waldenström macroglobulinemia /[WM/]), patients must have received at least two lines of systemic therapy, including at least one line of combination therapy containing anti-CD20 antibodies; for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), patients must have received at least two lines of systemic therapy, including BTK inhibitors or BCL-2 inhibitors; for MCL, patients must have received at least two lines of systemic therapy (including anti-CD20 antibodies, BTK inhibitors, etc.); for aggressive B-NHL (DLBCL), patients must have failed or relapsed after at least two lines of systemic therapy and are not suitable for hematopoietic stem cell transplantation.
• 2. For AML, diagnosed according to the 2016 World Health Organization (WHO) classification, meeting the definition of relapsed/refractory as per the "Chinese Guidelines for the Diagnosis and Treatment of Relapsed/Refractory Acute Myeloid Leukemia (2021 Edition)";
• 3. For MDS, pathologically confirmed MDS meeting the WHO 2016 classification criteria; and prognostic scoring system assessment as intermediate to high risk (IPSS-R score />3), relapsed or refractory;
• * B-cell lymphoma patients must have at least one radiographically measurable lesion (i.e., lymph node with long diameter /[LDi/] />1.5 cm, extranodal lesion with LDi />1.0 cm).
• * Patients must be willing to undergo bone marrow aspiration and/or bone marrow biopsy.
• * ECOG score of 0-1 for dose escalation phase; 0-2 for dose expansion phase.
• * Expected survival time ≥3 months.
• * For mature B-cell malignant tumors, during the screening period, there must be sufficient bone marrow not dependent on growth factor support, according to local laboratory reference ranges, as follows:
• a. Absolute neutrophil count (ANC) ≥1.0×10/^9/L (patients with neutrophils /<1.0×10/^9/L due to lymphoma bone marrow infiltration may be enrolled at the investigator`s discretion); b. Platelets ≥75×10/^9/L (dose escalation phase), platelets ≥50×10/^9/L (dose expansion phase), no transfusion within 14 days before the first dose; c. Hemoglobin ≥80 g/L. For AML, white blood cell count (WBC) must be ≤20×10/^9/L (hydroxycarbamide treatment to reduce white blood cells is allowed).
• * Adequate organ function, with laboratory tests within the following requirements within 7 days before the first dose:
• 1. Liver function: Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN, total bilirubin ≤1.5×upper limit of normal (ULN); if there is liver involvement, AST, ALT ≤5×ULN; total bilirubin ≤3×ULN;
• 2. Kidney function: Serum creatinine ≤1.5×ULN or estimated creatinine clearance ≥50 mL/min according to the Cockcroft-Gault formula;
• 3. Coagulation function: International normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN; activated partial thromboplastin time (aPTT) ≤1.5×ULN.
• * Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose during the screening period. Patients must agree to use reliable contraception methods from signing the informed consent form to 3 months after the last dose. These include but are not limited to: abstinence, male vasectomy, female sterilization surgery, effective intrauterine contraceptive device, effective contraceptive drugs.
• * Patients must be able to comply with study procedures and protocol-specified visits.

Критерии исключения

• Patients meeting any of the following conditions are not eligible for this clinical study:
• * Burkitt lymphoma/leukemia, plasma cell myeloma, plasmablastic lymphoma.
• * Acute promyelocytic leukemia (APL) or BCR-ABL positive AML patients or those with a history of myeloproliferative neoplasms (MPN).
• * Use of other cytotoxic drugs, investigational drugs, or other antitumor drugs within 14 days or 5 half-lives before the first dose of the study drug (whichever is shorter) (except hydroxycarbamide and leukapheresis). Patients who received tumor immunotherapy, antibody, or peptide antitumor drug treatment within 4 weeks before the first dose of the study drug.
• * Patients who underwent therapeutic surgery other than diagnostic, biopsy, or drainage procedures within 4 weeks before the first dose of the study drug, or who are expected to undergo major surgery during the study. For patients who underwent drainage procedures (e.g., thoracic, biliary, etc.) and/or placement of drainage tubes within 4 weeks before the study drug, related symptoms/signs must have substantially resolved, and no prophylactic/therapeutic use of antibiotics is required.
• * Systemic radiotherapy within 4 weeks before the first dose of the study drug.
• * Unresolved toxic reactions from previous antitumor treatments (/> NCI-CTCAE 5.0 grade 1), alopecia, pigmentation, neurotoxicity, or other toxicities assessed by the investigator as chronic and not affecting the safety of the study drug, resolved to NCI-CTCAE 5.0 grade 2 or below are allowed for enrollment.
• * Previous allogeneic stem cell transplantation; autologous stem cell transplantation or adoptive immune cell therapy within 3 months before the first dose of the study drug (mature B-cell malignant tumor patients) or within 6 months (AML, MDS patients).
• * Patients with lymphoma/leukemia involving the central nervous system (CNS).
• * Dysphagia, or a history of severe gastrointestinal disease (e.g., active inflammatory bowel disease, gastrointestinal perforation) with symptoms that cannot be reasonably controlled; or gastrointestinal diseases affecting drug absorption (e.g., Crohn`s disease, ulcerative colitis, ileus, short bowel syndrome) or other malabsorption conditions.
• * Patients with ocular conjunctival, corneal lesions (can be enrolled after treatment of ocular lesions is cured).
• * Patients with active or unstable cardiovascular and cerebrovascular diseases, including but not limited to:
• 1. Severe cardiac rhythm or conduction abnormalities requiring clinical intervention;
• 2. Acute coronary syndrome, congestive heart failure, myocardial infarction, unstable angina, coronary/peripheral artery bypass grafting, cerebral infarction, cerebral hemorrhage, pulmonary embolism, deep vein thrombosis (within 3 months before the first dose) or other severe cardiovascular events within 6 months before the first dose;
• 3. New York Heart Association (NYHA) heart function classification ≥II;
• 4. Left ventricular ejection fraction (LVEF) /<50%;
• 5. Presence of torsades de pointes, congenital long QT syndrome;
• 6. QTcF />450ms (male) or />470ms (female);
• 7. Uncontrolled hypertension despite optimal treatment (defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg under medication control).
• * History of interstitial lung disease (ILD), pulmonary interstitial fibrosis; or evidence of active pneumonia on chest CT scan during the screening period.
• * Patients with congenital immune deficiency diseases, or active autoimmune diseases, including but not limited to active and uncontrolled autoimmune cytopenia, persisting for 2 weeks or longer, including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura.
• * Patients with coagulopathy (e.g., hemophilia).
• * Currently using anticoagulant drugs.
• * History of severe allergies, or allergies to any active or inactive components of the study drug.
• * Uncontrolled systemic infection (viral, bacterial, fungal) within two weeks before the first dose of the study drug; hepatitis B surface antigen positive and hepatitis B virus DNA exceeding 1000 IU/ml; hepatitis C virus (HCV) antibody positive or HCV RNA positive; human immunodeficiency virus (HIV) antibody positive.
• * Patients with other primary malignant neoplasms, the following conditions can be enrolled: cured and completely excised basal cell and squamous cell skin cancer, completely excised carcinoma in situ of any type.
• * Need to continue using systemic immunosuppressants or systemic corticosteroids (≥10mg prednisone or equivalent of other corticosteroids) within two weeks before the study drug.
• * Use of strong CYP3A inhibitors or inducers within two weeks before the first dose.
• * Pregnant or lactating women.
• * Any other severe or uncontrolled acute or chronic disease or laboratory test abnormality or other reasons deemed unsuitable for participation in this clinical study by the investigator.

Описание

The goal of this clinical trial is to evaluate the effectiveness of CD123-CD16 bispecific antibody-modified NK cells in treating patients with CD123-positive relapsed or refractory Acute Myeloid Leukemia (RR AML). It will also assess the safety of this modified NK cell therapy.

The main questions： Does the infusion of CD123-CD16 bispecific antibody-modified NK cells induce remission in RR AML patients? What are the safety and potential adverse effects associated with the administration of these modified NK cells? Researchers will administer CD123-CD16 bispecific antibody-modified NK cells to RR AML patients and compare the outcomes to existing treatment options to determine efficacy and safety.

Participants will:

Undergo lymphocyte-depleting chemotherapy Fludarabine/&Cyclophosphamide from day -5 to day -3 before NK cell infusion.

Receive intravenous infusions of modified NK cells at escalating doses:

The first three patients will receive 1×10⁷ cells/kg. The next three patients will receive 2×10⁷ cells/kg. The final three patients will receive 4×10⁷ cells/kg. Have NK cell infusions administered every 96-120 hours for a total of three infusions, with each infusion completed within 10 to 15 minutes.

Undergo dose escalation with subsequent groups only after confirming the safety of the previous dose group.

Have their vital signs (temperature, heart rate, respiratory rate, blood pressure, etc.) monitored before and after each infusion.

Keep baseline data records during NK cell infusions. Participate in follow-up assessments to monitor disease remission and detect any adverse events.

This trial aims to provide new treatment options for RR AML patients by leveraging the targeted cytotoxic effects of CD123-CD16 bispecific antibody-modified NK cells to achieve disease remission.

Критерии включения

• 1. Age: Between18 years and 70 years.
• 2. Diagnosis and Treatment History:
• Diagnosed with Acute Myeloid Leukemia (AML) in the hospital. Has undergone multiple first-line clinical treatments and has developed resistance to current treatments. Relapse after original induction therapy failure with a predicted survival of more than three months.
• 3. CD123 Expression:
• Flow cytometry detection shows CD123-positive AML cells.CD123 expression level is not less than 20%.
• 4. Hospital Examination Criteria:
• 5. Performance Status:
• ECOG Performance Status score of 0-2 or Karnofsky Performance Status (KPS) score greater than 80.
• 6. Donor Availability:
• 7. Have a suitable healthy donor and agree to peripheral blood collection.

Критерии исключения

• 1. Specific AML Subtype:
• Diagnosed with Acute Promyelocytic Leukemia(APL).
• 2. CD123 Expression:
• Flow cytometry shows CD123 negative or CD123 expression level less than 20%.
• 3. Prior Treatment Toxicity:
• Persistent non-hematologic toxicity of grade 2 or higher related to previous treatments.
• 4. GVHD Requiring Immunosuppression:
• Patients requiring immunosuppressants for grade II-IV acute Graft-Versus-Host Disease (GVHD).
• 5. Recent Steroid Treatment:
• Systemic steroid treatment within 7 days prior to first study drug treatment (excluding topical and inhaled corticosteroids or short-term prophylactic steroid treatment).
• 6. Severe Cardiovascular and Cerebrovascular Diseases:
• Certain cardiovascular and cerebrovascular diseases within 6 months prior to first dose.
• New York Heart Association (NYHA) classification ≥3 or uncontrolled malignant arrhythmias.Other cardiovascular and cerebrovascular diseases deemed unsuitable by the investigator.
• 7. Pregnancy and Lactation:
• Pregnant or breastfeeding women (the safety of this treatment for unborn babies is unknown).
• For female participants, pregnancy must be confirmed negative by serum or urine pregnancy test within 48 hours before infusion.
• 8. Infections:
• Active Hepatitis B,Hepatitis C virus infection, Peripheral blood CMV-DNA ≥500 copies/mL, HIV/AIDS infection and any uncontrolled active infection.
• 9. Allergic Reactions:
• Allergic to immunotherapy and related drugs.
• 10. Neurological Diseases:
• Neurological diseases such as neurodegenerative diseases, primary central nervous system tumors/infections, multiple sclerosis, epilepsy, severe peripheral neuropathy, etc.

Описание

The objective of this study is to determine the safety, tolerability, and anti-leukemic activity of S227928 as single agent and in combination with venetoclax, and to determine the recommended Phase 2 dose (RP2D) of this combination. The study will begin as a Phase 1 Dose Escalation study to determine the RP2D and then will transition to a Phase 2 Dose Expansion study to assess the efficacy of the selected RP2D. During the treatment period participants will have study visits every two weeks, with additional visits occurring during the first and second cycle. Approximately 30 days after treatment has ended, an end-of-treatment visit will occur and then participants will be followed for survival every 12 weeks for the next 6 months. Study visits may include a bone marrow aspirate and/or biopsy, blood and urine tests, ECG, vital signs, physical examination, and administration of study treatment.

Критерии включения

• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• * Women of childbearing potential (WOCBP) must use a highly effective method of birth control during study treatment and at least 6 months after the last dose of Investigational Medicinal Product (IMP). In case of the use of oral contraception, women should have been on a stable dose of the same contraceptive drug (i.e., same active principle) for at least 3 months prior to the first IMP administration.
• * Male participants with WOCBP partners must use a condom during the study and for at least 3 months after the last dose of IMP. In addition, contraception should be considered for their female partners. Contraceptive measures do not apply if the participant is sterile, vasectomised or sexually abstinent. Sperm donation will not be allowed during the study and for at least 3 months after the last dose of IMP.
• * Patients with pathologically confirmed AML, MDS/AML, or CMML as defined by the World Health Organization (WHO) 2022 classification or ICC, who have been previously treated with at least one prior standard treatment and have relapsed and/or refractory disease.
• 1. Patients must not be candidates for further standard therapy,
• 2. Treatment with agents for lower risk MDS such as erythropoietin or luspatercept are not considered anticancer therapies.
• * Circulating leukocytes /< 10 x 109/L (use of hydroxycarbamide before study drug initiation is allowed to achieve this inclusion criterion).
• * Adequate renal function within 7 days before study enrollment defined as:
• a. Calculated creatinine clearance (determined by the modification of diet in renal disease /[MDRD/] equation) ≥ 60 mL/min
• * Adequate hepatic function within 7 days before study enrollment defined as:
• 1. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN),
• 2. Total bilirubin level ≤ 1.5 x ULN, except for patients with known Gilbert`s syndrome, who may be included if their total bilirubin is ≤ 3.0 x ULN and their direct bilirubin is ≤ 1.5 x ULN.

Критерии исключения

• * Pregnant or lactating women.
• * WOCBP tested positive in a serum pregnancy test within 7 days prior to the first day of IMP administration.
• * Legally incapacitated person under guardianship or trusteeship.
• * Failure to recover to ≤ Grade 1 (Common Terminology Criteria for Adverse Events version 5.0 /[CTCAE v5.0/]) from acute non-hematologic toxicities (to ≤ Grade 2 for neuropathy) due to previous therapy, prior to screening.
• * Diagnosis of myeloproliferative neoplasms (MPNs) or other non-CMML MDS/MPNs as defined by the WHO 2022 classification
• * Diagnosis of acute promyelocytic leukemia (French-American-British /[FAB/] M3 classification).
• * Diagnosis of acute leukemia of mixed or ambiguous lineage or histiocytic/dendritic cell neoplasms defined by the WHO 2022 classification
• * Uncontrolled infections requiring systemic antibiotics and/or antifungal agents as per investigator`s judgment. Patients receiving prophylactic antibiotics and/or antifungal agents are eligible for this study.
• * Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy, or with detectable HBV viral load.
• * Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load.
• * Human immunodeficiency virus (HIV) seropositive with any of the following:
• 1. CD4+ T-cell (CD4+) counts /< 350 cells/µL
• 2. Acquired immunodeficiency syndrome-defining opportunistic infection within 12 months prior to screening
• 3. Not on antiretroviral therapy, or on antiretroviral therapy for /< 6 weeks at the time of Day 1 in Cycle 1
• 4. HIV viral load ≥ 400 copies/mL
• * Participants with a known clinically significant cardiovascular disease or condition, including
• 1. Uncontrolled arterial hypertension per the investigator`s judgment
• 2. New York Heart Association class III or IV congestive heart failure
• 3. Congenital or substance-induced long QT defined as heart rate-corrected QT (QTc) interval />450 ms for males and />470 ms for females according to Fridericia`s formula
• 4. Uncontrolled cardiac arrhythmia (e.g., participants with rate-controlled atrial fibrillation are eligible)
• 5. Severe uncorrected conduction disturbances (e.g., 3rd degree heart block). Patients with severe conduction disturbances corrected by a pacemaker are eligible
• 6. Acute coronary syndrome (including unstable angina pectoris, acute myocardial infarction), coronary angioplasty or bypass grafting within 6 months prior to the first IMP administration
• 7. Troponin I /> ULN or troponin T /> ULN if troponin I cannot be assessed
• 8. Any factors that could increase the risk of QTc interval prolongation or risk of arrhythmic events such as heart failure, family history of QT syndrome, or family history of unexplained sudden death under 40 years of age
• * Known active central nervous system involvement by AML, MDS/AML, or CMML.
• * Coagulation disorders or abnormalities that may increase the risk of bleeding complications according to investigator`s judgment (e.g., disseminated intravascular coagulation).
• * Any clinically significant medical condition (e.g., organ dysfunction, gastric ulcer) or laboratory abnormality likely to jeopardize the patient`s safety or to interfere with the conduct of the study.
• * Major surgery within 4 weeks before the first IMP administration, or patients who have not recovered from the acute effects of surgery.
• * Allogeneic stem cell transplantation (SCT) within 3 months before the first dose of IMP
• a. Patients cannot be receiving any immunosuppressive treatment, except for corticosteroids used as physiologic replacement doses up to the equivalent of 10 mg of oral prednisone
• * Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: 1) malignancies that were treated curatively, which have not recurred within 3 years prior to study entry and do not require further treatment; 2) completely resected basal and squamous cell skin cancers; 3) any malignancy considered to be indolent and that has never required anticancer therapy; and 4) completely resected carcinoma in situ of any type.
• * History of severe allergic or anaphylactic reactions to BH3 mimetics (including venetoclax) or to any excipients of S227928.
• * Any previous anticancer treatment for the studied disease within 2 weeks or at least 5 half-lives (whichever is longer) prior to first dose of IMPs (except for hydroxycarbamide). In case of investigational biologic agents with a long half-life, such as immune checkpoint or bispecific antibodies, a flat wash-out period of 28 days will be acceptable. Participation in non-interventional registries or epidemiological studies is allowed. Hormonal therapies are not considered anticancer treatments for eligibility purposes.
• * Any cellular therapies (e.g., NK or CAR T cells) within 100 days prior to first dose of IMP.
• * Any radiotherapy within 2 weeks before the first dose of IMPs (except for palliative radiotherapy to localized lesions, i.e., chloromas).
• * Any drugs known to prolong the QT interval and induce Torsade de pointes (TdP) within 7 days prior to the first administration of IMP.
• * Dose Escalation Arm A ONLY: Although participants may be treated with strong inhibitors of CYP3A4 or of CYP2C8, they may not be treated with medications that are strong inhibitors of both CYP3A4 and CYP2C8, or with separate medications that when combined would cause strong inhibition of these two enzymes. In addition, participants may not be treated with a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2C8 and/or a moderate inhibitor of P-gp. These prohibitions begin 7 days prior to the start of IMP and continue for the entire duration of treatment. Triazole antifungal agents may be used, but only if they are in agreement with the criteria described above (i.e., they must not be dual strong inhibitors of both CYP3A4 and CYP2C8 or strong inhibitors of CYP3A4 and moderate inhibitors of either CYP2C8 or P-gp).
• * Dose Escalation Arm B and Dose Expansion ONLY: a malabsorption syndrome or other condition that precludes enteral route of administration.
• * Dose Escalation Arm B and Dose Expansion ONLY: Both moderate and strong inhibitors of CYP3A4 are prohibited, beginning 7 days prior to the start of IMP and continuing for the entire duration of treatment.
• * Dose Escalation Arm B and Dose Expansion ONLY: Both moderate and strong CYP3A4 inducers are prohibited, beginning 14 days before the start of IMP and continuing for the entire duration of treatment.
• * Dose Escalation Arm B and Dose Expansion ONLY: treatment with P-gp and BCRP inhibitors; or with medications with a narrow therapeutic index (NTIs) which are substrates of P-gp or BCRP; or with OATP1B1 substrates that cannot be discontinued 7 days before and during study treatment

Описание

This project is a prospective, single-center, randomized controlled clinical study. The subjects were high-risk or relapsed/refractory AML or ALL patients aged ≤ 65 years diagnosed by bone marrow cell morphology, immunology, genetics and therapeutic efficacy evaluation. The TmBU scheme or modified Bu/Cy (mBuCy) scheme was used for pretreatment in allo-HSCT. The primary endpoint of the study was the 2-year cumulative incidence of relapse (CIR) after allo-HSCT, and the secondary endpoints were 2-year overall survival rate (OS), progressing-free survival rate (PFS), non-relapse mortality rate (NRM), graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) rate.

Критерии включения

• * Confirmed diagnosis of AML or ALL according to WHO 2022 guideline criteria, with indications for allo-HSCT list below:
• 1. Relapsed/primary refractory (definitions refer to NCCN 2025) or genetic high-risk group AML at diagnosis (risk stratification refers to ELN 2022)
• 2. High-risk at diagnosis (risk stratification refers to ELN 2022) or MRD positive before transplantation B-ALL
• 3. Confirmed diagnosis of T-ALL
• 4. History of central nervous system leukemia (CNSL) or histopathologically confirmed extramedullary manifestation (EMD) during the course of the AML or ALL
• * Age 15-65 years old (≤ 65 years old)
• * HCT-CI score /< 2 points ECOG 0-2 points
• * Adequate organ function:
• 1. Cardiac NYHA grade ≤ 2, left ventricular ejection fraction ≥55%
• 2. Creatinine clearance ≥ 50ml/min
• 3. ALT and AST ≤ 2.5 times the upper limit of the normal range, and total bilirubin ≤ 1.5 times the upper limit of the normal range
• 4. Oxygen saturation /> 92% without oxygen
• * Expected survival time ≥ 3 months
• * Ability to understand and voluntarily sign the informed consent form

Критерии исключения

• * With other malignant tumors and have received any treatment for this tumor within the past 3 years
• * Previous or current other CNS disease (such as epilepsy, generalized seizure disorder, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, or psychosis) or any CNS-related autoimmune disease
• * HIV/Syphilis infection or uncontrolled active other infections (bacteria or fungus or virus is included)
• * With active hepatitis B or hepatitis C infection
• * Patients received cardiac angioplasty or stent implantation within 12 months before signing the informed consent form, or have symptoms requiring medical treatment for coronary heart disease
• * With primary immunodeficiency or active autoimmune disease
• * Previous history of severe immediate hypersensitivity reactions to any of the drugs to be used in this study
• * Received a live vaccine within 6 weeks prior to screening
• * Pregnant, lactating females and patients of childbearing potential who are unwilling to use contraception
• * Inability to cooperate with the requirements of study, treatment and monitoring due to psychiatric illness or other conditions
• * Patients not suitable for the study according to the investigator`s assessment

Описание

To learn about the safety and tolerability of the drug combination of Q702, azacitidine, and venetoclax when given to participants with relapsed/refractory AML.

Критерии включения

• 1. Patients need to have a confirmed diagnosis of AML, or MDS/AML with 10% to 19% blasts, per the International Consensus Classification 2022 or the WHO 2022 classification.23,24
• 2. Patients .18 years with R/R AML or R/R MDS/AML, other than acute promyelocytic leukemia (APL), with no available standard treatment options.
• 3. Relapsed or refractory disease defined by standard criteria as follows:
• a. Relapsed: Bone marrow blasts .5%, reappearance of blasts in the blood, or development of extramedullary disease following achievement of CR/CRi/MLFS b. Refractory: Failure to achieve CR/CRi/MLFS following initial treatment, with evidence of persistent leukemia by blood and/or bone marrow evaluation with blasts .5% c. Appropriate prior therapy in order for patient to be deemed relapsed or refractory include any of the following: i. At least 1 cycle of purine analogue containing intensive induction chemotherapy regimen, e.g., FLAG-Ida, CLIA or CLAG-M or similar regimens with or without venetoclax.25,26 ii. At least 1 cycle of intensive induction chemotherapy with venetoclax, e.g., 7 + 3 or CPX-351 with venetoclax or similar regimens iii. At least 2 cycles of intensive induction chemotherapy such as 7 + 3 or 5 + 2 or similar regimens without venetoclax iv. 2 cycles of BCL2 inhibitor with HMA/LDAC +/- other agents v. 4 cycles of HMA-based regimen without BCL2 inhibitor
• - Younger/fit patients (/<60 years) in first relapse following intensive chemotherapy, will only be eligible if the first remission (CR1) duration was .12 months.
• d. Patients relapsing with persistent or new TP53 mutation will be eligible irrespective of CR1 duration. e. Older/unfit patients who relapse on HMA + venetoclax based maintenance regimen will be eligible irrespective of CR1 duration.
• 4. ECOG PS 0 to 1
• 5. Patients relapsing after allo-SCT may be eligible if they have recovered from all transplant related toxicities and are off all immunosuppression, with no more than grade 1 chronic GVHD. Physiologic ( greplacement h) dose of steroids (.10 mg prednisone or equivalent) may be acceptable. Patients must be off all immunosuppression, including calcineurin inhibitors, for at least 2 weeks or 5 half-lives, whichever is longer, prior to enrollment on study.
• 6. Patients with actionable mutations with available FDA-approved therapies, e.g., FLT3, IDH1/2 inhibitors may be enrolled after they have exhausted appropriate lines of FDA approved treatment options.
• 7. Patients with antecedent hematological disorder (AHD), e.g., aplastic anemia, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or myeloproliferative disorder or neoplasm (MPD or MPN) who have previously received a regimen appropriate for AML for the antecedent hematological disorder, as described above, and have progressed to AML, will be eligible for the dose escalation and salvage dose expansion cohorts. This is due to recognized poor outcomes in such patients with "treated secondary AML".27,28
• 8. Adequate hepatic function (total bilirubin . 1.5 x upper limit of normal (ULN), and AST and/or ALT . 2 x ULN). Patients with Gilbert disease will be eligible with total bilirubin . 4.5 mg/dL.
• 9. Adequate renal function with creatinine clearance . 60 mL/min calculated by the Cockcroft- Gault formula or MDRD equation or measured by 24-hour urine collection.
• 10. The effects of these agents on the developing human fetus are unknown. For this reason, and because other therapeutic agents used in this trial may be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 90 days after last treatment.
• a. This includes all female patients between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: i. Postmenopausal (no menses in greater than or equal to 12 consecutive months).
• ii. History of hysterectomy or bilateral salpingo-oophorectomy. iii. Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range, who have received whole pelvic radiation therapy).
• iv. History of bilateral tubal ligation or another surgical sterilization procedure.
• b. Approved methods of birth control are as follows: Hormonal contraception (i.e., birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• c. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment.
• 11. Ability to understand and the willingness to sign a written informed consent document.

Критерии исключения

• 1. Patients with t(15;17) karyotypic abnormality.
• 2. Patient has a white blood cell count /> 15 x 10./L. Hydroxyurea, and/or cytarabine (up to 2 g/m2 total) used as supportive care is permitted to meet this criterion prior to enrollment.
• 3. Prior use of any cytotoxic chemotherapy, targeted therapy, radiation therapy, immunotherapy, or other clinical trial therapies within 2 weeks or 5 half-lives, whichever is shorter, prior to first dose of study treatment. Patients should have recovered from all prior therapy related toxicities. Patients may receive hydroxyurea or cytarabine for control of WBC count during this washout period.
• 4. Patients with known symptomatic or uncontrolled CNS leukemia.
• 5. Patient has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate treatment.
• 6. Active ophthalmological disorders, e.g., retinal pigment epithelium (RPE)/photoreceptor disorders such as retinitis pigmentosa, cone-rod dystrophies, Bests dystrophy, Stargardt disease (STGD), macular degeneration. Exceptions:
• 1. Mild blurry vision, either age-related or due to ocular or systemic disorder (e.g., diabetes, dry eyes, cataracts, uncorrected refraction abnormality) may be allowed at the discretion of an ophthalmologist if deemed as not constituting evidence of preexisting retinopathy or a condition with the potential to cause a predisposition to druginduced retinopathy.
• 2. Patients with only one assessable eye and no evidence of pre-existing retinopathy may be allowed at the discretion of the principal investigator.
• 7. Any known and active neurological disorder with residual neurological deficit or requiring pharmacotherapy.
• 8. Patients with known acute or chronic liver disease, cirrhosis, hepatic steatosis with elevated liver function tests or elevated LFTs of unknown etiology.
• 9. Active and uncontrolled comorbidities including decompensated congestive heart failure NYHA class III/IV, clinically significant, uncontrolled arrhythmia, acute respiratory failure, unstable or decompensated pulmonary disease, as judged by the treating physician.
• 10. Decompensated congestive heart failure, hypokalemia, prolonged QT interval corrected for heart rate (QTc) to greater than 470 msec or long QT syndrome, or history of Torsades de pointes. Appropriate corrections may be applied for patients with bundle branch block.
• 11. Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications as determined by the investigator.
• 12. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection with detectable viral DNA or RNA, respectively, or known HIV or HTLV-1 infection.
• 13. Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator.
• 14. Any previous malignancy, except when the patient has completed definitive curative-intent treatment with chemotherapy and/or surgery and/or radiotherapy at least 1 month prior to enrollment. Patients having completed definitive treatment for the following conditions may be eligible immediately after completion of definitive curative-intent therapy, after healing of wounds, and no evidence of residual disease by examination or imaging or cytology/pathology, e.g., non-melanoma skin cancers, or any carcinoma in-situ, e.g., ductal carcinoma in situ, urothelial cancer, cervical cancer, localized prostate cancer, pre-cancerous colon polyp, etc.
• 15. Major surgery within 4 weeks prior to screening or a major wound that has not fully healed.
• 16. Patients under legal protection measure (guardianship, trusteeship or safeguard of justice) and/or uncontrolled psychiatric comorbidities, ongoing illicit substance abuse, any impairment or unwillingness to comply with the treatments, follow-up, requirements and procedures of this clinical trial.
• 17. A known hypersensitivity or severe allergy to study drug components or diluents
• 18. Nursing women, women of childbearing potential (WOCBP) with positive urine or serum pregnancy test, or WOCBP who are not willing to maintain adequate contraception.
• 19. Pregnant women are excluded from this study because study agents may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (Aes) in nursing infants secondary to treatment of the mother with study agents, breastfeeding should be discontinued if the mother is treated on this study.

Описание

To determine the efficacy of the combination of tagraxofusp, cladribine, and cytarabine.

Критерии включения

• * Documented diagnosis of relapsed or refractory acute myeloid leukemia (AML) according to World Health Organization (WHO) 2022 criteria
• * Expression of CD123 by either flow cytometry or immunohistochemical staining with no minimum threshold for positivity
• * Must have received initial therapy with venetoclax in combination with a hypomethylating agent (either azacitidine or decitabine) with no subsequent therapy unless mutations in the IDH or FLT3 genes.
• If mutations in the IDH or FLT3 genes, treatment with IDH or FLT3 inhibitors after initial failure of venetoclax plus HMA is allowed, but not required.
• * Age ≥ 18 years of age
• * ECOG ≤ 2
• * Albumin ≥ 3.2 g/dL at time of screening (note that albumin supplementation is not permitted to enable eligibility)
• * Left ventricular ejection fraction ≥ 50%
• * No clinically significant abnormalities on 12-lead electrocardiogram (ECG) including: complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval />250ms, or QTcF (Friderica`s method) />450ms in 3 successive measurements
• * Stated willingness to comply with all study procedures and availability for the duration of the study
• * Females of reproductive potential need to either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption prior to starting treatment, during the study therapy, and for 30 days after last dose of study therapy
• * For males of reproductive potential: agreement to use of condoms
• * Adequate hepatic/renal function defined as:
• Hepatic function: total bilirubin ≤ 1.5 x ULN (unless attributable to Gilbert`s disease or leukemic involvement) AND AST or ALT ≤ 3 x ULN
• Renal function: creatinine clearance /> 30 mL/minute, calculated by Cockcroft Gault formula
• * Women of childbearing potential must have a negative urine or serum pregnancy test
• * Ability to understand and the willingness to provide written informed consent.

Критерии исключения

• * Prior therapy apart from Venetoclax in combination with a hypomethylating agent, or Venetoclax in combination with a hypomethylating agent followed by monotherapy with IDH or FLT3 inhibitors
• * Patients who received systemic anti-cancer therapy /<14 days prior to their first day of study drug administration.
• * Patients who received systemic anti-cancer therapy /<14 days prior to their first day of study drug administration. Concurrent hydroxyurea will be allowed. Hydroxyurea use will be allowed only during the first cycle if needed for disease control.
• * Significant cardiac disease (any NYHA Class 3 or 4 CHF, uncontrolled angina, history of MI, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension, or clinically significant arrhythmias not controlled by medication)
• * Any uncontrolled bacterial, fungal, viral or other infection.
• * Known HIV+ or active hepatitis B or C infection, defined as positive viral load for HBV or HCV or a positive surface antigen (HBsAg) test for hepatitis B.
• * The patient has persistent clinically significant toxicities Grade />/= 2 from previous therapies not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue).
• * The patient has an active malignancy and/or cancer history that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of study entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with study team before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease.
• * The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
• * The patient has known active or suspected CNS disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
• * The patient is receiving immunosuppressive therapy - with the exception of low-dose prednisone (/</= 10 mg/day).
• * Received allogenic stem cell transplant prior to the treatment.
• * The patient has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
• * Pregnant or breast feeding

Описание

The purpose of this study is to see the effects of an investigational combination treatment of venetoclax, azacitidine, and donor lymphocyte infusion (DLI) in patients with high-risk AML receiving allogeneic hematopoietic cell transplantation, and to assess if the combination treatment is well tolerated and prevents disease relapse after transplant.

Критерии включения

• 1. Male and female patients between the ages of 18-75.
• 2. Patients with a histologic diagnosis of AML in morphological remission (/<5% bone marrow (BM) blasts) prior to allogeneic hematopoietic cell transplantation and very high-risk for relapse defined as: (i) Presence of measurable residual disease (MRD) by multicolor flow cytometry (MFC) prior to transplant and receiving a reduced intensity conditioning (RIC) or nonmyeloablative (NMA) regimen (ii) Presence of MRD by MFC at day +30 post-transplant (iii) All patients with monosomal karyotype (MK) and those with 17p/tumor protein p53 (TP53) mutated disease irrespective of MRD status and intensity of conditioning regimen.
• 3. Adequate hematopoietic recovery after HCT, defined as:
• * Absolute neutrophil count (ANC) />= 1 x 10/^9/L without daily use of myeloid growth factors
• * Platelet count />= 50 x 10/^9/L without platelet transfusion within 1 week
• 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• 5. Serum creatinine =/< 1.5 mg/dL or creatinine clearance greater or equal than 40 cc/min
• 6. Serum bilirubin =/< 1.5 x upper limit of normal (ULN)
• 7. Aspartate transaminase (AST) or alanine transaminase (ALT) =/< 2.5 x ULN
• 8. Alkaline phosphatase =/< 2.5 x UL
• 9. Negative serum or urine pregnancy test for women with reproductive potential.
• 10. A negative donor-specific antibody (DSA) assay (i.e., Micro-Flow Imaging (MFI) /<m3000) for recipients of any mismatched graft (including haploidentical) HCT.

Критерии исключения

• 1. Active disease (/>5% blasts or any evidence of extra-medullary disease) at the time of transplantation or at day +30
• 2. Active acute graft-versus-host disease (aGVHD) requiring systemic IST or history of aGVHD grade III or higher.
• 3. Active chronic GVHD requiring systemic immunosuppressive therapy (IST).
• 4. Active uncontrolled systemic fungal, bacterial, or viral infection
• 5. Known active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
• 6. Significant active cardiac disease within the previous 6 months, including: New York Heart Association (NYHA) class III or IV congestive heart failure. Unstable angina, angina requiring surgical or medical intervention, and/or myocardial infarction.
• 7. History of any other malignancy within 2 years prior to study entry, except for: adequately treated in situ carcinoma of the cervix or carcinoma in situ of breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; myelodysplastic syndrome.

Описание

The aim of this study is to evaluate the safety and efficacy of homohartonine combined with venetoclax and azacitidine (HVA) versus intensive chemotherapy (IA/DA) or venetoclax combined with azacitidine (VA) in newly diagnosed high-risk AML patients.

Критерии включения

• * According to the world health organization (WHO) classification of newly diagnosed with AML patients;
• * Age ≥18 years old;
• * High-risk patients should meet any of the following criteria: ① High risk group according to the European Leukemia Risk stratification (ELN) 2022; (2) Secondary AML (sAML) which develops from myelodysplastic syndrome (MDS), bone marrow hyperplastic tumor (MPN) or chronic myeloid cell leukemia, et.; (3) Treatment-related AML (t-AML), Patients have a history of cytotoxic treatment record or ionizing radiation therapy.
• * Patients did not receive anti-AML therapy (except leukopenia therapy, such as hydroxyurea or cytarabine /< 1.0g/d) after the diagnosis of AML;
• * Expected survival ≥12 weeks;
• * The eastern tumor cooperation group (ECOG) score 3 points or less;
• * Kidney function: creatinine clearance acuity 30 ml/min;
• * Liver function: ALT /< 5 times normal value, bilirubin /< 3 times normal value;
• * Sign the informed consent form and understand and abide by the plan calls for process.

Критерии исключения

• * Acute promyelocytic leukemia;
• * With central nervous system leukemia (CNSL) ;
• * The cardiac function /> level 2;
• * The AIDS virus (HIV) infection;
• * Other clinical significance of uncontrolled condition, including but not limited to: (1) out of control, or active systemic infection (viruses, bacteria or fungi); (2) chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment; (3) need to actively deal with the merger of the second tumor;
• * Can`t take oral treatment or having a gastrointestinal disease impact ing the absorption;
• * Being allergy to the experimental drugs;
• * Pregnant and lactating women;
• * Patients who could not understand or adhere to the study protocol;
• * Patients deemed by the investigator to be ineligible for enrollment.

Описание

The study is a Phase II clinical trial. Patients will receive intensity-modulated total marrow irradiation (TMI) at a dose of 9 Gray (Gy) with standard myeloablative fludarabine intravenous (IV) and targeted busulfan (FluBu4) conditioning prior to allogeneic hematopoietic stem cell transplant (HSCT). Graft-versus-host disease (GVHD) prophylaxis will include Cyclophosphamide on Day +3 and +4, tacrolimus, and mycophenolate mofetil.

Критерии включения

• * 1. Age 18-65 years.
• * 2. Patients with CML, AML, or MDS who meet one of the following criteria: 2a. Relapsed or refractory AML (including AML in CR2) 2b. Poor-risk AML in first remission, with remission defined as /<5% bone marrow blasts morphologically:
• * AML arising from MDS, a myeloproliferative disorder, or secondary AML
• * Poor risk molecular features according to Leukemia Net including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2
• * Poor-risk cytogenetics: Monosomal karyotype, complex karyotype (/> 3 abnormalities), inv (3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7. 2c. Primary refractory disease 2d. MDS with at least one of the following poor-risk features:
• * Poor-risk cytogenetics including 3q abnormalities, 7/7q minus or complex cytogenetics (/>3 abnormalities).
• * Current or previous INT-2 or high IPSS score.
• * Treatment-related MDS.
• * MDS diagnosed before the age of 21 years.
• * Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy.
• * Life-threatening cytopenias, including those requiring regular PRBC or platelet transfusions. 2e. CML with a history of accelerated or blast phase.

Критерии исключения

• * 1. Presence of significant co-morbidity as shown by:
• * 1a. Left ventricular ejection fraction /< 50%
• * 2b. Creatinine clearance /<30ml/min.
• * 3c. Bilirubin /> 2.0 mg/dL (unless due to Gilbert`s syndrome or hemolysis), and ALT and AST /> 5 x ULN.
• * 4d. FEV1 and FVC /< 50% of predicted or DLCO /<50% of predicted once corrected for anemia.
• * 5e. Karnofsky score /<70
• * 6f. Active viral hepatitis or HIV infection.
• * 7g. Cirrhosis.
• * 2. Pregnancy or breast feeding
• * 3. Patients unable to sign informed consent.
• * 4. Patients previously received radiation to />20% of bone marrow-containing areas.

Описание

People with acute myeloid leukemia (AML) are usually treated with chemotherapy. When the cancer comes back (relapse) the next treatment is usually a stem cell transplant. Some people with AML have a changed FLT3 gene which causes leukemia cells to grow faster. This means their cancer may come back more quickly after treatment.

Gilteritinib is approved in many countries to treat people with AML with the changed FLT3 gene whose cancer has come back or have not responded to previous treatment. In some countries, more studies are needed to approve gilteritinib for use.

This study is about people with AML with the changed FLT3 gene. The main aim was to learn if gilteritinib improves how long people stay cancer-free (in remission) after a stem cell transplant. To do this, 2 groups were compared. 1 group were given gilteritinib after a stem cell transplant. This happened in previous studies called the ADMIRAL study and COMMODORE study. The other group received standard of care after their stem cell transplant. They did not receive gilteritinib after their stem cell transplant.

In this study, information about the people who received standard of care after their stem cell transplant will be collected. This study is about collecting information only. The study sponsor (Astellas) will not provide any treatment.

Information will be collected from the people`s medical records between 01 Jan 2015 and 31 Dec 2022. The study doctors will collect information from the first relapse, during and after the stem cell transplant. Then, they will record when any of the following happened after the stem cell transplant: the person passed away, their cancer came back, they decided to leave the study or could not be contacted.

Критерии включения

• Gilteritinib Group
• * Patients from ADMIRAL and COMMODORE phase 3 studies that resumed gilteritinib after HSCT to maintain remission
• External Comparator Group
• * Patient with a diagnosis of AML according to World Health Organization (WHO) classification
• * Patient with positive either FLT3-Internal Tandem Duplications (ITD) or FLT3- Tyrosine Kinase Domain (TKD) genetic testing or re-testing
• * Patient with pre-defined first R/R AML at enrollment:
• * Refractory to first-line AML therapy is defined as patient not achieving CR/Complete Remission with Incomplete Hematologic Recovery (CRi)/Complete Remission with Incomplete Platelet Recovery (CRp) under initial therapy. A patient eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A patient not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this patient.
• * Relapsed after first-line AML therapy. First-line AML therapy is defined as (all criteria must be met): Patient achieved a CR/CRi/CRp (as defined by International Working Group criteria) and Initial AML therapy must have consisted of up to 2 induction blocks with or without consolidation or maintenance, with or without transplantation
• * Patient underwent allogenic HSCT upon R/R AML diagnosis
• * Patient who was alive at 90 days post-HSCT and:
• * Patient had successful engraftment as demonstrated by absolute neutrophil count (ANC) ≥ 500/mm3 and platelets ≥ 20000/mm3 without transfusions
• * Patient did not have grade 3 or above acute GvHD
• * Patient was in any type of CR
• * Patient who received best supportive care after HSCT; Best supportive care refers to treatment(s) patients received in CR after HSCT and remained in CR when given the intervention. This may include prophylactic intrathecal chemotherapy, cranial radiation, and donor lymphocyte infusion as part of the HSCT treatment plan.

Критерии исключения

• External Comparator Group
• * Eastern Cooperative Oncology Group (ECOG) ≥ 2
• * Patients who received midostaurin, sorafenib, gilteritinib, or venetoclax, or chemotherapy post-HSCT as maintenance therapy prior to index date
• * Patient diagnosed with acute promyelocytic leukemia
• * Enrollment in drug interventional post-HSCT AML clinical trials during study period
• * Critical information is not available for abstraction; Critical information includes FLT3m+confirmation, R/R confirmation, transplantation outcomes (e.g., any type of CR, any grade 3 or above GvHD) at 90 days post-HSCT

Описание

A non-randomized phase Ib study of PC14586 (PMV therapeutics) in patients diagnosed with TP53Y220C-mutant myeloid malignancies, including AML and MDS.

Критерии включения

• 1. Patient is ≥ 18 years of age at the time of signing the informed consent form (ICF).
• 2. Patient is willing and able to adhere to the study visit schedule and other protocol requirements.
• 3. Patient has relapsed or primary refractory AML or MDS
• 4. Any other comorbidity that per the investigator renders a patient inappropriate for intensive chemotherapy.
• 5. Patients with MDS must be classified as MDS-IB1 or IB2 as per WHO 2022 criteria32
• 6. TP53Y220C mutation confirmed by CLIA-approved local testing with a variant allele frequency />2%.
• 7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
• 8. Patient has adequate organ function defined as:
• * Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered due to leukemic organ involvement.
• * Serum total bilirubin ≤ 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, leukemia organ involvement or Gilbert/'s syndrome.
• * Serum creatinine /< 2 x ULN or creatinine clearance /> 40 mL/min based on validated glomerular filtration rate (GFR) estimation (Cockcroft-Gault, CKD-epi, or MDRD equations).
• 9. Females of childbearing potential may participate provided they have a negative serum or urine pregnancy test at screening and a negative serum OR urine pregnancy test within 72 hours of starting on treatment. They also must agree to either abstain from sexual intercourse or use two forms of a highly effective method of contraception while on study and up to 3 months after the last dose of the study drug.
• 10. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) 14 days prior to study entry and for the duration of study participation. This includes all female patients between the onset of menses and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
• Postmenopausal (no menses in greater than or equal to 12 consecutive months). History of hysterectomy or bilateral salpingo-oophorectomy. Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
• History of bilateral tubal ligation or another surgical sterilization procedure.
• • Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of investigational agent administration.
• 11. Ability to understand and the willingness to sign a written informed consent document.

Критерии исключения

• 1. Patient has received prior chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent within 14 days or 5 half-lives (if half-life is known), whichever is shorter, before receiving their first dose of study drug.
• 2. Patient has received radiotherapy within 14 days.
• 3. Patients with acute promyelocytic leukemia
• 4. Subject has immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
• 5. Patients with active, uncontrolled leukemia involvement of the CNS
• 6. Subject has known active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
• 7. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
• 8. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
• 9. Patient has any unresolved toxicities from prior anti-cancer therapy greater than Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior chemotherapy induced neuropathy.
• 10. Patient has had major surgery within 2 weeks prior to the planned start of study treatment.
• 11. Female subject who is pregnant or lactating.
• 12. History of allergic reactions attributed to compounds of similar chemical or biologic composition to azacitidine, rezetapopt or other agents used in study.

Описание

The purpose of Part 1 (Dose Escalation) of the study is to assess the safety and tolerability, and to identify the recommended Phase 2 dose/[s/] (RP2D/[s/]) in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) (that is a type of blood cancer that has come back after treatment/or has stopped responding to treatment) or R/R higher-risk type of myelodysplastic neoplasms (MDS, type of blood cancer). The purpose of Part 2 (Cohort Expansion) is to further assess the safety, tolerability and efficacy in participants with R/R AML or higher-risk types of MDS.

Критерии включения

• * Have a diagnosis, per World Health Organization (WHO) 2022 criteria of:
• 1. relapsed/refractory acute myeloid leukemia (AML)
• 2. relapsed/refractory moderate high, high, or very high risk myelodysplastic neoplasms (MDS) per Molecular International Prognostic Scoring System (IPSS-M)
• * Body weight greater than or equals to (/>=) 40 kilograms (kg)
• * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
• * Have adequate renal function defined as Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Estimated Glomerular Filtration Rate (eGFR) />=40 milligrams per minute (mL/min)
• * Participants must have laboratory parameters in the required range

Критерии исключения

• * Has a medical history of clinically significant pulmonary compromise, particularly the need for current supplemental oxygen use to maintain adequate oxygenation
• * Has evidence of an uncontrolled systemic viral, bacterial, or fungal infection
• * Has known allergies, hypersensitivity, or intolerance to the excipients of JNJ-89853413
• * Had major surgery or had significant traumatic injury within 14 days of planned first dose of JNJ-89853413
• * Has known active central nervous system involvement

Описание

This is a phase 1 dose escalation study to determine the safety of anti-FLT3 CAR-T in subjects with R/R AML. The primary objective is to assess safety. Up to 18 evaluable subjects will be enrolled. Evaluable subjects are defined as those who have received an infusion of HG-CT-1.

Primary clinical objectives:

i. Determine the safety of HG-CT-1 based on the proportion of subjects infused with HG-CT-1 who experience a dose limiting toxicity (DLT).

Secondary clinical objectives:

i. Estimate the efficacy of HG-CT-1 according to standard clinical response criteria for AML.

ii. Estimate overall survival of evaluable subjects. iii. Estimate progression-free survival of evaluable subjects. iv. Estimate duration of response in evaluable subjects who achieve a response.

Secondary scientific objectives:

i. Describe the persistence and trafficking of HG-CT-1. ii. Describe HG-CT-1 bioactivity and its predictors.

Критерии включения

• * 18 years of age or older at enrollment
• * Subjects with AML unlikely to be cured with currently available therapies. Specifically, the following groups are eligible:
• 1. Refractory AML: i.e., newly diagnosed AML that after two cycles of intensive chemotherapy has not achieved a complete remission or morphologic leukemia free state by ELN criteria.1 Intensive chemotherapy must have included either the combination of cytarabine and an anthracycline (3+7 or similar) or combination of venetoclax with a hypomethylating agent.
• Patients with FLT3 ITD must also have failed treatment with a FLT3 inhibitor and patients with IDH1 or IDH2 mutations must have failed treatment containing ivosidenib or enasidenib respectively (i.e., progression on treatment, or failure to achieve CR after six months of treatment,) OR:
• 2. AML relapsed following allogeneic stem cell transplantation (including MDS evolved to AML post-allogeneic stem cell transplantation). Note: morphologic relapse is not required; persistent/recurrent disease-associated molecular, phenotypic, or cytogenetic abnormalities (measurable residual disease, MRD) at any time after allogeneic HCT is eligible. OR:
• 3. AML that has relapsed within 12 months after initial induction and consolidation therapy OR:
• 4. AML that has relapsed more than 12 months after initial induction but that has failed to achieve CR or morphologic leukemia free state after one reinduction OR:
• 5. AML after second or subsequent relapse.
• * FLT3 expression must be detectable in AML blast by flow cytometric analysis.
• * Subjects must have a suitable stem cell transplant donor. Donor may be matched or mismatched and must be found to be suitable according to the institution`s standard criteria. That donor shall be "cleared" for donation by institutional standards prior to administration of HG-CT-1. Adult donors can be either related or unrelated, HLA-matched or partially matched. Matched or partially matched umbilical cord blood donors are also eligible.
• * Subjects with relapsed disease after prior allogeneic transplant must be off systemic immunosuppression for at least 1 month at the time of enrollment without GvHD that requires systemic immunosuppression.
• * Satisfactory organ functions:
• 1. Creatinine ≤ 1.6 mg/dl and Creatinine clearance (CrCl) as calculated by the Cockcroft-Gault formula ≥ 60 mL/min.
• 2. ALT/AST must be ≤ 3 x upper limit of normal unless related to disease.
• 3. Direct bilirubin /< 2.0mg/dl unless subject has Gilbert`s syndrome (in which case it should be ≤3.0 mg/dL).
• 4. Left ventricular ejection fraction ≥ 45% as confirmed by echocardiogram or MUGA.
• 5. DLCO />45% predicted and O2 Saturation /> 90% on room air.
• * ECOG Performance status 0-1.
• * Written informed consent is given.
• * Subjects of reproductive potential must agree to use acceptable birth control methods (as described in protocol Section 4.7).

Критерии исключения

• * Pregnant or lactating (nursing) women.
• * Active second malignancy will not be eligible with the following exceptions:
• 1. Carcinoma in situ of the cervix (which may be considered for enrollment),
• 2. Indolent, non-metastatic prostate cancer
• 3. Non melanoma skin cancer
• 4. Other indolent and controlled malignancies not requiring urgent treatment.
• * Subjects with a history of a prior allogeneic stem cell transplantation are excluded if:
• 1. Subjects are less than 100 days post-transplant OR
• 2. Subjects have evidence of ongoing active GvHD and are taking immunosuppressive agents (/>0.5mg/kg/methylprednisolone equivalents or other immunosuppression for GvHD treatment) OR
• 3. Subjects have received DLI within 30 days prior to enrollment.
• * Active hepatitis B (HBV) or active hepatitis C (HCV) or any HIV infection. Note: prior HCV that has been appropriately treated or evidence of past HBV infection do not constitute exclusions.
• * Concurrent use of systemic steroids at a prednisone dose of greater than 10 mg or equivalent, recent, or current use of inhaled steroids is not exclusionary.
• * Concurrent use of immunosuppressant medications such as calcineurin inhibitors, methotrexate, or alemtuzumab.
• * Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the site Pl would pose an unacceptable risk to the subject.
• * Active or uncontrolled viral, bacterial, or fungal infection. May be receiving ongoing therapy for controlled infection.
• * Subjects with signs or symptoms indicative of active CNS involvement. A CNS evaluation shall be performed as clinically appropriate to rule out CNS involvement. Subjects with adequately treated CNS leukemia are eligible.
• * Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
• * Hyperleukocytosis (/>50,000 blasts/µL) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy.
• * Patients with Acute Promyelocytic Leukemia are not eligible.

Описание

This is a single-center, prospective, single-arm, exploratory clinical study. To explore the efficacy and safety of avapritinib in patients with recurrent acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation with C-KIT mutation RUNX1::RUNX1T1 or CBFB::MYH11.

Критерии включения

• 1. Subjects met the criteria for recurrence after allogeneic transplantation: re-emergence of leukemia cells or bone marrow original cells in peripheral blood />5% (except for other causes such as bone marrow recovery period) or extramedullary leukemia cell infiltration or molecular or cytogenetic recurrence.
• 2. Bone marrow molecular biology detected C-KIT D816 or C-KIT N822 mutations
• 3. Patients with CBFB::MYH11 gene or RUNX1::RUNX1T1 fusion gene detected.
• 4. Eastern Cancer Collaboration Group (ECOG) physical status score 0-2 points.
• 5. Liver, kidney and cardiopulmonary functions met the following requirements: Within 2 weeks before enrollment ① creatinine ≤1.5 upper limit of normal value; ② Left ventricular ejection fraction ≥50%; ③ Blood oxygen saturation />91%; ④ Total bilirubin ≤2×ULN; ALT and AST≤2.5 x ULN; Myocardial enzymes /< 2 times the upper limit of normal (for the same age)
• 6. Volunteer to participate in clinical studies and sign informed consent, willing to follow and able to complete all trial procedures.

Критерии исключения

• 1. Known allergy to KIT inhibitor drug analogues.
• 2. Patients who have received previous treatment with Midostaurin.
• 3. Patients who have previously been treated with mutation-specific C-KIT inhibitors and have developed disease progression during treatment.
• 4. FLT3-ITD mutation in patients with recurrent/refractory disease (except low gene ratio).
• 5. HIV infected persons, HBV, HCV active infected persons.
• 6. Accompanied by uncontrolled cardiovascular and cerebrovascular diseases, coagulation disorders, connective tissue diseases, serious infectious diseases and other diseases.
• 7. With uncontrolled active GVHD (NIH for GVHD diagnosis and classification standards, aGVHD classification refer to the improved Glucksberg standard).
• 8. Central nervous system leukemia.

Описание

This phase II trial tests how well venetoclax with cladribine and cytarabine alternating with azacitidine and venetoclax works in treating patients with newly diagnosed monocytic acute myeloid leukemia (AML) and active signaling mutated AML. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as cladribine, cytarabine and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax with cladribine and cytarabine alternating with azacitidine and venetoclax may kill more cancer cells in patients with newly diagnosed monocytic AML and active signaling mutated AML.

Критерии включения

• * Ability to comprehend the investigational nature of the study and provide informed consent (i.e., participant or legally authorized representative /[LAR/]). Written informed consent must be obtained prior to any study-specific procedures or interventions
• • Sign informed consent for the #4422 Biorepository prior to any study-specific procedures of interventions
• * Eligible AML patients of all races and ethnic groups will be considered for participation, irrespective of gender identity
• * Newly diagnosed, histologically confirmed monocytic AML, as defined by World Health Organization (WHO), or active signaling mutated AML defined as AML with mutation(s) to N/KRAS, FLT3 ITD/TKD, NF1, PTPN11 or CBL
• * Ineligible for standard of care induction therapy using intensive chemotherapy (IC) or unwilling to undergo IC induction therapy. Ineligible for IC is defined as
• * ≥ 75 yrs of age; OR
• * 18-74 yrs of age with one of the following:
• * Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2 at screening
• * Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina)
• * Severe pulmonary disorder (e.g., diffuse capacity of the lung for carbon monoxide /[DLCO/] ≤ 65% or forced expiratory volume in 1 second /[FEV1/] ≤ 65%)
• * Creatinine clearance /< 45 ml/min (calculated by the Cockcroft-Gault equation)
• * Hepatic disorder with total bilirubin /> 1.5 x upper limit of normal (ULN)
• * Any other comorbidity that the treating physician judges to be incompatible with IC
• * If ≥ 75 yrs of age, the following organ function values must be met and ECOG must be 0 to 2 at screening:
• * Creatinine clearance (calculated with the Cockcroft-Gault equation) ≥ 30 ml/min
• * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Unless due to leukemic infiltration)
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/]) or alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]) ≤ 3 x ULN (Unless due to leukemic infiltration) (With the exception of documented Gilbert`s syndrome or similar conditions. Liver function testing (LFT) and timepoints may be added, as clinically indicated, in such cases)
• * Note: In cases of confirmed leukemic organ involvement, exceptions may be made
• * Willing and able to provide bone marrow (BM) samples, including BM samples for research use only analysis
• * Willing and able to accept supportive and prophylactic care for hematologic toxicities, infection, and immediate sequalae
• * Willingness to adhere to (a) study schedule of activities; (b) requirements for bio samples collections; and (b) lifestyle restrictions while on-treatment
• * Negative urine pregnancy test at screening and within 24 hours of cycle 1 day 1 (C1D1) for persons of childbearing potential (PCBP). Serum pregnancy testing will be used for confirmation in cases of equivocal results. Pregnancy is exclusionary because the agents used in this study have the potential for teratogenic or abortifacient effects
• * Willingness to comply with study requirements for contraception within the specified timeframe, as follows:
• * Sperm producing participants who are active with PCBP must use approved contraception from C1D1 to 30 days, 3 months, or 6 months, after the last dose of venetoclax (30 days), azacitidine (3 months), cladribine (6 months), or cytarabine (6 months), whichever is later in time
• * PCBP who are sexually active with sperm-producing persons must use contraception from C1D1 to 30 days after the last dose of venetoclax or to 6 months after the last dose of azacitidine, cladribine, or cytarabine, whichever is later in time

Критерии исключения

• * Symptomatic central nervous system involvement with AML
• * Prior treatment for AML, with the exception of cytoreduction for proliferative disease (per institutional protocol) with any of the following: Hydroxyurea, hematopoietic growth factors, leukapheresis
• * Another active malignancy within the previous 5 years of C1D1
• * Investigational therapy within 28 days of C1D1, or within 5 half-lives or longer, if known
• * Recent and significant medical interventions, such as major surgery within 28 days or stem cell transplant within 100 days (and without active treatment for graft versus host disease /[GVHD/]) of C1D1. Standard of care procedures for patients with hematologic malignancies, such as biopsies and lumbar punctures, are not exclusionary
• * Hypersensitivity to any of the components of the investigational regimen (i.e., cladribine, cytarabine, venetoclax, azacitidine) or any excipients in the formulations
• * Treatment based on agents targeting or inhibiting BCL-2 (for other, prior indication/malignancy) within the previous 5 years
• * History of dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
• * Use of drugs with documented drug-drug interaction toxicities with the study drugs
• * Strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half lives whichever is longer, prior to C1D1 are exclusionary. Dose adjustments and other modifications may be considered if the wash-out period has not been met, with the approval of the investigator and the research pharmacy
• * Uncontrolled infection. Participants with controlled infection must be afebrile and hemodynamically stable for at least 72 hours prior to C1D1 and must be amenable to alternate treatment if current treatment will interact with investigational regimen
• * Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Enrollment of individuals with evidence of chronic HBV or HCV infection will be considered on a case-by-case basis by the principal investigator
• * Individuals with serology positive for human immunodeficiency virus (HIV) and under active treatment with highly active antiretroviral therapy (HAART) (or another therapy that may interfere with metabolism of study agents)
• * Pregnancy at enrollment or unwillingness to stop breastfeeding. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding be discontinued from start of treatment until 1 week after the final dose of any study drug
• * Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, unstable cardiac or pulmonary function or acute insufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), or psychiatric illness or social situation that could limit compliance with study requirements

Описание

The purpose of this study is to find out if azacitidine and venetoclax are an effective treatment approach to get rid of or lower measurable residual disease (MRD) in people with acute myeloid leukemia (AML) who have received standard chemotherapy and are planning to have an allogeneic hematopoietic stem cell transplant (HSCT). Allogeneic HSCT, sometimes called a bone marrow transplant, involves receiving healthy blood-forming cells (stem cells) from a donor in order to replace the patient`s immune system and lower the chances of the disease returning (relapse).

Критерии включения

• * 1. Adult patient ≥18 years of age at the time of signing the informed consent form (ICF). Legal Authorized Representatives (LAR) are permitted.
• 2. Patient is willing and able to adhere to the study visit schedule and other protocol requirements.
• 3. Patient has a confirmed diagnosis of de-novo AML (non-APL) as per World Health Organization (2022) guidelines. All (non-APL) subtypes of AML are permitted, irrespective of ELN risk category or mutational status.
• 4. Patient has received 2 cycles of intensive chemotherapy (either induction + consolidation or 2 induction cycles).
• 5. Patient is in a morphologic remission, defined as less than 5% percent blasts seen by aspirate differential (or immunohistochemistry if no aspirate available) from bone marrow biopsy.
• 6. Patient and is either in CR, or CR with partial count recovery, either CRi/CRh///^1.
• 1CR= BM with /<5% blasts, absence of circulating blasts; absence of extramedullary disease, absolute neutrophil count (ANC) ≥ 1000 cells/µL and platelet (PLT) count ≥ 100,000/µL. CRh = CR with ANC 500-1000 cells/µL and PLT 50,000-100,000 /µL. CRi = CR without meeting CRh criteria (residual neutropenia or thrombocytopenia).
• 7. Patient has positive measurable residual disease (MRD) at or above a level of 0.1%, by flow cytometry or in molecular cases (NPM1 mutated or one of the CBF translocations) RT-qPCR reported at or above 0.01%, as described above (see section 3.6).
• 8. Patient is eligible for intensive chemotherapy and immediate allogeneic transplant, with intention to proceed to transplant after trial intervention.
• 9. Patient has an ECOG performance status of ≤3 10. Patient has adequate organ function defined as:
• 1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
• 2. Serum total bilirubin /< 1.5 x ULN (or direct bilirubin normal in subjects with total bilirubin /> 1.5 ULN). Except in cases of Gilbert`s disease.
• 3. Creatinine clearance greater than 30 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation.
• 11. Absence of active uncontrolled infection, heart failure or severe psychiatric or neurological disease.
• 12. Females of childbearing potential may participate provided they have a negative serum pregnancy test at screening and a negative serum OR urine pregnancy test within two weeks of starting on treatment.
• 13. Females of reproductive potential should use effective contraception during the study, and for 6 months after last dose of azacitidine. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after.
• Exclusion Criteria:
• 1. Patients with acute promyelocytic leukemia (APL) or relapsed/refractory AML 2. Blast crisis of chronic myeloid leukemia 3. Patient with 5% blasts or more by flow or bone marrow aspirate differential (or IHC if no aspirate available) 4. Patient without count recovery (CBC less than CRh) 5. Patient has received previous therapy with a venetoclax containing regimen. 6. Patient has presence of any other condition that may increase the risk associated with study participation, and in the opinion of the investigator, would make the patient inappropriate for entry into the study.
• 7. Patient has active uncontrolled systemic fungal, bacterial, or viral infection.
• 8. Patient had recent, significant venous or arterial thrombotic event that would necessitate full anticoagulation or dual anti-platelet therapy, including PE within 30 days prior to start of treatment or insertion of drug eluting stent within 6 months prior to start of treatment. Chronic indications for anticoagulation such as atrial fibrillation, can be included if CHADS2 score below 4.
• 9. Patient has mechanical heart valve. 10. Patient had recent significant hemorrhagic episode, at the discretion of investigator.
• 11. Patient has significant active cardiac disease within 6 months prior to start of study treatment.
• 12. Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
• 13. Female subject who is pregnant or lactating.

Критерии исключения

Описание

A Clinical Study on the Safety and Effectiveness of targeting CD33 CAR-T Cell in the treatment of Relapsed/Refractory Acute Myeloid Leukemia

Критерии включения

• * 1. Male or female, age ≥ 18 years old;
• * 2. CAR-T cells can be prepared normally, or who have failed to prepare autologous CAR-T cells (including the number of autologous lymphocytes /<1×10/^9 or the expansion during the preparation process is insufficient or cannot reinfusion);
• * 3. Patients diagnosed with CD33 positive acute myeloid leukemia (AML) through histological or immunological examination，and CD33 positive expression rate />80%;
• * 4. Complies with the 2016 WHO classification for AML diagnosis and meets the diagnostic criteria for recurrence and refractory acute myeloid leukemia in the "Chinese Guidelines for the Diagnosis and Treatment of relapsed and refractory acute myeloid leukemia (2017 edition)", and currently there are no clinically relevant treatments or suitable clinical trials for registration:
• * a) Diagnostic criteria for recurrent AML: After complete remission (CR), leukemia cells reappear in peripheral blood or primitive cells in bone marrow/>0.050 (excluding other reasons such as bone marrow regeneration after consolidation chemotherapy) or leukemia cell infiltration appears outside the bone marrow;
• * b) Diagnostic criteria for refractory AML: initial treatment cases that have failed to respond to two courses of standard protocol treatment; Patients who relapse within 12 months after consolidation and intensive treatment after CR; Patients who relapse after 12 months but fail conventional chemotherapy; Patients with 2 or more relapses; Persistent extramedullary leukemia;
• * 5. The number of primitive cells (promyelocytes and/or promyelocytes) in the bone marrow /> 5% (morphology) and/or /> 1% (flow cytometry detection);
• * 6. Total bilirubin ≤ 51 μmol / L, ALT and AST ≤ 3 times of the upper limit of normal value, serum creatinine ≤ 176.8 μmol / L；
• * 7. Echocardiography shows left ventricular ejection fraction (LVEF) ≥ 50%;
• * 8. There is no active pulmonary infection, and the oxygen saturation during air inhalation is more than 92%;
• * 9. The estimated survival time is more than 3 months;
• * 10. ECOG score was 0-2;
• * 11. Pregnant/lactating women, or male or female patients who have fertility and are willing to take effective contraceptive measures at least 6 months after the last cell infusion during the study period;
• * 12. Those who voluntarily participated in this trial and provided informed consent

Критерии исключения

• * 1. Patients with the history of epilepsy or other CNS disease;
• * 2. Patients with prolonged QT interval time or severe heart disease;
• * 3. Active infection with no cure;
• * 4. Active infection of hepatitis B virus or C virus ;
• * 5. Before using any gene therapy products;
• * 6. The proiferation rate is less than 5 times response to CD3/CD28 co-stimulation signal;
• * 7. Suffering from other uncontrolled diseases that the researchers consider unsuitable for joining;
• * 8. Infected with AIDS virus;
• * 9. Any situation that researchers believe may increase the risk to the subjects or interfere with the trial results.

Описание

This research is being conducted to determine a safe and effective dose of revumenib that can be given in combination with standard induction (initial therapy to induce a remission) + FLT3 targeted therapy (midostaurin) and a single cycle of post-remission therapy + FLT3 targeted therapy (midostaurin) to participants with newly diagnosed Nucleophosmin (NPM1) and FMS-like tyrosine kinase 3 (FLT3) mutated Acute Myeloid Leukemia (AML).

The names of the study drugs involved in this study are:

* Revumenib (SNDX-5613) (a type of menin inhibitor)
* Midostaurin (a type of multi-kinase including FLT3 inhibitor)
* Cytarabine (a type of antineoplastic agent)
* Daunorubicin (a type of antineoplastic agent)

Критерии включения

• * Patients with AML who are newly diagnosed according to the WHO 2022 Classification and previously untreated except for hydroxyurea. ATRA pretreatment for suspected APL for less than 5 days is allowed. Eligible patients with AML arising from an antecedent hematologic disease (AHD) including MDS, may have been treated for their prior hematologic disease (except for allogenic transplant).
• * Patients must be ≥ 18 and /< 75 years old.
• * Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.
• * Presence of FLT3-ITD and/or TKD mutation(s) AND NPM1 mutation in bone marrow or peripheral blood
• * Dose escalation phase only: Presence of any of the following adverse risk genetic characteristics:
• * 2022 ELN adverse risk genetic features:
• * t(6;9)(p23.3;q34.1)/DEK::NUP214
• * t(v;11q23.3)/KMT2A-rearranged
• * t(9;22)(q34.1;q11.2)/BCR::ABL1
• * t(8;16)(p11.2;p13.3)/KAT6A::CREBBP
• * inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1)
• * t(3q26.2;v)/MECOM(EVI1)-rearranged
• * -5 or del(5q); -7; -17/abn(17p)
• * Complex karyotype, monosomal karyotype
• * Mutations in either one of these genes: ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2
• * Mutated TP53
• * NPM1 + FLT3-ITD + DNMT3A mutation
• * LVEF ≥ 50% by MUGA or ECHO at screening.
• * Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min; determined by the Cockcroft Gault formula.
• * Adequate liver function as demonstrated by:
• * aspartate aminotransferase (AST) ≤ 2.5 × ULN/*
• * alanine aminotransferase (ALT) ≤ 2.5× ULN/*
• * total bilirubin ≤ 1.5 × ULN/* /* Unless considered due to leukemic organ involvement. Note: Subjects with Gilbert`s Syndrome may have a total bilirubin /> 1.5 × ULN per discussion with the Sponsor-Investigator
• * Resolution of adverse reactions to prior drug therapy (such as hydroxyurea) to ≤ grade 1
• * Eligible for intensive cytarabine/daunorubicin (7+3) chemotherapy based on the opinion of the treating physician.
• * Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug.
• * Females of childbearing potential (i.e., not postmenopausal for at least 1 year or not surgically sterile) must have negative results by a serum or urine pregnancy test performed within 7 days of day 1.
• * Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)
• * Consolidation should occur between 1-4 weeks following count recovery after induction and remission (must be confirmed by labs to document maximal response) is established. Subjects will receive medium intensity cytarabine -based consolidation in combination with midostaurin and revumenib if the following criteria are fulfilled.
• * an induction response /< 5% blasts in the bone marrow and ANC />1000 and PLT />75000 for whom documented path report is submitted.
• * sufficiently fit (performance status /<3)
• * resolution of any adverse reactions to no greater than grade 1 severity

Критерии исключения

• * Subject has acute promyelocytic leukemia, inversion (16), t(8;21) AML as described below. Contact Sponsor-Investigator with questions. Inversion 16 and t(8;21): CBF chromosomal abnormalities may be assessed by molecular (PCR), metaphase cytogenetics, or FISH.
• * Subject has known active CNS involvement with AML.
• * Subject has received a strong CYP3A4 inducer (APPENDIX C) within 7 days prior to the initiation of study treatment
• * Strong CYP3A4 inhibitors (APPENDIX C) are contraindicated except strong CYP3A4 inhibitor antifungal azole medications (systemic itraconazole, ketoconazole, posaconazole, voriconazole). For strong CYP3A4 inhibitor antifungal azole medications, the starting dose of revumenib has to be adjusted (Table 1).
• * QTc using Fridericia`s correction /[QTcF/]) /> 450 msec. Drugs that prolong QTc should be avoided if possible. A list of common QTc prolonging drugs and alternatives that are not QTc prolonging can be found in APPENDIX D.
• * Subject has tested positive for HIV (due to potential drug-drug interaction between antiretroviral medications and Midostaurin/revumenib). Note: HIV testing is not required.
• * Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV /[i.e., HBs Ag-, and antiHBs+/] are allowed.
• * Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
• * Subject has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
• * Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
• * Subject has chronic respiratory disease that requires continuous oxygen use.
• * Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
• * Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to uncontrolled systemic infection.
• * Subject has a history of other malignancies prior to study entry, with the exception of:
• * Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
• * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
• * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
• * Prior malignancies treated with (surgery+/- chemotherapy+/- radiation) that have remained disease free for at least two years after completion of therapy
• * Subject treated with any form of chemotherapy, immunotherapy, or investigative agent within 1 month of enrollment.
• * Patients who have had prior exposure to a menin inhibitor.

Описание

This phase I trial tests the safety, side effects, best dose and effectiveness of revumenib in treating patients with acute leukemia after allogeneic stem cell transplant. Revumenib is in a class of medications called menin inhibitors. Revumenib targets and binds to the protein menin, thereby preventing the interaction between menin and the mixed lineage leukemia protein. Disrupting this interaction prevents the activation of specific genes that fuel the development of leukemia cells and inhibits the survival, growth, and production of certain kinds of leukemia cells. Giving revumenib may be safe, tolerable, and/or effective in treating patients with acute leukemia after allogeneic stem cell transplant.

Критерии включения

• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HEMATOPOIETIC CELL TRANSPLANTATION (HCT) OR THOSE WHO HAVE UNDERGONE HCT: Documented informed consent of the participant and/or legally authorized representative
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Agreement to allow the use of archival tissue from diagnostic tumor biopsies; if unavailable, exceptions may be granted with study principal investigator (PI) approval
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant is willing and able to adhere to the study visit schedule and other protocol requirements
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Age: />= 2 years
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Have a date for transplant within the next 4 weeks or have received transplant within the last 4 months
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant was diagnosed with an acute leukemia as defined by the World Health Organization (WHO) 5th edition criteria for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute leukemia with ambiguous lineage
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant must meet one of the following disease characteristics:
• * Confirmed NPM1m AML with at least one of the following additional characteristics
• * FLT3-ITD co-mutation
• * Pre-transplant MRD+ disease by flow cytometry or real time polymerase chain reaction (qPCR)
• * Requires more than one AML induction regimen to acquire complete response (CR)1
• * In second or later complete remission
• * Confirmed KMT2Ar acute leukemia obtained by fluorescence in situ hybridization (11q23 MLL-break apart fluorescence in situ hybridization /[FISH/]) or next-generation sequencing (NGS)
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Any donor (sibling, unrelated, mismatched related/unrelated, cord and haploidentical) or graft source (peripheral blood /[PB/] stem cell or bone marrow /[BM/]) will be included
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Conditioning regimen: investigator`s choice based on center guidelines
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: GVHD prophylaxis: investigator`s choice based on center guidelines
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Patients receiving menin inhibitors prior to alloHCT are eligible
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Negative serum pregnancy test for female patients of childbearing potential who have already undergone alloHCT
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: If a female of childbearing potential, must be willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: If male of childbearing potential, must agree to use barrier contraception from the time of enrollment through 120 days following the last study drug dose
• * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant has an Eastern Cooperative Oncology Group (ECOG) =/< 2 or Karnofsky Performance Status (KPS) />= 70, or a Lansky Performance Score of />= 70 (if aged /< 18 years)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant must be eligible for alloHCT by City of Hope (COH) standard operating procedure (SOP) guidelines
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients should be in complete remission (CR) by day + 30 (± 7 days) post-HCT BM biopsy
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No evidence of active or uncontrolled infection at the time of start of revumenib therapy
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has an ECOG =/< 2 or KPS />= 70, or Lansky Performance Score of />= 70 if aged /< 18 years
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No active grade 2-4 acute GVHD (prednisone dose of =/< 0.5 mg/kg daily is allowed)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Hemoglobin (Hgb) />= 9. Transfusion or growth factors are not allowed to achieve these levels
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Platelets />= 75 thousand (k). Transfusion or growth factors are not allowed to achieve these levels
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients must be fully engrafted after HCT, defined as absolute neutrophil count (ANC) />= 500 for 3 days. Patients may NOT be given granulocyte colony-stimulating factor (GCSF) to meet eligibility criteria; however, they may receive GCSF after start of treatment
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No morphologic evidence of relapse post-HCT (pre-HCT MRD+ is)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant is between day + 50 and + 150 after first alloHCT with no morphologic evidence of relapse post-HCT
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Total bilirubin =/< 1.5 x upper limit of normal (ULN) (unless considered to be due to Gilbert`s syndrome)
• * Note: Participants who are /< 75 years of age may have a bilirubin of =/< 3.0 x ULN. Patients with abnormal liver function tests (LFTs) in the context of active GVHD will not be included
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Aspartate aminotransferase (AST) =/< 2.5 x ULN
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Alanine aminotransferase (ALT) =/< 2.5 x ULN
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: QTc using Fridericia`s correction (QTcF) =/< 450 msec (males) or =/< 470 msec (females)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Ejection fraction (EF) of />= 50% by echocardiogram or multigated acquisition (MUGA) scan
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Creatinine clearance of />= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula

Критерии исключения

• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Prior diagnosis of acute promyelocytic leukemia
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participants who are unable to take a strong CYP3A4 inhibitor such as voriconazole or posaconazole. Note: Patients must be taking a strong CYP3A4 inhibiting antifungal at least 7 days prior to starting revumenib cycle 1
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Patients requiring the concurrent use of medications known or suspected to prolong the QT/corrected QT (QTc) interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (e.g., diphenhydramine, famotidine, ondansetron, bactrim, tacrolimus, azoles)
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the investigator`s opinion might confound the results of the study, interfere with the patient`s participation for the full duration of the study, or is not in the best interest of the patient to participate
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant has detectable human immunodeficiency virus (HIV) viral load within the previous 6 months (must have viral load testing prior to study enrollment if participant has a known history of HIV 1/2 antibodies)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Active uncontrolled hepatitis B or C, defined as hepatitis B or C virus (HBV/HCV) surface antigen positive and HBV/HCV core antibody positive, with positive HBV/HCV deoxyribonucleic acid (DNA), or HBV/HCV positive core antibody alone with positive HBV/HCV DNA
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Hepatitis C, defined as positive HCV antibody with reflex to positive HCV ribonucleic acid (RNA)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Other active malignancy; patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Active grade II-IV acute GVHD, chronic GVHD (moderate or severe) and/or requiring systemic steroids with prednisone dose equivalent of />= 0.25mg/kg within 4 weeks of revumenib administration
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participants who are unable to take a strong CYP3A4 inhibitor such as voriconazole or posaconazole. Note: Patients must be taking a strong CYP3A4 inhibiting antifungal at least 7 days prior to starting revumenib in cycle 1
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (e.g., diphenhydramine, famotidine, ondansetron, bactrim, tacrolimus, and azoles)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Female participant who is pregnant or lactating
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has a malabsorption syndrome or other condition that precludes enteral route of administration
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has chronic respiratory disease that requires continuous oxygen, or significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect participation in this study
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Cardiac disease: any of the following within the 6 months prior to study entry:
• * Myocardial infarction
• * Uncontrolled/unstable angina
• * Congestive heart failure (New York Heart Association Classification class />= II)
• * Life-threatening or uncontrolled arrhythmia
• * Cerebrovascular accident
• * Transient ischemic attack
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Gastrointestinal disease:
• * Any gastrointestinal issue of the upper gastrointestinal (GI) tract likely to affect oral drug absorption or ingestion (e.g., gastric bypass, gastroparesis, etc.)
• * Cirrhosis with a Child-Pugh score of B or C
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: GVHD: Signs or symptoms of acute or cGVHD /> grade 0 within 4 weeks of enrollment. Patients may be on physiological doses of steroids

Описание

Evaluate the safety, tolerability , pharmacokinetics , and preliminary efficacy of ICP-248 in Combination with azacitidine in Patients with Acute Myelogenous Leukemia . This study consists of two parts: Part 1 dose escalation period and Part 2 dose expansion period.

Критерии включения

• * Eligible subjects must meet all of the following criteria:
• 1. Subject must have confirmation of diagnosis of AML, except for acute promyelocytic leukemia (APL) per 2016 World Health Organization (WHO) criteria.
• 2. Previously treated relapsed/refractory AML subjects per 2017 European Leukemia Net (ELN) criteria.
• 3. Treatment-naïve AML subjects should be:
• * ≥60 years of age;OR
• * ≥18 years and /<60 years will be eligible if the subject has at least one of the following co-morbidities, which make the subject unfit for intensive chemotherapy:
• 1. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 2 - 3;
• 2. History of congestive heart failure requiring treatment or Ejection Fraction (EF) ≤ 50% or chronic stable angina;
• 3. Clinically significant respiratory failure or diffusing capacity for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1)
• ≤ 65%;
• 4. Creatinine clearance ≥ 30 mL/min to /< 45 mL/min (calculated by Cockcroft Gault formula);
• 5. Total bilirubin /> 1.5 to ≤ 3.0 ×upper limit of normal (ULN);
• 6. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Sponsor medical monitor before study enrollment.
• 4. Subject must have a projected life expectancy of at least 12 weeks.
• 5. Subject must have adequate renal function as demonstrated by a creatinine clearance≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft-Gault formula.
• 6. Subject must have adequate liver function.

Критерии исключения

• 1. Previously treated subject, who are refractory to previous azacitidine-based therapy defined as failure to achieve CR/CRi/MLFS per 2017 ELN criteria or intolerable to previous azacitidine-based treatment defined as discontinuation from azacitidine-based therapy due to clearly documented toxicity.
• 2. Previously treated subject, who are refractory to previous BCL-2 inhibitor-based therapy defined as failure to achieve CR/CRi/MLFS per 2017 ELN criteria or intolerable to previous BCL-2 inhibitor-based treatment defined as discontinuation from BCL-2 inhibitor-based therapy due to clearly documented toxicity.
• 3. Subject has acute promyelocytic leukemia (French-American-British Class M3 AML) or AML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1.
• 4. Subject has known central nervous system (CNS) leukemia.
• 5. Subject has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.
• 6. Subject has a white blood cell count /> 25 × 109/L (Cytoreductive therapy for leucocytosis are permitted to meet this criterion).
• 7. The serologic status suggestive of active hepatitis B or C virus infection.
• 8. History of immunodeficiency, including a positive human immunodeficiency virus (HIV) antibody test.
• 9. Subjects have another active malignancy within the past 2 years before study entry, except for who have received curatively treated.
• 10. History of significant cardiovascular disease.

Описание

This study will be divided into 2 parts (Part 1 and Part 2). Part 1 will evaluate 2 doses of tagraxofusp (9 and 12 micrograms/kilogram/day /[μg/kg/day/]), used in combination with venetoclax and azacitidine, to determine the dose for Part 2. This determined dose, in combination with venetoclax and azacitidine, will then be further evaluated in Part 2 in 2 cohorts (TP53 mutated and TP53 wild type). Both parts will be conducted in participants with previously untreated CD123+ AML who are ineligible for intensive chemotherapy.

Критерии включения

• * Previously untreated with histological confirmation of AML by World Health Organization 2022 criteria and are ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age, or comorbidity.
• * Participant has any level of CD123 expression on blasts confirmed centrally by flow cytometry.
• * Must be considered ineligible for intensive chemotherapy, defined by the following:
• * ≥75 years of age; or
• * ≥18 to 74 years of age with at least 1 of the following comorbidities:
• * Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3.
• * Diffusing capacity of the lung for carbon monoxide of ≤65% or forced expiratory volume in 1 second ≤65%.
• * Baseline creatinine clearance ≥30 to /<45 milliliters/minute calculated by the Cockcroft Gault formula or measured by 24-hour urine collection.
• * Hepatic disorder with total bilirubin />1.5 x upper limit of normal.
• * Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Sponsor.
• * ECOG performance status:
• * 0 to 2 for participants ≥75 years of age, or
• * 0 to 3 for participants ≥18 to 74 years of age.

Критерии исключения

• * Participant has received prior therapy for AML.
• * Willing and able to receive standard induction therapy.
• * Treatment for an antecedent hematologic disease with a hypomethylating agent, venetoclax, tagraxofusp, purine analogue, cytarabine, intensive chemotherapy, chimeric antigen receptor-T therapy, or other experimental therapies.
• * AML with central nervous system involvement.
• Note: Other inclusion/exclusion criteria may apply.

Описание

The Phase I/II trial is to learn the safety, pharmacokinetics, and preliminary efficacy of BN104 taken twice daily combined with Intensive Chemotherapy or Venetoclax/Azacitidine in patients with acute myeloblastic leukemia.

Критерии включения

• * Have been fully informed about the study and have voluntarily signed the ICF;
• * Patients with newly diagnosed primary AML according to the 2022 World Health Organization (WHO) criteria (Groups A and B) or patients with relapsed/refractory AML who have been previously treated with menin inhibitor monotherapy (Group C) and have an intermediate or poor prognosis according to the 2022 ELN Risk Stratification, as well as a defined combination of NPM1 mutation or NUP98 rearrangement or KMT2A rearrangement
• * Peripheral blood leukocyte count ≤ 25 x 109/L (limited to patients enrolled in groups B and C, where hydroxyurea is allowed to control peripheral blood leukocyte count)
• * Aged 18 years or older;
• * ECOG (GroupA and B:0,1,2; GroupC:0,1,2,3)
• * For patients in group B, unfit for intensive chemotherapy is defined as:≥75 years of age or;Age ≥18 years and age /<75 years with any of the following co-morbidities;ECOG score of 2 or 3;Cardiac history: congestive heart failure requiring treatment, or ejection fraction ≤50%, or chronic stable angina;DLCO ≤ 65% or FEV1 ≤ 65%;Creatinine clearance ≥30 ml/min and /<45 ml/min;Liver injury total bilirubin /> 1.5 x ULN but ≤ 3 x ULN.
• * For patients in group C, previous failed treatment with menin inhibitors is required;
• * adequate hepatic, renal, and cardiac function, as defined:Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal range (ULN);Total bilirubin ≤ 1.5 x ULN/* and in patients with Gilbert disease, total bilirubin ≤ 3 x ULN;Creatinine clearance ≥ 45 ml/min/* as estimated by the Cockcroft-Gault formula (if /<45 ml/min, enrollment is allowed if creatinine ≤ 130 µmol/L); Left ventricular ejection fraction ≥ 45%/*; Note: In Phase II studies, ALT or AST may be relaxed to ≤5 x ULN if the investigator assesses that the elevated ALT or AST is due to leukemia invasion of the liver;For patients /<75 years of age enrolled in Group B, total bilirubin ≤ 3 × ULN, creatinine clearance ≥ 30 ml/min, or left ventricular ejection fraction /< 50% are allowed;
• * for patients with D-dimer test result /> 5×ULN in the screening period, relevant tests (e.g. review of coagulation function after a certain time interval, ultrasound of deep veins of the lower limbs, etc.) are required to exclude deep vein thrombosis, hypercoagulable state of blood and disseminated intravascular coagulation before enrollment;
• * expected survival of more than 12 weeks as judged by the investigator;
• * Be willing to attend study visits as required by the study protocol
• * female patients of childbearing potential or male patients whose female partners are of childbearing potential must agree to use an effective method of contraception, such as a double-barrier method of contraception, condoms, oral or injectable contraceptives, and intrauterine devices (IUDs), for the duration of the study and within 30 days of the last study dose. Postmenopausal women (/>45 years of age and menopause of more than 1 year) and surgically sterilized women are exempt from this condition.

Критерии исключения

• * have active central nervous system (CNS) leukemia;
• * a known history of clinically significant liver disease, including viral or other hepatitis or cirrhosis:Positive hepatitis B surface antigen (HBsAg) serology requires a negative hepatitis B virus (HBV) DNA test for enrollment; For patients with hepatitis C virus (HCV) antibody serology positive, a negative HCV RNA test result is required for enrollment.
• * known human immunodeficiency virus (HIV) infection;
• * pregnant (positive screening pregnancy test) or lactating females;
• * meet any of the following cardiac-related criteria:Hereditary long QT interval syndrome or QTcF /> 450 msec;Various clinically significant cardiovascular diseases, including acute myocardial infarction, unstable angina pectoris, coronary artery bypass grafting within 6 months prior to enrollment, congestive heart failure graded by the New York Heart Association (NYHA) as grade 2 or higher (inclusive);
• * the patient has suffered from other malignant tumors within the past 5 years, except for radically treated basal cell carcinoma of the skin, carcinoma in situ of the breast or carcinoma in situ of the cervix;
• * have received prior anti-leukemia therapy (for patients in Groups A and B), except for the following: use of hydroxyurea or leukocyte monocloning for control of white blood cell count, or treatment with all-trans retinoic acid due to initial suspicion of acute promyelocytic leukemia, or use of nondemethylating medications for the treatment of MDS
• * for patients in Group C, prior anti-leukemia therapy, including chemotherapy, radiotherapy, hormonal therapy, targeted therapy, or immunotherapy, administered less than 2 weeks or 5 half-lives (whichever is shorter) prior to the start of study treatment; for patients who have undergone autologous hematopoietic stem cell transplantation or CAR-T therapy within 60 days prior to the start of study treatment, or have not recovered from toxicity associated with ASCT or CAR-T therapy Exclusion will be required for those who have had an allogeneic HSCT within 100 days prior to the start of study treatment, or if the patient still has a combination of active acute and chronic graft-versus-host disease, or if the patient still requires immunosuppressive therapy;
• * pre-existing treatment with targeted menin (for Group A and B patients)
• * pre-existing non-hematologic toxicities that have not returned to grade 0 or 1 (except alopecia areata);
• * patients who have had a chest CT within 1 month prior to screening and suggestive of pulmonary nodules need to undergo T-SPOT (T-cell spotting test for tuberculosis infection) during the screening period, and those with positive results need to be excluded (no additional tests are required if no chest CT has been performed within 1 month prior to screening);
• * uncontrolled active infection:Patients with non-serious infectious complications (e.g., oral Candida infection or uncomplicated urinary tract infection, etc.) for which oral/topical anti-infective therapy is being applied may be enrolled;Patients with severe infections requiring hospitalization or intravenous antibiotic therapy within 14 days prior to enrollment, patients with no evidence of infection, and patients receiving prophylactic anti-infective, antifungal, or antiviral therapy for prolonged neutropenia may be enrolled;Patients treated with intravenous antibiotics or hospitalized for febrile neutropenia, but no evidence of infectious etiology is found, and patients with a normal temperature for more than 72 hours without antipyretic medication may be enrolled;
• * patients with known dysphagia, short bowel syndrome, gastroparesis, or other conditions that limit oral drug intake or gastrointestinal absorption;
• * patients with a history of severe allergy to menin inhibitors or hypersensitivity to any component of BN104
• * inadequate patient compliance with participation in this clinical study as judged by the investigator
• * any other disease, metabolic abnormality, physical examination abnormality, or clinically significant laboratory test abnormality that, in the judgment of the investigator, gives reason to suspect that the patient has a disease or condition that is inappropriate for the use of the study medication, or that will interfere with the interpretation of the results of the study, or that places the patient at high risk.

Описание

To investigate the safety and efficacy of the CVA regimen, composed of Chiglitazar Sodium in combination with Venetoclax and Azacitidine, in the treatment of patients with refractory/relapsed acute myeloid leukemia (R/R AML).

Критерии включения

• 1. Acute myeloid leukemia (AML) confirmed by histology. Relapsed or refractory AML, including: a) Refractory disease is defined as no remission after at least one prior treatment. b) Disease relapse is defined as 5% or more blasts in the bone marrow after remission. c) Patients with AML arising from myelodysplastic syndromes (including CMML) or myeloproliferative neoplasms (secondary AML, t-AML) are also eligible;
• 2. Age ≥18 years, male or female, with an expected survival of more than 3 months;
• 3. Estimated creatinine clearance ≥ 50 mL/min;
• 4. AST and ALT ≤ 3.0 x ULN (unless considered due to leukemia organ involvement), bilirubin ≤ 3.0 x ULN (unless considered due to leukemia organ involvement);
• 5. ECOG ≤ 2;
• 6. Subjects are non-pregnant or using contraceptive measures during treatment;
• 7. Capable of understanding and voluntarily providing informed consent.

Критерии исключения

• 1. Acute promyelocytic leukemia (APL);
• 2. Active central nervous system leukemia;
• 3. Patients with clinically significant QTc interval prolongation (males /> 450 ms; females /> 470 ms), ventricular tachycardia and atrial fibrillation, second-degree heart block, history of myocardial infarction and congestive heart failure within the year prior to enrollment, and patients with clinically symptomatic coronary heart disease requiring medication;
• 4. Active, uncontrolled severe infection;
• 5. Other non-myeloid malignancies within the past 2 years;
• 6. Mental disorders that would impede study participation;
• 7. Previous solid organ transplantation (pre-treatment with SCT is allowed, but not allowed if the patient has GVHD or is still receiving immunosuppressive/GVHD treatment);
• 8. Any other conditions that, in the opinion of the investigator, make the patient unsuitable to participate in this trial.

Описание

A Clinical Study to Investigate the Safety and Efficacy of CT0991 in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Критерии включения

• 1. Volunteer to participate in the clinical trial; Fully understand and are informed of this study and sign the informed consent form; Willing to follow and able to complete all trial procedures；
• 2. Age 18-75 years (inclusive), male or female；
• 3. Estimated survival /> 12 weeks;
• 4. Patients with relapsed or refractory AML as defined in the Chinese Guidelines for the Diagnosis and Treatment of Relapsed and Refractory Acute Myeloid Leukemia (Version 2023);
• 5. ECOG score 0-2;
• 6. Participants should meet the following test results (no ongoing ongoing supportive care): a)Left ventricular ejection fraction (LVEF) /> 50%; b)ALT ≤ 2.5 × ULN, AST ≤ 2.5 × ULN, total bilirubin ≤ 2 × ULN; c)Endogenous creatinine clearance ≥ 30 mL/min (creatinine clearance calculated using the Cockcroft-Gault formula); d) Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN and prothrombin time (PT) ≤ 1.5 × ULN.
• 7. Female participants of childbearing potential must have a negative serum pregnancy test at screening and before receiving cleansing, be willing to use a highly effective and reliable method of contraception for 1 year after receiving trial treatment, and be absolutely prohibited from donating eggs for 1 year after receiving trial treatment during the trial;
• 8. Male participants willing to use a highly effective and reliable method of contraception for 1 year following trial treatment if sexually active with a woman of childbearing potential. All male participants were absolutely prohibited from donating sperm for 1 year after receiving trial treatment during the trial.

Критерии исключения

• 1. The participant has any serious illness, laboratory abnormality, or psychiatric disorder that may impair the ability to receive or tolerate planned trial treatment; or the investigator judges that the participant `s participation in the clinical trial is not in his/her best interest (e.g., compromised health), or may hinder, limit, or confound protocol-specific assessments;
• 2. Participants were diagnosed with acute promyelocytic leukemia (APL), BCR-ABL positive leukemia (chronic myeloid leukemia in acute phase), secondary AML (other than MDS), central nervous system leukemia;
• 3. Participants with a history of epilepsy or other central nervous system disease;
• 4. Participants who have received autologous stem cell transplantation within 12 weeks or allogeneic stem cell transplantation within 6 months prior to screening;
• 5. Participant has clinically significant active GVHD or is receiving systemic corticosteroids for GVHD;
• 6. Participant has a second primary malignancy other than AML that has required treatment or has not been in complete remission within the past 2 years. The following cancers were considered curable, including nonmetastatic basal cell or squamous cell skin cancer, nonmetastatic prostate cancer, breast or cervical carcinoma in situ, and nonmuscle-invasive bladder cancer. Participants receiving ongoing hormonal therapy may be included in this trial at the discretion of the medical monitor in consultation with the investigator;
• 7. Participants had positive serology for human immunodeficiency virus (HIV) and syphilis, active hepatitis C virus (HCV) infection, or active hepatitis B virus (HBV) infection. Participants with a history of previously treated hepatitis B or C were allowed to be included in this trial if viral load could not be detected by qPCR and/or nucleic acid testing;
• 8. Major surgery within 14 days prior to washout or planned major surgery within 28 days after receiving CT0991 infusion. If required, the medical monitor and investigator must discuss to confirm whether the surgery is considered a major surgery before the participant is included in this trial;
• 9. Received anti-tumor therapy 14 days before Preconditioning, including chemotherapy, molecular targeted therapy;
• 10. Systemic therapeutic doses of glucocorticoids (defined as ≥ 20 mg prednisone or other equivalent per day) within 14 days prior to cleansing; however topical glucocorticoids such as topical dermal, eye drops, nasal sprays, inhalations, and physiologic replacement therapy doses of glucocorticoids are permitted ;
• 11. Vaccination with live attenuated vaccine or mRNA vaccine within 4 weeks prior to clear shower;
• 12. Allergic or intolerant to clear shower drugs and tocilizumab, or allergic to DMSO in cell infusion preparations, or previous history of other serious allergies such as anaphylactic shock;
• 13. Toxicities caused by previous treatment did not recover to Common Terminology Criteria for Adverse Events (CTCAE) ≤ Grade 1, except alopecia, peripheral neuropathy, and other events that were judged by the investigator to be unlikely to be cumulative toxicities due to clear shower or CT0991 infusion;
• 14. Pregnant or lactating women.

Описание

This phase I trial tests the safety, side effects, best dose, and effectiveness of 225Ac-DOTA-Anti-CD38 daratumumab monoclonal antibody in combination with fludarabine, melphalan and total marrow and lymphoid irradiation (TMLI) as conditioning treatment for donor stem cell transplant in patients with high-risk acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Radioimmunotherapy is treatment with a radioactive substance that is linked to a monoclonal antibody, such as daratumumab, that will find and attach to cancer cells. Radiation given off by the radioisotope my help kill the cancer cells. Chemotherapy drugs, such as fludarabine and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. TMLI is a targeted form of body radiation that targets marrow, lymph node chains, and the spleen. It is designed to reduce radiation-associated side effects and maximize therapy effect. Actinium Ac 225-DOTA-daratumumab combined with fludarabine, melphalan and TMLI may be safe, tolerable, and/or effective as conditioning treatment for donor stem cell transplant in patients with high-risk AML, ALL, and MDS.

Критерии включения

• * Documented informed consent of the participant and/or legally authorized representative
• * Assent, when appropriate, will be obtained per institutional guidelines
• * ≥ 60 years. Note: Patients ≥ 18 years and /< 60 years with HCT-comorbidity index (CI) ≥ 2 are also included
• * Karnofsky performance status ≥ 70
• * Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories :
• * Acute myelogenous leukemia:
• * Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5,5q-,-7,7q-,11q23-non t(9;11), inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease, OR
• * Patients with a complete morphological remission (CR) with minimal residual disease (MRD)-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetic after at least 2 prior induction therapies, OR
• * Patients with chemosensitive active disease defined as at least 50% reduction in their blast count after last treatment
• * Myelodysplastic syndrome in high-intermediate (int-2) and high-risk categories per Revised International Prognostic Scoring System- (IPSS-R)
• * Acute lymphocytic leukemia
• * Patients with de novo or secondary disease according to NCCN guidelines for ALL hypoploidy (/< 44 chromosomes); t(v;11q23): MLL rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p, OR
• * Patients with a complete response (CR) with MRD-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetics after at least 2 prior induction therapies, OR
• * Patients with chemosensitive active disease defined as at least 50% reduction in their blast count after last treatment
• * A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Patients must have a serum bilirubin ≤ 2.0 mg/dl (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Patients must have a serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Patients must have a serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) ≥ 50% (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Diffusion capacity of the lung for carbon monoxide (DLCO) /> 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Forced expiratory volume in 1 second (FEV1) /> 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy
• * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only)
• * DONOR SPECIFIC CRITERIA: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate mobilized peripheral blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched unrelated donor. DQ or DP mismatch is allowed per discretion of the principal investigator. City of Hope (COH) standards of practice (SOP) (B.001.11) will be used for allogeneic donor evaluation, selection, and consent. Donor screening will be in compliance with all requirements of Food and Drug Administration (FDA) regulation 21 CFR Part 1271 including donor screening for COVID-19 exposure or infection

Критерии исключения

• * Patients who had a prior allogeneic transplant
• * All patients with prior radiation treatment to the lung, liver, and kidney
• * Patients who have received prior radiopharmaceutical therapy
• * Inclusion of other patients with previous radiation exposure will be determined based on the radiation oncologist medical doctor (MD) principal investigator (PI) evaluation and judgement
• * For patients with leukemia or MDS: Patients may not have received more than 3 prior regimens, where the regimen intent was to induce remission
• * Receiving any other investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning
• * Patients should have discontinued all previous intensive therapy, chemotherapy, or radiotherapy for 2 weeks prior to commencing therapy on this study. Note: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted. These include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• * Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancers
• * Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
• * The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the investigator (treating physician) would place the recipient at unacceptable risk
• * Females only: Pregnant or breastfeeding
• * Any other condition that would, in the Investigator`s judgment, contraindicate the patient`s participation in the clinical study due to safety concerns with clinical study procedures
• * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Описание

This trial will evaluate whether luveltamab tazevibulin is well tolerated and active against a rare form of AML carrying a particular genetic abnormality called CBFA2T3::GLIS2 that arises in infants and children. To be treated in this trial children must have a leukemia which did not respond or recurred after prior treatment. Luveltamab tazevibulin is an antibody-drug conjugate, which brings tazevibulin, an anticancer drug, to a molecule called FOLR1, present on the surface of CBFA2T3::GLIS2 AML cells.

Критерии включения

• * AML with CBFA2T3::GLIS2 gene fusion centrally confirmed
• * Refractory or relapsed disease with ≥ 5% bone marrow involvement with leukemic blasts by morphology
• * Age /< 12 years.
• * Lansky performance of ≥ 50
• * Adequate organ functions

Критерии исключения

• * Active central nervous system (CNS) disease (CNS3)
• * Pre-existing clinically significant corneal disorders or constitutional diseases associated with an increased risk of AML treatment toxicities
• * Active or uncontrolled infections or other active severe intercurrent illnesses,
• * Prior treatment with a FOLR1- targeting ADCs or with ADCs that contain a tubulin inhibitor
• * History of allogeneic hematopoietic stem cell transplant or any organ transplant in the prior 84 days
• * Graft versus host disease (GVHD) of any grade or GVHD treatment with exception of low dose steroids

Описание

This phase I trial studies the side effects and best dose of TAK-243 in treating patients with acute myeloid leukemia or myelodysplastic syndromes with increased blasts that has come back (relapsed) or that is not responding to treatment (refractory). TAK-243 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Критерии включения

• * Diagnosis of AML or MDS with increased blasts (MDS-IB) assessed by local laboratory review according to the 2022 World Health Organization (WHO) criteria for myeloid neoplasms. Both patients with MDS-IB1 (5-9% bone marrow blasts) and MDS-IB2 (10-19% bone marrow blasts) are eligible.
• * Patients must have relapsed or refractory disease after receiving at least one prior line of therapy
• * AML-specific inclusion criteria: Patients with relapsed or refractory AML with />= 5% bone marrow blasts after receiving at least two courses of intensive induction chemotherapy (including, but not limited to, 7+3 regimen, fludarabine, cytarabine, idarubicin and filgrastim /[FLAG-Ida/] and mitoxantrone, etoposide, and cytarabine /[MEC/]) or 2 cycles of venetoclax-based lower intensity regimen (azacitidine plus venetoclax or low-dose cytarabine plus venetoclax), and without any other approved therapies available that would be more appropriate in the investigator`s judgment. Patients who have received only one course of intensive induction chemotherapy but are not eligible for a second course because of decreased performance status or clear disease progression may be eligible for participation after discussion with the study principal investigator (PI). Patients with concomitant extramedullary disease relapse are eligible to participate, but not patients with isolated extramedullary relapse without bone marrow disease.
• * MDS-specific inclusion criteria: Patients with relapsed or refractory MDS-IB with />= 5% bone marrow blasts after at least 4 cycles of hypomethylating agent (HMA)-based therapy or at least two courses of intensive induction chemotherapy and meet criteria for stable disease (SD), progressive disease (PD) or disease relapse according to the International Working Group 2023 response criteria for higher-risk MDS. Patients must not have access to any other approved therapies that would be more appropriate in the investigator`s judgment. Patients who have received less than 4 cycles of HMA-based therapy may be eligible to participate after discussion with the study PI if there is clear evidence of progression or intolerance to HMA-based therapy that precludes its continuation.
• * Patients must have recovered from the effects of any prior systemic therapy, radiotherapy or surgery:
• * Patients should not have received other investigational therapy within 2 weeks.
• * Patients should not have received standard chemotherapy within 1 week of administration of study drug; hydroxyurea administration (for leukocyte count control) is permitted.
• * Age />=18 years. Because no dosing or adverse event data are currently available on the use of TAK-243 in patients /<18 years of age, children are excluded from this study.
• * Eastern Cooperative Oncology Group (ECOG) performance status =/< 2 (Karnofsky />= 50%).
• * Serum bilirubin =/< 1.5 × institutional upper limit of normal (ULN).
• * Patients with a known history of Gilbert`s syndrome may enroll.
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase /[SGPT/]) =/< 3 × institutional ULN.
• * Serum creatinine /< 176 mcmol/L (2 mg/dL) OR
• * Creatinine clearance /> 60 mL/min based on the Cockcroft-Gault equation.
• * Documented normal cardiac function (/>= 50%) by echocardiogram or multi-gated acquisition (MUGA) scan.
• * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load withing 6 months are eligible for this trial.
• * For patients with evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
• * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• * The effects of TAK-243 on the developing human fetus are unknown and ubiquitin-activating enzyme inhibitors are known to be teratogenic. For this reason, female patients must be:
• * Postmenopausal (age-related amenorrhea />= 12 consecutive months or follicle-stimulating hormone /> 40 mIU/mL), for at least 1 year before the screening visit, OR
• * Surgically sterile (i.e., who had undergone hysterectomy or bilateral oophorectomy), OR
• If they are of childbearing potential:
• * Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
• * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence /[e.g., calendar, ovulation, symptothermal, postovulation methods/] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.) Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• * Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
• * Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
• * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence /[e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner/] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
• * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
• * Patients should have a minimum life expectancy of 1 month.

Критерии исключения

• * Patients with acute promyelocytic leukemia (APL) or AML with t(15;17)(q22;q12) - PML::RARA).
• * Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities /> grade 1), except anemia, neutropenia or thrombocytopenia of any grade and grade 2 peripheral neuropathy.
• * Presence of any other malignancy requiring active therapy.
• * Patients who are receiving any other investigational agents.
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAK-243.
• * Concomitant treatment with organic anion transport protein (OATP) and BCRP inhibitors or strong inducers/inhibitors of cytochrome P450 (CYP)3A4/5. Treatment with these agents must be discontinued at least 14 days prior to TAK-243 dosing. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• * Presence of an active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
• * Presence of active graft-versus-host disease (GVHD) or continued treatment with systemic immunosuppressive agents following allogeneic hematopoietic stem cell transplantation (HSCT).
• * Presence of any co-morbid condition that, in the opinion of the investigator, might compromise the patient`s safety, might interfere with participation in the trial or might interfere with the interpretation of trial results.
• * Pregnant and lactating/breast-feeding women are excluded from this study because TAK-243 is a UAE-inhibiting agent with the potential for teratogenic or abortifacient effects and there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with TAK-243. Females of child-bearing potential must have a negative serum pregnancy test within 7 days before enrollment and should not be lactating/breast-feeding. Breastfeeding should be discontinued if the mother is treated with TAK-243.
• * Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period.
• * Patients with uncontrolled coagulopathy or bleeding disorder.
• * Patients with known hepatic cirrhosis.
• * Patients with known active cardiopulmonary disease defined as:
• * Unstable angina withing 3 months prior to first dose of TAK-243;
• * Myocardial infarction (MI) within 6 months prior to first dose of TAK-243 (patients who had MI and/or coronary revascularization more than 6 months before screening and who are without cardiac symptoms may enroll);
• * Congestive heart failure (New York Heart Association /[NYHA/] Class III or IV;
• * Cardiomyopathy with left ventricular ejection fraction (LVEF) /< 50%;
• * Symptomatic pulmonary hypertension.
• * Presence of active central nervous system (CNS) involvement (patients with prior CNS leukemia who have negative CNS cytology and who receive periodic prophylactic intrathecal chemotherapy are eligible).
• * Patients with clinically significant arrhythmia:
• * History of ventricular fibrillation or torsade de pointes at any time,
• * Episode of grade />= 3 atrial fibrillation or flutter in the last 3 months, defined as symptomatic episode, requiring urgent intervention (cardioversion, pacemaker or ablation) or with life-threatening consequences.
• * Uncontrolled high blood pressure (i.e., systolic blood pressure />180 mm Hg, diastolic blood pressure /> 95 mm Hg).
• * Prolonged rate corrected QT (QTc) interval />= 480 msec, calculated using the Fridericia method.
• * Patients with known severe or very severe chronic obstructive pulmonary disease (defined as forced expiratory volume in one second (FEV1) less than 30% or less than 50% of predicted), interstitial lung disease, or pulmonary fibrosis.
• * Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
• * Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).
• * Patients with history of neutrophilic dermatosis (e.g. Sweet syndrome, pyoderma gangrenosum), relapsing polychondritis, polyarteritis nodosa and/or giant cell arteritis.
• * Patients with VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome) or any other autoinflammatory disease.

Описание

This phase Ib trial tests the safety, side effects, best dose and effectiveness of tagraxofusp in combination with azacitidine as maintenance therapy in treating patients with CD123 positive acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after a donor (allogeneic) hematopoietic cell transplant. An allogeneic hematopoietic cell transplant (HCT) is a type of transplant where the cancer patient receives cells from another person. Maintenance therapy is given after the transplant to prevent the cancer from coming back. Tagraxofusp is a drug that targets cells that have CD123 on their surface in order to kill the cancer cells to help prevent the cancer from coming back. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving tagraxofusp in combination with azacitidine may be safe, tolerable and/or effective maintenance therapy in patients with CD123 positive AML and MDS after an allogeneic HCT.

Критерии включения

• * Documented informed consent of the participant and/or legally authorized representative
• * Agreement to allow the use of archival tissue from diagnostic tumor biopsies.
• * If unavailable, exceptions may be granted with study principal investigator (PI) approval
• * Age: 18-75 years old
• * Eastern Cooperative Oncology Group (ECOG) ≤ 2
• * First or second allogeneic HCT-eligible patients with AML or MDS with high-risk cytogenetics per European LeukemiaNet (ELN) (AML) or Revised International Prognostic Scoring System (R-IPSS) (MDS); or by having active (morphological) or minimal residual disease (MRD)+ status at the time of HCT (by multicolor flowcytometry, cytogenetics or molecular testing) OR patients who underwent HCT for AML or MDS with high-risk cytogenetics per ELN (AML) or R-IPSS (MDS)
• * Positive for CD123 by flow cytometry of either peripheral blood or bone marrow aspirates at the time of diagnosis at any time-point prior to HCT. (Note: CD123 measurement will be conducted using the 10-color Beckman Coulter Navios XL flow cytometer. We will use CD123 PE /[Beckman Coulter #A32535/] to gate the abnormal population of interest. This population will be compared to the internal negative control population /[e.g., T-cells/]. If more than 20% of the abnormal population is positive relative to this control, it will be classified as positive.)
• * Any conditioning regiment or GVHD prophylaxis is allowed
• * Any donor (i.e., match related/unrelated, mismatched, haploidentical, etc.) or graft source (i.e., bone marrow, mobilized peripheral blood stem cells, etc.) is allowed
• * Prior treatment with CD123-therapy is allowed if no progression is documented on therapy
• * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy
• * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only)
• * STUDY MAINTENANCE TREATMENT: Complete response (CR) or MRD-positive on day 30 bone marrow biopsy (BMB) for disease assessment
• * STUDY MAINTENANCE TREATMENT: Patients must be fully engrafted after HCT before starting the first cycle of maintenance. Full engraftment is defined as absolute neutrophil count (ANC) of 500 or above for 3 days and platelet count of more than 20,000 without transfusion for 7 consecutive days
• * STUDY MAINTENANCE TREATMENT: ECOG ≤ 2
• * STUDY MAINTENANCE TREATMENT: No treatment with anti-CD123 therapy after allogeneic HCT
• * STUDY MAINTENANCE TREATMENT: No evidence of active or uncontrolled infection
• * STUDY MAINTENANCE TREATMENT: No active GVHD; prednisone dose of ≤ 10 mg/daily is allowed
• * STUDY MAINTENANCE TREATMENT: ANC ≥ 1.5 (within 7 days of day 1 of the cycle 1)
• * NOTE: Transfusion (red blood cells /[RBC/] or platelet) to achieve the above-mentioned counts is allowed
• * STUDY MAINTENANCE TREATMENT: Hemoglobin (HbG) ≥ 7 (within 7 days of day 1 of the cycle 1)
• * NOTE: Transfusion (RBC or platelet) to achieve the above-mentioned counts is allowed
• * STUDY MAINTENANCE TREATMENT: Platelet count ≥ 20K (within 7 days of day 1 of the cycle 1)
• * NOTE: Transfusion (RBC or platelet) to achieve the above-mentioned counts is allowed
• * STUDY MAINTENANCE TREATMENT: Total bilirubin ≤ 2 x upper limit of normal (ULN) (unless has Gilbert`s disease) (within 7 days of day 1 of the cycle 1)
• * STUDY MAINTENANCE TREATMENT: Aspartate aminotransferase (AST) ≤ 2.5 x ULN (within 7 days of day 1 of the cycle 1)
• * STUDY MAINTENANCE TREATMENT: Alanine aminotransferase (ALT) ≤ 2.5 x ULN (within 7 days of day 1 of the cycle 1)
• * STUDY MAINTENANCE TREATMENT: Serum albumin /> 3.2 (within 7 days of day 1 of the cycle 1) (note that albumin infusions are not permitted in order to enable eligibility but can be given after treatment starts)
• * STUDY MAINTENANCE TREATMENT: Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 7 days of day 1 of the cycle 1)
• * STUDY MAINTENANCE TREATMENT: If not receiving anticoagulants: International normalized ratio (INR) or prothrombin (PT) ≤ 1.5 x ULN (within 7 days of day 1 of the cycle 1)
• * If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
• * STUDY MAINTENANCE TREATMENT: Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 7 days of day 1 of the cycle 1)
• * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• * STUDY MAINTENANCE TREATMENT: The Patient should agree to use acceptable contraceptive methods for the duration of the time in the study, and to continue to use contraceptive methods for 6 months following the end of study therapy
• * STUDY MAINTENANCE TREATMENT: The patient may not have persistent clinically significant toxicities grade ≥ 1 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue)
• * STUDY MAINTENANCE TREATMENT: The patient has not received treatment with another investigational agent within 14 days of study entry
• * STUDY MAINTENANCE TREATMENT: The patient does not have clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication)
• * STUDY MAINTENANCE TREATMENT: The patient does not have uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study
• * STUDY MAINTENANCE TREATMENT: The patient does not have known active or suspected central nervous system (CNS) disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid
• * STUDY MAINTENANCE TREATMENT: The patient does not have uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements
• * STUDY MAINTENANCE TREATMENT: The patient does not have any condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities

Критерии исключения

• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents (tagraxofusp and azacitidine)
• * Females only: Pregnant or breastfeeding
• * Any other condition including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness, that would, in the Investigator`s judgment, contraindicate the patient`s participation in the clinical study due to safety concerns with clinical study procedures
• * The patient has an active malignancy and/or cancer history that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease
• * The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication)
• * The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study
• * The patient has known active or suspected central nervous system (CNS) disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid
• * Active hepatitis B or C or HIV infection
• * The patient has any condition which, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities
• * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Описание

This phase I trial tests safety, side effects and best dose of iadademstat with azacitidine and venetoclax for the treatment of patients with acute myeloid leukemia (AML) who have not receive treatment (treatment naive). Chemotherapy drugs, such as iadademstat and azacitidine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving iadademstat with azacitidine and venetoclax may be safe and tolerable in treating patients with treatment naive AML.

Критерии включения

• * Patients must have established and confirmed diagnosis of intermediate or adverse-risk AML according to the European LeukemiaNet 2022 classification criteria
• * Previously untreated AML excluding hydroxyurea and all-trans retinoic acid (ATRA). ATRA would only be used for suspected AML
• * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of iadademstat in combination with venetoclax and azacitidine in patients /< 18 years of age, children are excluded from this study
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• * Patient is able to swallow oral medications
• * Patient must have a body weight of at least 50 kg due to the use of flat doses
• * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) OR direct bilirubin ≤ ULN for patients with total bilirubin levels /> 1.5 x ULN or ≤ 3 x ULN if patient has Gilbert`s disease
• * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase /[SGOT/])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]) ≤ 3 × institutional ULN or /< 5 ULN if due to AML
• * Chronic kidney disease (CKD)-epidemiology collaboration (EPI) glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m/^2
• * Peripheral white blood cell (WBC) count /< 25 x 10/^9/L on day 1 prior to treatment initiation. Hydroxyurea for up to 2 weeks is allowed for cytoreduction until 24 hours prior to study treatment
• * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better. Patients with a troponin leak (i.e. elevated troponin levels at presentation without evidence of an active myocardial infarction (MI) are eligible
• * The effects of iadademstat on the developing human fetus are unknown. For this reason and because LSD1 inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, females of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 180 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males with female partners of child-bearing potential treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 180 days after the last dose of study medication. Women of child-bearing potential agree not to donate or freeze egg(s) during the course of this study or within 180 days after receiving their last dose of study drug. Male patients agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug
• * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Критерии исключения

• * Patients are willing and able to receive intensive induction chemotherapy
• * Patients have isolated myeloid sarcoma or acute promyelocytic leukemia (APL) French-American-British (FAB) M3
• * Patients who have not recovered from adverse events of grade 3 or more due to prior anti-cancer therapy (i.e., have residual toxicities /> grade 1) with the exception of alopecia
• * Patients who are receiving any other investigational agents
• * Patients who have active central nervous system (CNS) involvement by AML
• * Patients who have disseminated intravascular coagulopathy with active systemic bleeding or venous or atrial signs of thrombosis
• * Patients who require treatment while on study with concomitant drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline) except for drugs that are considered absolutely essential for the care of the patient and with appropriate treatment monitoring
• * Patients with manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of oral drugs. In addition, patients with enteric stomata are also excluded
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to iadademstat, azacitidine, mannitol, or venetoclax
• * Iadademstat Concomitant Medication Considerations: Patients are not allowed to receive prophylactic hematopoietic colony stimulating factors, any complementary or alternative medicine (any of various systems of healing or treating disease /[as non-prescription drugs, herbal medicine and homeopathy/])
• * Patients should not use strong CYP3A inhibitors with the exception of antifungals for which standard of care (SOC) dose modifications of venetoclax exist
• * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous. This includes, but is not limited to:
• * Myocardial infarction with evidence of residual abnormalities within 3 months prior to enrollment (Troponin leak alone not included if no residual dysfunction);
• * New York Heart Association (NYHA) Class III or IV heart failure;
• * Severe uncontrolled ventricular arrhythmias;
• * Electrocardiographic evidence of acute ischemia or active life-threatening conduction system abnormalities:
• * Since patients with AML frequently require supportive care with agents that affect the QTc, if clinically indicated, obtain an electrocardiogram (ECG) prior to enrollment
• * As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control (i.e., no signs of severe systemic inflammatory response that makes patient clinically unstable in the opinion of the investigator, and the patient is hemodynamically stable). Patients with uncontrolled infection shall not be enrolled until the infection is treated and brought under control
• * Pregnant women are excluded from this study because iadademstat is LSD1 inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with iadademstat, breastfeeding should be discontinued if the mother is treated with iadademstat. These potential risks may also apply to other agents used in this study

Описание

to observe the dose-limiting toxicity (DLT) of liposomal mitoxantrone hydrochloride injection combined with cytarabine and decitabine in the initial treatment of acute myeloid leukemia (AML), to explore the maximum tolerated dose (MTD) of the combined D-CMG regimen, and to evaluate its safety and efficacy

Критерии включения

• 1. Histologically confirmed acute myeloid leukemia (non-M3) that has not been previously treated and cannot receive standard cytarabine and anthracycline induction therapy due to age, comorbidities, or patient preference.
• 2. Aged 60-75 years, both male and female, with an expected survival time of more than 3 months.
• 3. Estimated creatinine clearance rate ≥ 30 mL/min.
• 4. AST and ALT ≤ 3.0 x ULN (unless considered due to leukemic organ involvement). Bilirubin ≤ 1.5 x ULN (unless considered due to leukemic organ involvement).
• 5. ECOG Performance Status ≤ 2.
• 6. Able to understand and voluntarily provide informed consent.

Критерии исключения

• 1. Acute promyelocytic leukemia (APL) and low-risk cytogenetics, such as t(8;21), inv(16), or t(16;16).
• 2. Active central nervous system leukemia.
• 3. History of myeloproliferative neoplasms (MPN), including myelofibrosis, primary thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation, and AML with BCR-ABL1 translocation.
• 4. HIV-positive patients and/or active HBV or HCV infection (as documented by positive HBV-DNA and HCV-RNA tests).
• 5. Clinically significant QTc prolongation (men /> 450 ms; women /> 470 ms), ventricular tachycardia, atrial fibrillation, second-degree heart block, history of myocardial infarction within the past year, congestive heart failure, and coronary artery disease requiring medication.
• 6. Active, uncontrolled severe infection.
• 7. History of other malignancies within the past 2 years, except for adequately treated in situ carcinoma of the cervix or breast; skin basal cell carcinoma or localized squamous cell carcinoma of the skin.
• 8. White blood cell count /> 25 x 10/^9/L. (This criterion can be met with hydroxyurea or leukapheresis.)
• 9. Mental impairment that would compromise the ability to participate in the study.
• 10. Any other situation in which the investigator believes that it would not be in the best interest of the patient to participate in the trial.

Описание

This phase I trial tests the safety, side effects, and best dose of imetelstat in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) that has not responded to previous treatment (refractory) or that has come back after a period of improvement (recurrent). Imetelstat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving imetelstat in combination with fludarabine and cytarabine may work better in treating patients with refractory or recurrent AML, MDS, and JMML.

Критерии включения

• * Patients must be ≥ 1 year and ≤ 18 years of age at the time of study enrollment
• * Patients, with or without down syndrome (DS), and with de novo acute myeloid leukemia, therapy-related AML, MDS or JMML and meet one of the following:
• * Second or greater relapse or refractory AML, including isolated extramedullary disease (EMD), but excluding isolated central nervous system (CNS) or isolated testicular relapse
• * First or greater relapse of MDS
• * First or greater relapse of JMML
• * For flow cytometry, it`s strongly recommended to enroll onto APAL2020SC or to send samples to Hematologics, Inc. Otherwise, assessments must be performed at a College of American Pathologists (CAP)/Clinical Laboratory Improvement Act (CLIA) certified lab that has expertise in AML.
• * For FISH/Karyotype, samples must be sent to a Children`s Oncology Group (COG)-approved Cytogenetics Lab
• * Bone marrow relapse AML:(patients must meet one of the following criteria to be defined as having relapsed disease)
• * A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing, or other molecular method
• * A single bone marrow with at least two tests showing ≥ 1% leukemic blasts; examples of tests include:
• * Flow cytometry showing ≥ 1% leukemic blasts by multidimensional flow cytometry (MDF)
• * Karyotypic abnormality with at least one metaphase similar or identical to diagnosis
• * Fluorescence in situ hybridization (FISH) abnormality identical to one present at diagnosis
• * Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and ≥ 1%
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ uL (i.e., a white blood cell /[WBC/] count ≥ 10,000/uL with ≥ 10% blasts or a WBC count of ≥ 5,000/uL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
• * Extramedullary relapse: Biopsy proven extramedullary disease after documented complete remission
• * Refractory disease AML: Following a re-induction cycle after a second relapse, or refractory to two reinduction attempts after first relapse with:
• * A single bone marrow sample showing ≥5% leukemic blasts by flow cytometry, FISH testing, or other molecular method
• * A single bone marrow with at least two tests showing ≥1% leukemic blasts: examples of tests include:
• * Flow cytometry showing ≥1% leukemic blasts by multidimensional flow cytometry (MDF)
• * Karyotypic abnormality with at least one metaphase similar or identical to diagnosis.
• * FISH abnormality identical to one present at diagnosis
• * Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and ≥ 1%
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ uL (i.e., a WBC count ≥ 10,000/uL with ≥ 10% blasts or a WBC count of ≥ 5,000/uL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
• * Extramedullary refractory disease:
• * Biopsy proven persistent extramedullary disease
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ µL (i.e., a WBC count ≥ 10,000/μL with ≥ 10% blasts or a WBC count of ≥ 5,000/μL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
• * Central nervous system disease: Patients with relapsed or refractory disease with central nervous system (CNS) 1 and CNS 2 status are eligible
• * MDS: Bone marrow relapse:(patients must meet one of the following criteria to be defined as having relapsed disease)
• * A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, FISH testing, or other molecular method
• * A single bone marrow with at least two tests showing ≥1% leukemic blasts; examples of tests include:
• * Flow cytometry showing ≥ 1% leukemic blasts by multidimensional flow cytometry (MDF)
• * Karyotypic abnormality with at least one metaphase similar or identical to diagnosis
• * FISH abnormality identical to one present at diagnosis
• * Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of MDS associated lesion identical to diagnosis and ≥ 1%
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy
• * JMML: Diagnosis: Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease. The diagnosis is made based on the following criteria
• * JMML category 1 (all of the following):
• * Splenomegaly
• * /> 1000 (1x10/^9 /uL) circulating monocytes
• * /< 20% Blasts in the bone marrow or peripheral blood
• * Absence of the t(9;22) or BCR/ABL fusion gene
• * The diagnostic criteria must include all features in category 1 andeither (i) one of the features in category 2 or (ii) two features from category 3 to make the diagnosis
• * JMML category 2 (at least one of the following if at least two category 3 criteria are not present):
• * Somatic mutation in RAS or PTPN11
• * Clinical diagnosis of NF1 or NF1 gene mutation
• * Homozygous mutation in CBL
• * Monosomy 7
• * JMML category 3 (at least two of the following if no category 2 criteria are met):
• * Circulating myeloid precursors
• * White blood cell count, />10 000 (10x10/^9 / uL)
• * Increased hemoglobin F for age
• * Clonal cytogenetic abnormality
• * Granulocyte-macrophage-colony-stimulating factor {GM-CSF) hypersensitivity
• * Patients with relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid (DNA) hypomethylating agent with persistence of disease, defined by clinical symptoms or the presence of a clonal abnormality. Frontline therapy is defined as one cycle of intravenous chemotherapy that includes of any of the following agents: fludarabine, cytarabine, or any anthracycline but specifically excludes oral 6-mercaptopurine. Frontline therapy will also include any conditioning regimen as part of a stem cell transplant. Patients who transform to AML at any point with more than 20% blasts are eligible for this trial per the AML specific criteria
• * Patient`s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky (≥ 50) for patients /> 16 years of age and Lansky for patients ≤ 16 years of age (≥ 50)
• * Patients must have fully recovered (grade /< 2) from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required time frame, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• * Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: See DVLhomepage on the COG Members site for commercial and investigational agent classifications (https://cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyelosuppressiveAnti-CancerAgents.pdf). For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• * ≥ 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy
• * Note: Cytoreduction with hydroxyurea must be discontinued ≥ 24 hours prior to the start of protocol therapy
• * Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil (ANC) counts):
• * ≥ 7 days after the last dose of agent. See the DVL homepage on the COG Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research Ccoordinator prior to enrollment
• * Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade ≤ 1
• * Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
• * Interleukins, interferons and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon, or cytokines (other than hematopoetic growth factors)
• * Stem cell Infusions (with or without total body irradiation /[TBI/]):
• * Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: ≥ 84 days after infusion and no evidence of graft-versus-host disease GVHD
• * Patients must be off calcineurin inhibitors for at least 28 days prior to the date of enrollment. Patients may be on physiological doses of steroids (equivalent to ≤ 10 mg prednisone daily for patients ≥ 18 years or ≤ 10mg/m/^2/day /[up to a maximum of 10 mg/day/] for patients /< 18 years)
• * Autologous stem cell infusion including boost infusion: ≥ 30 days
• * Cellular Therapy: ≥ 30 days after the completion of any type of cellular therapy (eg, modified T cells, NK cells, dendritic cells, etc.)
• * External Beam Radiation (XRT)/external beam irradiation including protons: ≥ 14 days after local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to ≥ 50% of the pelvis; ≥ 42 days if other substantial bone marrow (BM) radiation
• * Radiopharmaceutical therapy (eg, radiolabeled antibody, 131I MIBG): ≥ 42 days after systemically administered radiopharmaceutical therapy
• * Patients must not have received prior exposure to imetelstat
• * For patients with leukemia:
• * Platelet count ≥ 25,000/uL (may receive platelet transfusions). These patients must not be known to be refractory to red cell or platelet transfusion
• * Hemoglobin />= 8.0 g/dL at baseline (may receive red blood cell (RBC) transfusions)
• * Adequate renal function defined as:
• * Estimated glomerular filtration rate (GFR) (eGFR) ≥ 70 mL/min/1.73 m/^2 "Bedside" Schwartz formula (2009): eGFR = 0.413 x (height /[cm/] / serum creatinine /[mg/dL/]) OR
• * a 24 hour urine creatinine clearance ≥ 70 mL/min/1.73 m/^2 OR
• * a GFR ≥ 70 mL/min/1.73 m/^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
• * Adequate liver function defined as:
• * Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
• * Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase /[ALT/]) ≤ 3 x ULN, unless attributed to leukemia involvement
• * AST ≤ 3 x ULN, unless attributed to leukemia involvement
• * Albumin ≥ 2 g/dL
• * Shortening fraction of ≥ 27% by echocardiogram, or
• * Ejection fraction of ≥ 50% by gated radionuclide study

Критерии исключения

• * Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, or because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control. Women of childbearing potential must use highly effective contraception in addition to a barrier method during treatment and for at least 1 month after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Male patients who can father a child should use contraception during treatment and for 3 months after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Imetelstat should not be administered to nursing mothers
• * Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid
• * Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
• * Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy
• * Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• * Specific to MDS patients: Low-grade MDS/refractory cytopenia of childhood (RCC) - MDS with less than 2% blasts in peripheral blood (PB) or less than 5% blasts in the bone marrow (BM) by morphology
• * Uncontrolled seizure disorder that is not stabilized with anti-convulsants
• * Patient has undergone surgery that requires general anesthesia within 3 weeks before enrollment (line placement/removal/revision or tissue collection is allowed)
• * Known hypersensitivity to the study drug or excipients of the preparation
• * Patients with acute promyelocytic leukemia (APL) with PML-RARA genetic abnormality according to World Health Organization (WHO) classification or t(15;17) are not eligible
• * Patients known to have a congenital bone marrow failure syndrome where increased risk of toxicity may be expected as judged by the Investigator, for example dyskeratosis congenita, are not eligible
• * Patients with isolated or refractory CNS or isolated or refractory testicular relapse are not eligible
• * Patients who have an uncontrolled infection are not eligible
• * Patients who have received a prior solid organ transplantation are not eligible
• * Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Описание

This phase I trial tests the safety, side effects, and effectiveness of olutasidenib in preventing the return of disease (relapse) in patients who have undergone donor (allogeneic) hematopoietic cell transplant for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML) carrying an IDH1 mutation. Olutasidenib is in a class of medications called IDH1 inhibitors. It works by slowing or stopping the growth of cancer cells. Giving olutasidenib may be safe, tolerable and/or effective in preventing relapse in patients with IDH1 mutated AML, MDS or CMML after an allogeneic hematopoietic cell transplant.

Критерии включения

• * Documented informed consent of the participant and/or legally authorized representative
• * Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with study principal investigator (PI) approval
• * Age: ≥ 18 years
• * Eastern Cooperative Oncology Group (ECOG) ≤ 2 or Karnofsky performance status (KPS) ≥ 70
• * Patients who are scheduled to receive or have already undergone allogeneic hematopoietic cell transplantation (alloHCT) from any donor type, any conditioning regimen, and regardless of GVHD prophylaxis will be include
• * Patients must have AML, MDS, or CMML with mIDH1 diagnosis at diagnosis (regardless of time from HCT). Note: Patient with pre-HCT disease relapse will no be included if mIDH1 is not detected after relapse
• * Day 30 marrow post alloHCT should show evidence of morphologic remission with /< 5% bone marrow (BM) blasts. Patients with MRD-positive status either by flow cytometry or IDH1 mutation testing will be eligible
• * Patients with previous therapy with IDH1 inhibitors will be included
• * Absolute neutrophil count (ANC) /> 1000/mm/^3 (within 28 days prior to day 1 of protocol)
• * Hemoglobin ≥ 8.0 gm/dL (within 28 days prior to day 1 of protocol)
• * Platelets ≥ 50,000/mm/^3 (within 28 days prior to day 1 of protocol) Note: Patients with lower counts can enroll if infection cytomegalovirus (CMV)/human herpes virus 6 (HHV6), etc. is being treated actively
• * Bilirubin ≤ 2 x upper limit of normal (ULN) (within 28 days prior to day 1 of protocol) (unless has Gilbert`s disease). Patients with abnormal liver function tests (LFTs) due to active GVHD will not be eligible
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]) ≤ 2 x ULN (within 28 days prior to day 1 of protocol). Patients with abnormal LFTs due to active GVHD will not be eligible
• * Creatinine clearance of ≥ 30/min/1.73 m/^2 for participants with creatinine levels above institutional normal per 24 hour urine test or the Cockcroft-Gault formula (within 28 days prior to day 1 of protocol)
• * Corrected QT interval (QTc) ≤ 480 ms (Note: To be performed within 28 days prior to day 1 of protocol therapy)
• * Seronegative for HIV antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV) (if positive, hepatitis C ribonucleic acid /[RNA/] quantitation must be performed), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin /[RPR/]) (within 28 days prior to day 1 of protocol)
• * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 28 days prior to day 1 of protocol). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• * Agreement by females and males of childbearing potential, defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only), to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

Критерии исключения

• * Patients with more than one allogeneic HCT
• * History of allergic reactions attributed to compounds of similar chemical or biological composition to study agent
• * Active diarrhea considered clinically significant and may impair oral drug administration
• * Clinically significant uncontrolled illness
• * Uncontrolled infection requiring systemic antimicrobials
• * Active infection: Patients with treated viral, bacterial or fungal infections that are controlled on therapy will be allowed to participate
• * Participant has detectable human immunodeficiency virus (HIV) viral load within the previous 6 months (must have viral load testing prior to study enrollment if participant has a known history of HIV 1/2 antibodies)
• * Active hepatitis B or C, or HIV
• * Other active malignancy. Participants with history of prior malignancy treated with curative intent who achieved CR more than 2 years before study entry are eligible. This exclusion rule does not apply to non-melanoma skin tumors and in-situ cervical cancer
• * Females only: Pregnant or breastfeeding
• * Active grade II-IV acute GVHD per Mount Sinai Acute Graft Versus Host Disease International Consortium (MAGIC) criteria and/or requiring systemic steroids with prednisone dose equivalent of ≥ 0.25 mg/kg at end of 4 weeks. Patients with a mild form of acute GVHD involving skin, gut or liver requiring topical steroid creams or oral beclomethasone (8 mg/day), entocort, (9 mg/day) and/or solumedrol (and equivalent prednisone) will be allowed
• * Any other condition that would, in the investigator`s judgment, contraindicate the patient`s participation in the clinical study due to safety concerns with clinical study procedures
• * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)