OncoTrials - мониторинг клинических исследований

Описание

A prospective study in which hematological oncology patients who were vaccinated against RSV will undergo a blood test to assess their immune response to the vaccine. As part of the study, hematological oncology patients with CLL, lymphoma, acute leukemia, myelodysplastic syndrome, and multiple myeloma, who are being monitored at the Hematology Institute at Ichilov, will be offered a blood test to evaluate their immune response to the RSV vaccine (serology, neutralizing antibodies, and cellular response). In the study, a blood sample of up to 10 ml will be taken in a chemistry tube and blood bank on the day of vaccination and about one month after that. The serological test will be conducted in the hospital`s virology laboratory. The test result and its significance will be communicated to the patient by the treating hematologist in our clinic. In this group of patients, a follow-up will be conducted over a 12-month period (during routine clinic visits) to document the incidence of RSV infection and complications related to the vaccine.

Критерии включения

• * Patients aged 60 years and older
• * Patients diagnosed with multiple myeloma(MM) or lymphoma or CLL or myelodysplastic syndrome (MDS) or acute leukemia

Критерии исключения

• * Patients who have been previously vaccinated against RSV
• * Patients who have experienced a severe reaction to any vaccine in the past

Описание

This is a multicenter, single-arm, open-label study to characterize long-term safety and tolerability of MY008211A tablets and to provide access to MY008211A tablets to patients with PNH who have completed Phase 2 or 3 studies with MY008211A tablets.

Критерии включения

• 1. Patients who have previously received and completed MY008211A study treatment, and are judged by the investigator to have treatment benefit and may benefit from continued treatment of MY008211A.
• 2. Prior vaccinations against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae infections.

Критерии исключения

• 1. History of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus.
• 2. Known or suspected hereditary complement deficiency.
• 3. Any comorbidity or medical condition (including but not limited to any active systemic bacterial, viral or fungal infection or malignancy) that, in the opinion of the investigator, could put the subject at increased risk or potentially confound study data.

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

Patients with graft failure or delayed engraftment may benefit from a hematopoietic stem cell boost or an additional hematopoietic stem cell transplantation procedure. In such settings standard immune suppression strategies are avoided due to their myelosuppressive nature. Therefore those patients are at increased risk of graft versus host disease, and the infusion of a CD34 selected graft would reduce such a risk. The infusion of CD34 selected graft using CliniMACS plus is currently FDA FDA-approved indication for acute myeloid leukemia. However, the use of the Prodigy would streamline the processing, in terms of hands-off procedure, allowing to provision of this product to the patients without strains on the cell therapy lab team. This procedure has been demonstrated safe and effective in several single-center studies and is currently in advanced phase investigation in several studies for malignant and non-malignant conditions.

Критерии включения

• 1. AML in morphologic remission with intermediate/high-risk features or relapsed disease 1 or 2
• 2. ALL in morphologic remission with high-risk features or relapsed disease 1 or 2
• 3. Lymphoid malignancies in CR or PR (e.g. non-Hodgkin`s lymphoma, prolymphocytic leukemia, CLL)
• 4. Myelodysplastic syndromes with /<=10% blasts
• 5. CML in morphologic remission after blast phase or accelerated phase
• 6. Primary myelofibrosis with /<=10% blasts /^morphologic remission is defined as /<5% blasts on the bone marrow biopsy. Negative test for donor-specific antibody within 28 days of starting conditioning regimen, or adequate for standard desensitization protocol.

Критерии исключения

• 1. Non-compliant patients.
• 2. No appropriate caregivers identified.
• 3. Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of the attending physician).
• 4. Patients with known allergy to DMSO.
• 5. Pregnant or breastfeeding women

Описание

In an effort to reduce graft versus host disease (GVHD) and enhance graft versus leukemia (GVL) effect post allogenic hematopoietic stem cell transplantation (AHSCT), recent research has focused on host immune cell depletion. Frame shifting anti-thymocyte globulin (ATG) backwards to earlier days before days 0 can result in deeper host and less graft T-cell depletion, leading to better immune reconstitution. Preliminary data where 80% of the ATG dose is given on days -6,-5,-4 and 20% given on day -1, showed effective prevention of severe acute GVHD, chronic GVHD and favorable early immune reconstitution. We hypothesize that our 2 step ATG dosing platform when combined with standard tacrolimus and mini methotrexate can prevent grade III-IV acute GVHD and chronic GVHD, resulting in improvement of GVHD/relapse free survival at one year post transplant.

Критерии включения

• 1. Adult male or female, age 18-75 years
• 2. Patients must have a related or unrelated peripheral blood stem cell donor. Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation. Unrelated donor must be 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells and be medically eligible to donate stem cells according to NMDP criteria.
• 3. A candidate for reduced intensity preparative regimen, based on age≥60, or HCT-CI of ≥4, or considered by the treating physician to have high risk for toxicity with myeloablative preparative regimen.
• 4. Cardiac function: Ejection fraction />40%
• 5. Measured creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
• 6. Pulmonary function: DLCO ≥50% (adjusted for hemoglobin) and FEV1≥50%
• 7. Liver function: total bilirubin /< 1.5x the upper limit of normal and ALT/AST /< 2.5x the upper normal limit. Patients who have been diagnosed with Gilbert`s Disease are allowed to exceed the defined bilirubin value of up to /<3mg/dl.
• 8. Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two effective methods of contraception or agree to complete abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
• 9. Male subjects (even if surgically sterilized), of partners of women of childbearing potential must agree to practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
• 10. Karnofsky performance status KPS ≥ 70
• 11. Patients must have a diagnosis of one of the following:
• A-AML with either detectable AML on pre AHSCT bone marrow (microscopic ≤5, flow or cytogenetic), or adverse cytogenetic, or molecular features (≥ 4 clonal abnormalities, or monosomal karyotype, inv(3)/t(3;3) or, EV11+, FLT3-ITD (+) without MPN1, P53 mutation positive, ASXL1+, mutant RUNX1.
• B- MDS with the following features: Residual blasts /> 5% blasts in the bone marrow after hypomethylating agents +/- venetoclax, MDS with high IPSS-R and monosomal karyotype, MDS with P-53 or JAK2 mutation.
• C-Myelofibrosis with blasts in the peripheral blood.
• 12. The subject is willing and able to signed informed consent and abide by the protocol requirements.

Критерии исключения

• 1. Autologous hematopoietic stem cell transplant /< 3 months prior to enrollment.
• 2. Patients with florid residual AML with /> 5% blast in the marrow or circulating blast in the peripheral blood are not eligible for this study.
• 3. Previous allogeneic stem cell transplant.
• 4. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.
• 5. Known hypersensitivity to one or more of the study agents
• 6. Received any investigational drugs within the 14 days prior to the first day of transplant conditioning
• 7. Pregnant and/or breastfeeding
• 8. Evidence of HIV infection or known HIV positive serology.
• 9. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
• 10. Patient with documented cirrhosis
• 11. Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma. Patients with prior malignancies except resected localized non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent /< 5 years previously must be reviewed and approved by the PI
• 12. Participation in another clinical study with an investigational product during the last 28 days.

Описание

This phase II MyeloMATCH treatment trial compares the usual treatment of cedazuridine-decitabine (ASTX727) to the combination treatment of ASTX727 and enasidenib in treating patients with higher-risk, IDH2-mutated myelodysplastic syndrome (MDS). ASTX727 is a combination of two drugs, decitabine and cedazuridine. 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. Enasidenib is an enzyme inhibitor that may stop the growth of cells by blocking some of the enzymes needed for cell growth. Giving ASTX727 in combination with enasidenib may be effective in treating patients with higher-risk IDH2-mutated MDS.

Критерии включения

• * GENERAL MYLEOMATCH MSRP REGISTRATION CRITERIA:
• * Patients must be registered to the Master Screening and Reassessment Protocol (MSRP) and assigned to this protocol by the MATCHBox Treatment Verification Team.
• * Participants must not have received prior anti-cancer therapy for AML or MDS.
• * Note: Hydroxyurea to control the white blood cell count (WBC) is allowed.
• * Note: Prior erythroid stimulating agent (ESA) is not considered prior therapy for the purposes of eligibility.
• * 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 is allowed.
• * REGISTRATION ELIGIBILITY CRITERIA (STEP 1)
• * Patients must have a morphologically-confirmed diagnosis of MDS with a Revised International Prognostic Scoring System (IPSS-R) score ≥ 4.
• * Patients must have a detectable pathogenic IDH2 mutation based on the National Cancer Institute (NCI) Myeloid Panel.
• * No prior treatment with deoxyribonucleic acid (DNA) methyltransferase inhibitors (ASTX727, azacitidine, or decitabine).
• * Prior treatment with growth factors (ESA, granulocyte colony-stimulating factor /[g-CSF/], TPO agonist), lenalidomide or luspatercept is allowed with a maximum limit of 1 month of exposure.
• * Age ≥ 18 years
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• * Total bilirubin ≤ 2.0 x upper limit of normal (ULN)
• * Unless elevated due to Gilbert`s syndrome. In patients with Gilbert`s syndrome if direct bilirubin is within normal limits, then they are eligible for enrollment.
• * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase /[SGPT/[) ≤ 3.0 x upper limit of normal (ULN)
• * Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m/^2
• * Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.
• * Therefore, for women of childbearing potential only, a negative pregnancy test done as part of screening lab work prior to registration is required.
• * 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.
• * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration 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.
• * RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)
• * Patients on the ASTX727 monotherapy arm (Arm A) that do not achieve a CR (complete response), CRL (CR with limited count recovery), or CRh (CR with partial count recovery) after completing 6 cycles of study treatment.
• * ECOG performance status ≤ 2
• * Total bilirubin ≤ 2.0 x upper limit of normal (ULN).
• * Unless elevated due to Gilbert`s syndrome. In patients with Gilbert`s syndrome if direct bilirubin is within normal limits, then they are eligible for enrollment.
• * AST (SGOT)/ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN)
• * GFR ≥ 30 mL/min/1.73m/^2
• * Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.

Критерии исключения

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

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

Myelodysplastic syndromes (MDS) are clonal diseases of hematopoietic stem cells (HSC) characterized by dysplastic and inefficient hematopoiesis related to excessive progenitor cell death. Ferroptosis is a recently described cell death mechanism and we think that it could be a major player in the pathophysiology of MDS, involved in the cell death that characterizes these diseases and contributing to cytopenias. The study aims to demonstrate that there is a significant activation of this phenomenon in MDS patients compared to a population of subjects without MDS.

Критерии включения

• For all :
• * Patients of legal age (age ≥ 18 years)
• * Subjects affiliated to or benefiting from a social security scheme
• * Free, written and informed consent signed by the participant and the investigator
• For MDS patients :
• * Sampling at diagnosis for MDS patients (WHO 2016 criteria)
• * Presence of ring sideroblasts on bone marrow smear
• For MGUS patients :
• - Sampling as part of the exploration of monoclonal gammopathy of undetermined significance (MGUS) for controls (WHO 2016 criteria).

Критерии исключения

• For all
• * Patient transfused with red blood cells within 120 days prior to collection
• * Patients treated with haematopoietic growth factors (EPO, TPO, G-CSF) within 30 days prior to collection
• * Patients with conditions that affect systemic iron metabolism: hemochromatosis, Gaucher disease, ferroportin disease, porphyria cutanea tarda
• * Person under a legal protection measure (legal protection, guardianship or curatorship)
• * Person deprived of liberty by judicial or administrative decision
• * Person who is unable to give consent
• * Subject who is in an exclusion period after another study or who has participated in another interventional drug study within 30 days prior to entry into the protocol

Описание

Somatic mutations as seen in myeloid malignancies can also be detected in healthy, elderly individuals (clonal hematopoiesis of indeterminate potential, CHIP), in patients with unex-plained cytopenia, that do not fulfill the criteria for myeloid malignancy (clonal cytopenia of un-determined significance, CCUS) It has been shown that these conditions predispose to hema-tological cancer. For patients with CCUS, it has been reported that in a 5-year period up to 50-90 % of the patients will progress to myelodysplastic syndrome (MDS) or acute myeloid leu-kemia (AML), both devastating diseases with poor outcomes, especially for the elderly popula-tion. There is currently no treatment available for patients with CCUS besides supporting agents. Since the somatic mutations can be detected up to 10 years before a diagnosis of MDS, it opens the potential for early intervention.

Physical inactivity is associated with multiple solid cancers, and it has been suggested that exercise can prevent for example certain colon- or breast cancers. Studies in mice have shown that exercise can reduce tumor size and incidence of solid cancers, and different mechanisms have been suggested including increased immune cell infiltration, reduced systemic inflamma-tion, and metabolic changes. The mechanisms of disease progression of pre-leukemia and MDS are complex and probably multifactorial, but recent studies suggest that components such as natural killer cells, adipocytes, and inflammatory substances in the bone marrow mi-croenvironment play a crucial role; factors that exercise may modulate. In addition, recent stud-ies have shown that increased bone marrow adipose tissue (BMAT) may create a microenvi-ronment that supports the expansion of leukemic cells and thus may facilitate disease progres-sion, and earlier studies among healthy, younger individuals have shown that exercise can reduce the amount of BMAT significantly.

Therefore, the investigators hypothesize that exercise may prevent or delay the progression from pre-leukemia to leukemia by altering the microenvironment in the bone marrow.

The purpose with this clinical, pilot trial where patients with the preleukemic condition CCUS or early stage of leukemia (i.e., lower-risk MDS) will undergo an individualized exercise interven-tion, is to investigate:

1. whether an exercise intervention and the trial set-up, are feasible and safe in this cohort,
2. potential mechanisms in leukemogenesis affected by exercise in controlling dis-ease progression,
3. and the effect hereof on quality of life and activities of daily living. The above will inform the decision-making on designing a larger randomized, controlled trial.

Критерии включения

• * A diagnosis of either Lower-risk of Myelodysplastic Syndrome or Clonal Cytopenia of undetermined significance(WHO 2022 Classification)
• * Written informed consent prior to study procedures
• * Performance status ≤ 2
• * Age /> 18 years old

Критерии исключения

• * Physically not able to undergo exercise intervention (e.g., arthrosis, physical disabilities)
• * Exercising on a regular basis (i.e., participants must score in the category "low" when screening with International Physical Activity Questionnaire-Short Form; IPAQ-SF27)
• * Unwillingness to undergo exercise intervention
• * Use of metformin
• * Treatment with chemotherapy, therapeutic radiation, or immunosuppressive therapy within the last year
• * Treatment with hypomethylating agents
• * Any absolute contraindication to undergo cardiopulmonary exercise testing according to working papers from American Heart Association and Danish Society of Cardiology
• * Hemoglobin levels /< 5.5 mmol OR /<6.5 mmol and simultaneous cardiac insufficiency OR pacemaker.
• * Blood transfusion-dependent ≥ 8 units of red blood cell transfusion in 16 weeks (IWG 2018-criteria)
• * Uncontrolled co-morbidity

Описание

The primary objective of this study is to evaluate efficacy of danicopan as add-on treatment to ravulizumab or eculizumab as assessed by hemoglobin (Hgb) change from Baseline at Week 12 in pediatric participants with paroxysmal nocturnal hemoglobinuria (PNH) and clinically significant extravascular hemolysis (CS-EVH).

Критерии включения

• * Confirmed diagnosis of PNH.
• * CS-EVH defined by: Anemia: Hgb ≤ 10.5 g/dL, and absolute reticulocyte count ≥ 100 × 109/L
• * Treated with ravulizumab or eculizumab for at least 12 weeks immediately preceding Day 1, the dose received should be stable during this period, and there should be no anticipated changes in dosage or interval during the first 12 weeks of this study.
• * all participants must be vaccinated against meningococcal infection from serogroups A, C, W, and Y and serogroup B within 3 years prior to, or at least 14 days prior to Day 1
• * vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae

Критерии исключения

• * Platelet count /< 30000/μL or there is a need for platelet transfusions.
• * ANC /< 500/μL.
• * Clinically significant laboratory abnormalities related to liver function, including:
• * ALT /> 2 × ULN or ALT /> 3 × ULN for participants with documented liver iron overload defined by serum ferritin values ≥ 500 ng/mL.
• * Direct bilirubin /> 2 × ULN, unless, in the Investigator`s opinion, is due to hemolysis or Gilbert`s syndrome based on medical history.
• * Current evidence of biliary cholestasis.
• * Known aplastic anemia or other bone marrow failure that requires HSCT or other therapies, including anti-thymocyte globulin and immunosuppressants unless the dosage of immunosuppressant has been stable for at least 12 weeks before Day 1 and is expected to remain stable through Week 12.
• * History of a major organ transplant (eg, heart, lung, kidney, liver) or HSCT.
• * Known or suspected complement deficiency.
• * Active bacterial or viral infection, a body temperature /> 38°C on 2 consecutive daily measures, evidence of other infection, or history of any febrile illness within 14 days prior to first study intervention administration.

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 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

A global multicenter, randomized, double-blind, placebo-controlled, pivotal phase III study. To evaluate overall survival (OS) of Lisaftoclax (APG-2575) combined with azacitidine (AZA) vs. placebo combined with azacitidine in newly diagnosed patients with HR-MDS.

Критерии включения

• 1. Newly diagnosed higher-risk MDS.
• 2. ECOG score of ≤2.
• 3. Expected survival ≥ 3 months.
• 4. Adequate organ function.
• 5. Female subjects of potential childbearing potential have a negative urine or serum pregnancy test before dosing. Subjects of childbearing potential as well as their partners voluntarily use contraception deemed effective by the investigator during the treatment period and for at least six months after the last dose of study drug.
• 6. Able to understand and voluntarily sign a written informed consent form, which must be signed prior to the performance of any trial-specified study procedures.
• 7. Subjects are able to complete study procedures and follow-up examinations.

Критерии исключения

• 1. Concomitant other malignancies or prior malignancies with disease-free intervals of less than 1 year at the time of signing the informed consent.
• 2. Have undergone hematopoietic stem cell transplantation.
• 3. Uncontrolled active infection
• 4. Use of moderately potent inducers and moderately potent inhibitors of CYP3A4 within 7 days prior to the first dose of study drug.
• 5. MDS or other conditions that cannot be administered enterally.
• 6. Any condition that the subject is deemed to be inappropriate to participate in this study after evaluation by the investigator.

Описание

To learn if olutasidenib can help to control CCUS, MDS, and/or CMML. The safety of the drug will also be studied.

Критерии включения

• 1. Pathologically proven CCUS or lower-risk MDS/CMML
• 1. CCUS is defined as the presence of cytopenia (absolute neutrophil count /< 1.8 x 109/L, hemoglobin /< 13 g/dL in males or /< 12 g/dL in females, and/or platelets /< 150 x 109/L) for at least 30 days that are otherwise unexplained and with no diagnostic hematopathologic features of myeloid neoplasms.
• 2. Lower-risk MDS/CMML includes patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk disease and Revised IPSS (IPSS-R) score ≤ 3.5 and Molecular IPSS (IPSS-M) very low-, low-, or moderate low-risk categories.
• 2. Participants must have a documented IDH1 mutation with VAF ≥ 0.02
• 3. Participants ≥ 18 years old
• 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Appendix A)
• 5. Acceptable liver function
• 1. Bilirubin ≤ 2 times upper limit of normal (ULN) or ≤ 3 times ULN in participants with Gilbert Syndrome
• 2. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase ≤ 3 times ULN
• 6. Acceptable renal function with serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance ≥ 50 mL/min (as assessed by Cockcroft-Gault, MDRD, or CKD-Epi validated measures)
• 7. Negative serum or urine pregnancy test if female of childbearing potential
• 8. For fertile men and women, agreement to use highly effective contraceptive methods for the duration of study participation and 90 days after the last dose of study medication. Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)
• 9. Agreement for male patients not to donate sperm and for female participants of childbearing potential not to donate ova during the study and for 90 days after the final dose of study drug
• 10. Ability and willingness to signed informed consent prior to beginning study and undergoing procedures

Критерии исключения

• 1. Participants unable to swallow oral medications, or patients with gastrointestinal conditions (e.g., malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption
• 2. Participants with any concurrent uncontrolled clinically significant medical condition, including life-threatening severe infection or psychiatric illness, which could place the patient at unacceptable risk of study treatment
• 3. Known active hepatitis B (HBV) or hepatitis C (HCV) or HIV infection
• 4. Pregnant or nursing women or women of childbearing potential not using highly effective contraception; male participants not using highly effective contraception as defined in the inclusion criteria
• 5. Participant with white blood cell count /> 25 x109/L Note: hydroxyurea use is permitted to meet this criterion with no washout required
• 6. Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care

Описание

The PNH-RECORD study, a Polish multicenter observational (non-interventional), open-label, retrospective with prospective follow-up.

Критерии включения

• 1. Adult (aged ≥18) patients with PNH receiving ravulizumab treatment in the frames of NDP in Poland.
• 2. Patients willing to participate in the study and signed ICF.

Критерии исключения

• 1. Those who participated in ravulizumab clinical trial in the past, and/or those who participated/plans to participate in clinical trial on/after the date of first ravulizumab infusion through NDP.
• 2. Cognitive incapacity, unwillingness or language barriers precluding adequate understanding or cooperation.

Описание

This is a phase I study with a primary objective of determining the recommended phase II dose of iadademstat with azacitidine in adult subjects with myelodysplastic syndrome (MDS).

Критерии включения

• 1. Male or female 18 years or older.
• 2. Patients must have a diagnosis of myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML) as defined by the World Health Organization (WHO) criteria.
• 3. Intermediate, high, or very-high risk by the Revised International Prognostic Scoring System (IPSS-R).
• 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (0-3 if performance status is considered due to MDS).
• 5. Patient must have a body weight of at least 50 kg.
• 6. Patient must meet the following screening clinical laboratory values as specified below:
• a. Hematologic: white blood cell (count) (WBC) below 30 x 109/L. Hydroxyurea can be used to achieve this level b. Hepatic: i. Total bilirubin ≤1.5 x upper limit of normal (ULN). Patients with Gilbert`s syndrome can enroll if conjugated bilirubin is within normal limits.
• ii. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN.
• c. Renal: Serum creatinine ≤1.5 x ULN.
• 7. Patient is able to swallow oral medications.
• 8. Female subjects who:
• 1. Are postmenopausal for at least one year before the screening visit, OR
• 2. Are surgically sterile, OR
• 3. If they are of childbearing potential:
• i. Agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through six months after the last dose of study drug (female and male condoms should not be used together), OR ii. 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, post-ovulation methods/], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception).
• iii. Agree to 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.
• 9. Male subjects, even if surgically sterilized (i.e., status post vasectomy), who:
• 1. Agree to practice effective barrier contraception during the entire study treatment period from the time of signing the informed consent through and through six months after the last dose of study drug (female and male condoms should not be used together), OR
• 2. 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, post-ovulation methods for the female partner/] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
• 3. Agree to not to donate or freeze sperm during the course of this study or within 180 days after receiving their last dose of study drug.
• 10. Ability to provide informed consent or have a legally authorized representative provide consent.

Критерии исключения

• A potential study subject who meets any of the following exclusion criteria is ineligible to participate in the study:
• 1. Prior therapy with hypomethylating agent or Lysine-specific histone demethylase 1A (LSD1) inhibitor. If patients were treated with any other agents having KDM1A/LSD1 inhibitory activity (such as tranylcypromine or phenelzine or similar drugs), they are only allowed if treatment finalized at least 3 weeks prior to first dose on study.
• 2. Patient will require treatment while on study with concomitant drugs that target the 5- hydroxytryptamine2B (5-HT2B) 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.
• 3. Treatment with systemic antineoplastic chemotherapy within 14 days or 5 half-lives from the last dose - whichever is sooner - before Cycle 1, Day 1 of therapy. Radiation within 14 days before Cycle 1, Day 1 of therapy. The use of hydroxyurea for leukoreduction is permitted. Similarly, prior ESA, luspatarcept, or lenalidomide is allowed. Subjects must have recovered from the side effects of prior therapy per the treating physician`s discretion.
• 4. Patient is on treatment with any investigational products within 3 weeks prior to the first dose of study treatment.
• 5. Patient has had major surgery within 4 weeks prior to the first study dose.
• 6. Patients with uncontrolled hypertension (i.e., systolic blood pressure />180 mm Hg, diastolic blood pressure />95 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle 1, Day 1 is allowed.
• 7. Patients with known poorly controlled diabetes (glycosylated hemoglobin (HbA1c) ≥8%) unless actively managed with appropriate therapy; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.
• 8. Patient has known active congestive heart failure New York Heart Association (NYHA) class 3 or 4 or patients with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 1 month prior to study entry demonstrates a left ventricular ejection fraction that is ≥40%.
• 9. Patients with known long QT Syndrome at screening.
• 10. History of allogeneic stem cell transplantation or CAR-T therapy within past 60 days.
• 11. Patient has evidence of active uncontrolled viral, bacterial, or systemic fungal infection (i.e., no signs of severe systemic inflammatory response that makes patient clinically unstable in the opinion of the investigator, and patient is hemodynamically stable, with sustained body temperature under 38°C for 48-72 hours before starting study treatment and does not need oxygen supplementation or pressors to maintain blood pressure). Patients with uncontrolled infection shall not be enrolled until the infection is treated and brought under control.
• 12. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease that may alter the absorption of iadademstat.
• 13. Pregnant or lactating / breastfeeding women.
• 14. Patient has any condition which, in the investigator`s opinion, makes the patient unsuitable for study participation. For example, any inter-current illness or social situation that will limit compliance with study requirements. Any serious underlying medical or psychiatric condition (e.g., alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to understand the informed consent form or that in the opinion of the investigator would contraindicate the patient`s participation in the study or confound the results of the study.
• 15. Patient presents a known contraindication to any of the treatment drug excipients.
• 16. Patient has known active hepatic disorder or is known to be positive for hepatitis B or C infection with the exception of those with undetectable viral load within 3 months (Hepatitis B or C testing is not required for eligibility assessment).
• 17. Patient is known to have human immunodeficiency virus infection. (HIV testing is not required for eligibility assessment).

Описание

The purpose of this study is to learn about the impact that the services and programs provided by the Leukemia and Lymphoma Society have among patients with blood cancer, such as access to care, quality of life, and financial burden.

Критерии включения

• * Be currently receiving primary or relapse treatment for a diagnosis of leukemia, lymphoma, myeloma, myelodysplastic syndromes (MDS), or myeloproliferative neoplasms (MPN)
• * Report experiencing at least one unmet need addressed by the LLS Program (i.e., medical care including second opinions, travel for care, clinical trial access, financial and insurance needs, supportive programs, disease and treatment education)
• * Not be currently participating in any LLS programs or services
• * Be willing to be followed for 6 months
• * Speak English or Spanish

Критерии исключения

• * Are not receiving primary or relapse treatment for a diagnosis of leukemia, lymphoma, myeloma, myelodysplastic syndromes (MDS), or myeloproliferative neoplasms (MPN)
• * Are not experiencing unmet needs addressed by the LLS Program (i.e., medical care including second opinions, travel for care, clinical trial access, financial and insurance needs, supportive programs, disease and treatment education)
• * Are currently participating in any LLS programs or services
• * Are not willing to be followed for 6 months
• * Do not speak English or Spanish.

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

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

To learn if olutasidenib, when combined with a drug called a hypomethylating agent (HMA) can help to control MDS, CMML, and/or MPN. The safety of the drug combination will also be studied.

Критерии включения

• 1. Pathologically proven higher-risk MDS/CMML or advanced MPN
• 1. MDS participants must have International Prognostic Scoring System (IPSS) intermediate-2- or high-risk disease or Revised IPSS (IPSS-R) score />= 3.5 or Molecular IPSS (IPSS-M) moderate high-, high-, or very high-risk disease or bone marrow blast percentage.
• 2. CMML patients must have CPSS-Mol int-1, int-2, or high-ris disease (Elena C et al, Blood 2016)
• 3. Advanced MPN is defined as bone marrow blast percentage />=/=10%.
• 4. Participants on the treatment-naive arm must not have received a prior HMA. Agents such as growth factors (e.g. erythropoietin stimulating agents, luspatercept, eltrombopag, granulocyte colony stimulating factors), cyclosporine, and/or hydroxyurea are allowed.
• 5. Patients on the previously-treated arm must have received a prior HMA and/or ivosidenib. Prior stem cell transplantation in allowed/>
• 2. Participants must have a documented IDH1 mutation
• 3. Patients with previously-treated MDS must be ineligible to receive treatment with ivosidenib or have progressed on treatment with ivosidenib.
• 4. Participants />=/= 18 years old
• 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Appendix A)
• 6. Acceptable liver function
• 1. Bilirubin /</= 2 times upper limit of normal (ULN) or /<;/= 3 times ULN in participants with Gilbert Syndrome
• 2. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase /</= 3 times ULN
• 7. Acceptable renal function calculated creatinine clearance />/= 50 mL/min (as assessed by Cockcroft-Gault, MDRD, or CKD-Epi validated measures)
• 8. Negative serum or urine pregnancy test if female of childbearing potential c. For fertile men and women, agreement to use highly effective contraceptive methods for the duration of study participation and 90 days after the last dose of study medication d. Agreement for male participants not to donate sperm and for female participants of childbearing potential not to donate ova during the study and for 90 days after the final dose of study drug
• 9. Ability and willingness to sign informed consent prior to beginning study and undergoing procedures

Критерии исключения

• 1. Participants unable to swallow oral medications, or participants with gastrointestinal conditions (e.g., malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption
• 2. Participants with any concurrent uncontrolled clinically significant medical condition, including life-threatening severe infection or psychiatric illness, which could place the participant at unacceptable risk of study treatment
• 3. Patients must have discontinued prior chemotherapy at least 1 week prior to the start of study treatment. Patients with MPN must be off JAK inhibitors at the start of study treatment
• 4. Patients with active graft-versus-host-disease (GVHD) status post stem cell transplantation, including active chronic GVHD requiring topical therapy. Patients must have discontinued calcineurin inhibitors at least 4 weeks prior to the start of study treatment
• 5. Known active hepatitis B (HBV) or hepatitis C (HCV) or HIV infection
• 6. Pregnant or nursing women or women of childbearing potential not using highly effective contraception; male participants not using highly effective contraception
• 7. Participants with white blood cell count /> 25 x109/L Note: hydroxyurea use is permitted to meet this criterion
• 8. Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care

Описание

The purpose of this study is to evaluate the efficacy and safety of HSK39297 tablets compared to eculizumab in Patients with PNH who Are Naive to Complement Inhibitor Therapy.

Критерии включения

• 1. Age ≥ 18 and ≤ 75 years, Male and female patients;
• 2. Diagnosis of PNH based on flow cytometry with clone size /> 10% by granulocytes;
• 3. Have not received complement inhibitor treatment;
• 4. Blood LDH values /> 1.5 ×upper limit of the normal range (ULN) ;
• 5. Hemoglobin level /< 10 g/dL at screening.

Критерии исключения

• 1. Hereditary or acquired complement deficiency;
• 2. Active primary or secondary immunodeficiency;
• 3. History of splenectomy, bone marrow/ hematopoietic stem cell or solid organ transplants;
• 4. History of recurrent invasive infections caused by encapsulated organisms( e.g. meningococcus or pneumococcus) or Mycobacterium tuberculosis;
• 5. Patients with laboratory evidence of bone marrow failure (reticulocytes /< 100x10/^9/L, or platelets /< 30x10/^9/L or neutrophils /< 0.5x10/^9/L) ;
• 6. Active systemic infection within 2 weeks prior to study drug administration;
• 7. History of serious comorbidities that have been determined to be unsuitable for participation in the study.
• 8. Pregnant or Lactating women.

Описание

This trial is a multi-center, single-arm, open-label phase III clinical trial. A total of approximately 35 patients with paroxysmal nocturnal hemoglobinuria who remained anemic despite stable use of C5 complement inhibitor (eculizumab/Kevacumab) for the first 6 months before randomization were included in the study. Approximately 40% of the subjects had received at least one red blood cell (RBC) transfusion within the first 6 months before receiving the experimental intervention. Subjects who met the criteria were all treated with HRS-5965 capsules. This trial includes an 8-week screening period, a 24-week treatment period, a 2-week dose reduction period, and a 4-week safety follow-up period.

Критерии включения

• 1. Understand the specific process of the experiment, voluntarily participate in this experiment, and sign a written informed consent form.
• 2. Age ≥18 on the day of signing the informed consent, regardless of gender
• 3. It was confirmed to be PNH during screening, and the clone size of red blood cells or granulocytes was detected by flow cytopy />10%
• 4. Stable use of C5 complement inhibitor ikuzumab/covalimab for the first 6 months of random treatment
• 5. The average hemoglobin level of at least two tests in 4 months before screening /< 10 g/dL
• 6. The average hemoglobin level of two tests in the central laboratory during screening /< 10 g/dL
• 7. Inoccution of Neisseris meningitis and Streptococcus pneumoniae vaccine at least 2 weeks before the first administration of HRS-5965; if HRS-5965 treatment must begin less than 2 weeks after vaccination, preventive antibiotic treatment must begin at least 2 weeks after vaccination.
• 8. Male and female subjects with fertility must agree to adopt efficient contraceptive measures with their partners within 30 days from the signing of the informed consent form to the last administration, and have no family planning and no sperm/egg donation.

Критерии исключения

• 1. In addition to C5 complement inhibitors (ikuzuzumab/covalimamab), those who have participated in clinical trials of any other drug or medical device within 1 month before and are expected to have a residual effect of experimental treatment (judged by researchers), or those who were still in the follow-up period of a clinical trial or the 5 half-life of the experimental drug before screening Inside (whichever is longer)
• 2. Known or suspected hereditary or acquired complement deficiency
• 3. Currently active primary or secondary immunodeficiency
• 4. Those who have a history of splenectomy or plan to perform surgery during the trial
• 5. History of bone marrow/hematopoietic stem cells or solid organ transplantation
• 6. Diagnosed malignant tumors in the past 5 years
• 7. There is laboratory evidence for patients with bone marrow failure during screening
• 8. History of infection with pod bacteria (such as Neisseris meningitis, Streptococcus pneumoniae, etc.)
• 9. There is or is suspected of systemic active bacteria, virus or fungal infection 2 weeks before the first administration of HRS-5965 (according to the researcher`s judgment)
• 10. Fever occurs within 1 week before the first administration of HRS-5965 (body temperature ≥38 ℃)
• 11. Human immunodeficiency virus (HIV) infection
• 12. Hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCVAb) are positive during screening, or abnormal liver function test during screening
• 13. Use any of the following drugs, unless there is a stable treatment plan before screening: a) erythropoietin (ESA), hypoxic-inducing factor proaminoyl hydroxylase inhibitor (HIF-PHI) or immunosuppressant for at least 8 weeks b) Systemic use of glucocorticoids (≤15 mg/day Prednisone or equivalent doses of glucocorticoids) at least 4 weeks c) Vitamin K antagonists (such as warfarin) have a stable international standardized ratio (INR) at least 4 weeks d) Low molecular weight heparin, oral anticoagulants such as aspirin, rvaroxaban, apifloxaban, etc. at least 4 weeks e) Iron supplements , vitamin B12, folic acid or androgen for at least 4 weeks
• 14. During screening, there are serious concurrent diseases, such as severe kidney disease (such as eGFR/<30 mL/min/1.73 m2, dialysis), advanced heart disease (such as NYHA level IV), severe lung disease such as pulmonary hypertension (WHO level IV) or liver disease (such as active hepatitis), etc. , judged by the researcher that it is not suitable to participate in the researcher
• 15. Any medical condition determined by the researcher that it may affect the patient`s participation in the trial, chronic anemia or unstable thrombosis events that may exist for other causes, and other conditions judged by the researcher to be unsuitable for participation in the trial
• 16. Those who are suspected of being allergic to experimental drugs or any ingredient in experimental drugs
• 17. Screening positive blood pregnancy test and breastfeeding women at the time of the visit

Описание

This study (KER-050-D301) is evaluating the efficacy and safety of elritercept (KER-050) versus placebo in adult participants with transfusion-dependent anemia with very low, low, or intermediate risk MDS, or more recently defined as myelodysplastic neoplasms, with or without ring sideroblasts. The study is divided into the Screening Period, Double-blind Treatment Period, Safety Follow-Up Period and Long-term Follow-up Period. Approximately 255 participants will be enrolled, randomized 2:1 to receive either elritercept or placebo.

Критерии включения

• * Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information and/or protected personal data in accordance with national and local study participant data protections and privacy regulations.
• * Male or female ≥ 18 years of age at the time of signing informed consent.
• * Diagnosis of MDS with or without RS (as determined in an evaluable bone marrow aspirate, read by an independent central reader to confirm diagnosis at Screening) according to the World Health Organization 2016 classification that meets the IPSS-R classification of very low, low, or intermediate risk disease.
• * Transfusion dependence assessed in the 16 weeks immediately preceding randomization in two 8-week blocks, classified as either:
• a. LTB, defined as 4 to 7 RBC units per 16 weeks; or b. HTB, defined as ≥ 8 RBC units per 16 weeks; and c. For all participants: i. Only transfusion events for a pretransfusion Hgb /< 10 g/dL are counted toward eligibility; ii. At least 1 transfusion event in each 8-week period and a minimum of 2 transfusion events separated by ≥ 7 days within the 16-week period immediately preceding randomization; and iii. No consecutive 56-day period can be RBC transfusion-free during the 16-week period immediately preceding randomization.
• * Refractory or intolerant to prior ESA treatment (discontinued ≥ 8 weeks before randomization), or unlikely to respond to ESA treatment, defined as follows:
• a. Refractory to prior ESA treatment: documentation of nonresponse or a response that was no longer maintained with a prior ESA-containing regimen, either as a single agent or combination (e.g., with granulocyte colony-stimulating factor /[G-CSF/]); ESA regimen must have been either: i. Recombinant human EPO ≥ 40,000 IU/week for ≥ 8 doses or equivalent; or ii. Darbepoetin alpha ≥ 500 μg every 3 weeks for ≥ 4 doses or equivalent.
• b. Intolerant to prior ESA treatment: documentation of discontinuation of a prior ESA-containing regimen, either as a single agent or combination (e.g., with G-CSF), at any time after introduction due to intolerance or an AE.
• c. Unlikely to respond to ESA treatment: low chance of response to ESA based on an endogenous serum EPO level /> 200 U/L.
• * Less than 5% blasts in an evaluable bone marrow aspirate collected at Screening, read by an independent central reader.
• * Eastern Cooperative Oncology Group performance status of 0 to 2
• * Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception
• * In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).

Критерии исключения

• * Del(5q) MDS or secondary MDS.
• * Anemia due to any other known cause (e.g., thalassemia, hemolytic anemia, bleeding events, or deficiency of iron, B12, and/or folate).
• * Receipt of RBC transfusion for any reason(s) other than underlying MDS within 16 weeks before randomization.
• * Clinically significant cardiovascular disease defined as:
• 1. New York Heart Association heart disease class III or IV;
• 2. Fridericia corrected QT (QTcF) interval /> 500 milliseconds during Screening;
• 3. Mean systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mm Hg during Screening; or
• 4. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before Screening.
• * Known ejection fraction /< 35%, confirmed by a local echocardiogram performed during Screening, or a previously performed echocardiogram if collected within 6 months before Screening.
• * Child-Pugh class C hepatic impairment
• * Stroke, deep vein thrombosis, or pulmonary embolism within 6 months before Screening
• * Any known history of AML
• * Prior history of malignancies, other than MDS, unless participant has been free of the disease (including completion of any treatment, including maintenance, for prior malignancy) for ≥ 5 years. However, participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
• 1. Basal or squamous cell carcinoma of the skin;
• 2. Carcinoma in situ of the cervix;
• 3. Carcinoma in situ of the breast; and/or
• 4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis /[TNM/] clinical staging system).
• * History of solid organ or bone marrow transplantation
• * Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 14 days before randomization
• * Known positive for HIV, active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
• * Body mass index ≥ 40 kg/m2
• * Major surgery within 28 days before randomization
• * History of allergy/anaphylaxis to investigational medicinal product (IMP) excipients (refer to the current elritercept IB for a list of excipients) or recombinant proteins.
• * Prior use of elritercept, luspatercept, or sotatercept.
• * Prior use of hypomethylating agents (HMAs), isocitrate dehydrogenase inhibitor, lenalidomide, imetelstat, or immunosuppressive therapy given for treatment of MDS.
• * Iron chelation therapy initiated within 8 weeks before randomization. Participants on stable doses of iron chelation therapy for ≥ 8 weeks are allowed.
• * Vitamin B12 or folate therapy initiated within 4 weeks before randomization. Participants on stable replacement doses for ≥ 4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
• * Androgen use within 8 weeks before randomization. Participants on stable androgen dosing for hypogonadism for ≥ 8 weeks are allowed.
• * High-dose corticosteroid use within 4 weeks before randomization. Participants on stable chronic steroid doses of prednisone ≤ 10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed.
• * Treatment with any investigational drug within 28 days before Screening or, if the half-life of the product is known, within 5 times the half-life before Screening, whichever is longer.
• * Ongoing participation in another interventional clinical study.
• * Serum EPO level /> 500 U/L
• * Platelet count ≥ 450 × 10/^9/L or ≤ 25 × 10/^9/L.
• * Absolute neutrophil count ≤ 500/mL
• * Serum aspartate aminotransferase or alanine aminotransferase ≥ 3 × the upper limit of normal
• * Total bilirubin ≥ 2 × ULN unless attributable to Gilbert`s syndrome
• * Ferritin ≤ 50 μg/L
• * Folate ≤ 2.0 ng/mL.
• * Vitamin B12 ≤ 200 pg/mL.
• * Estimated glomerular filtration rate /< 40 mL/min/1.73m2 as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (National Kidney Foundation 2021; Delgado 2022)
• * Pregnant or lactating female
• * Any other condition not specifically noted above that, in the opinion of the Investigator, would preclude the participant from participating in the study or could confound interpretation of data from the study.
• * Investigational site staff members directly involved in the conduct of the study and site staff members otherwise supervised by the Investigator, employees of the Sponsor or contract research organization (CRO) directly involved in the conduct of the study, or immediate family members (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
• * For Participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults (per applicable French law /[Art. L. 1121-6, Art. L. 1121-8, Art. L. 1121-8-1/]).

Описание

This is a multicenter, open-label study to evaluate the long-term safety, tolerability and efficacy of HSK39297. Adult patients with PNH who had previously received and completed HSK39297 study treatment will be included. Eligible subjects can maintain HSK39297 treatment until the end of the study.

Критерии включения

• 1. Patients With PNH who have previously received and completed HSK39297 treatment , and According to the researchers` judgment, the benefits of treatment outweigh the risks and may benefit from continued treatment with HSK39297;
• 2. Understand the study procedures and methods, voluntarily participate in this trial.

Критерии исключения

• 1. Hereditary or acquired complement deficiency;
• 2. Active primary or secondary immunodeficiency;
• 3. History of splenectomy, bone marrow/ hematopoietic stem cell or solid organ transplants;
• 4. History of recurrent invasive infections caused by encapsulated organisms( e.g. meningococcus or pneumococcus) or Mycobacterium tuberculosis;
• 5. History of serious comorbidities that have been determined to be unsuitable for participation in the study;
• 6. Pregnant or Lactating women.

Описание

Presently, multiparameter flow cytometry (MFC) and polymerase chain reaction (PCR) have been used for disease load, including measurable residual disease (MRD), monitoring in patients with myelodysplastic syndrome (MDS). MFC is the most commonly method for disease load evaluation. In patients with acute myeloid leukemia, leukemia stem cells (LSCs) determined using MFC for leukemia load and MRD detection is superior to traditional MFC method. In the investigators previous single center study, the investigators demonstrated that detection of disease load, including MRD, by MFC in patients with MDS-EB is superior to predict outcomes after allogeneic stem cell transplantation. Here, the investigators will perform a multi-center, prospective clinical trial to investigate the predictive values of MDS-SC in patients with MDS-EB who received allografting.

Критерии включения

• * Patients with Myelodysplastic syndromes;
• * Between 15 and 70 years old;
• * Subjects are able to provide written informed consent.

Критерии исключения

• * Subjects who cannot comply with the study;
• * Patient has severe cardiac (ejection fraction /<50%), hepatic (total bilirubin />34μmol/L, ALT, AST />2x upper limit of normal) or renal (blood creatinine />130μmol/L) disease；
• * Uncontrolled serious infection;
• * Other conditions that do not tolerate transplantation or other therapies.

Описание

This study will enroll participants with myelodysplastic syndromes (MDS) with an Isocitrate dehydrogenase protein, 1 (IDH1) mutation, who have not received treatment with a hypomethylating agent previously. Participants will be randomized to receive either ivosidenib (IVO) alone or azacitidine (AZA) alone. IVO will be administered daily throughout the 28-day treatment cycle and AZA will be administered for the first 7 days of each 28-day cycle. Study visits will be conducted every week during Cycle 1 (Days 1, 8, 15, and 22), and Day 1 of each cycle thereafter. After the last dose of treatment, participants will attend an safety follow-up visit and participants will be followed to assess overall survival. Study visits may include a bone marrow aspirate, physical exam, echocardiogram (ECHO), electrocardiogram (ECG), blood and urine analysis, and questionnaires.

Критерии включения

• * Diagnosis of HMA naive IDH1 R132 mutated MDS defined according to WHO criteria (5th edition):
• * Moderate high, high and very high-risk MDS per IPSS-M score will be eligible regardless of blood counts and with blast counts 0-19%.
• * Low and moderate low-risk MDS per IPSS-M score must:
• * Have cytopenias related to MDS, defined as: /<100 platelets/microliter, or absolute neutrophil count (ANC) /<1000/mm3, or hemoglobin /<10g/dL AND
• * Have a blast count between 5-19% AND
• * Be eligible for HMA therapy (very low risk participants are to be excluded)
• * Locally or centrally confirmed IDH1 R132 C/G/H/L/S mutation

Критерии исключения

• * Received prior anticancer/disease modifying treatment for MDS (including HMA`s, cytotoxic chemotherapy, investigational agents, bcl-2 inhibitor based-regimens, hematopoietic stem cell transplant (HSCT), IDH1 inhibitors). For LR-MDS patients, prior treatment with growth factors, luspatercept, lenalidomide, and imetelstat are allowed.
• * />20% blasts by morphology or immunohistochemistry on screening bone marrow aspirate/biopsy

Описание

By collecting interventional clinical data to assess the survival and relapse conditions of patients post-transplantation and comparing them with historical data, the primary study endpoint is the 1-year and 2-year relapse-free survival (RFS) post-transplantation. This includes the time from the start of treatment until the documentation of disease progression (bone marrow smear blast cells /> 5% or extramedullary relapse) or death due to any cause, whichever occurs first. This experiment aims to improve the post-transplant survival rates of MDS patients classified as very high risk under the IPSS-M stratification and to explore pathways to prevent relapse.

Критерии включения

• 1. Age between 18 and 70 years, inclusive, both male and female. Diagnosed with MDS according to WHO criteria and classified as very high-risk by IPSS-M scoring. The patient must have a suitable hematopoietic stem cell donor for allogeneic transplantation: Related donors must be at least 5/10 matched for HLA-A, -B, -C, -DQB1, and -DRB1
• 2. Unrelated donors must be at least 8/10 matched for HLA-A, -B, -C, -DQB1, and -DRB1. Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) score of ≤ 2. ECOG performance status of 0-2. Adequate liver, kidney, cardiac, and pulmonary functions as follows: Serum creatinine ≤ 1.5× upper limit of normal (ULN)
• 3. Cardiac function: Ejection fraction ≥ 50%
• 4. Baseline oxygen saturation /> 92%
• 5. Total bilirubin ≤ 1.5× ULN
• 6. ALT and AST ≤ 2.0× ULN
• 7. Pulmonary function: DLCO (corrected for hemoglobin) ≥ 40% and FEV1 ≥ 50%. Patients must be capable of understanding and willing to participate in the study, and must sign an informed consent form.

Критерии исключения

• 1. Failure to proceed with stem cell reinfusion after unsuccessful pre-transplant conditioning. History of previous hematopoietic stem cell transplantation (HSCT). ECOG performance status /> 2. Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) score ≥ 3. Any unstable systemic disease including, but not limited to: unstable angina, cerebrovascular accident or transient ischemic attack within the past 3 months, myocardial infarction within the past 3 months, congestive heart failure (New York Heart Association /[NYHA/] class ≥ III), post-pacemaker implantation requiring medication for severe arrhythmias, severe liver, kidney, or metabolic diseases
• 2. patients with pulmonary arterial hypertension. Active, uncontrolled infection: hemodynamic instability related to infection, new symptoms or signs of worsening infection, radiological evidence of new infectious foci, persistent fever without signs or symptoms that cannot exclude infection. Need for treatment for Grade ≥2 epilepsy, paralysis, aphasia, new cerebral infarction, severe brain trauma, dementia, Parkinson/'s disease, schizophrenia. HIV infection. Active hepatitis B (HBV) or hepatitis C (HCV) requiring antiviral treatment
• 3. patients at risk of HBV reactivation, indicated by positive hepatitis B surface antigen or core antibody without antiviral therapy for hepatitis B. Pregnant or breastfeeding women. Men and women of childbearing potential unwilling to use contraception during the treatment and for 12 months post-treatment. Allergic to intervention drugs such as azacitidine, decitabine, or venetoclax.

Описание

This is a Phase I dose finding study of GTB-3650 (anti-CD16/IL-15/anti-CD33) Tri-Specific Killer Engager (TriKE®) for the treatment of select CD33-expressing refractory/relapsed myeloid malignancies in adults ≥ 18 years of age who are not a candidate for potentially curative therapy, including hematopoietic stem cell transplantation, and are refractory to, intolerant of, or ineligible for therapy options that are known to provide clinical benefit. The hypothesis is GTB-3650 TriKE will induce natural killer (NK) cell function by targeting malignant cells, as well as, CD33+ myeloid derived suppressor cells (MDSC) which contribute to a tumor induced immunosuppression. Because CD16 is the most potent activating receptor on NK cells, this single agent may induce a targeted antiCD33+ tumor response

Критерии включения

• * Absolute lymphocyte count (ALC) ≥ 200 cells/µL OR absolute circulating CD56+/CD3- NK cell count />25 cells/µL within the 14 days prior to Cycle 1 Day 1.
• * Peripheral blasts ≤20,000 at the time of treatment start. Hydroxyurea may be used up to Day 1 of the 1st cycle to achieve this threshold and continued for the 1st two weeks of Cycle 1 to maintain it.
• * Adequate organ function within 14 days (30 days for cardiac) of Cycle 1 Day 1
• * Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 4 months after the last dose of GTB-3650. Non-childbearing is defined as />1 year postmenopausal or surgically sterilized.
• -For the Dose Finding Component Only: Must agree to stay within a 60- minute drive of the Study Center through the Cycle 1 Day 29 visit (end of the Dose Limiting Toxicity period).
• * Provides voluntary written consent prior to the performance of any research related activity.

Критерии исключения

• * Pregnant or breast-feeding. The effect of GTB-3650 TriKE on the fetus is unknown. Persons of childbearing potential must have a negative serum or urine test within 7 days prior to Cycle 1 Day 1 to rule out pregnancy.
• * A candidate for hematopoietic stem cell transplant (HSCT) or newly relapsed after HSCT (e.g. no post-HSCT therapy given).
• * Bi-phenotypic acute leukemia or mixed lineage leukemia.
• * Acute promyelocytic leukemia (APL).
• * New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan unless cleared for study by Pulmonary. Infiltrates attributed to infection must be stable/improving with associated clinical improvement after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections).
• * Active systemic infection requiring parenteral antibiotic therapy. Any prior systemic infections must have resolved following optimal therapy.
• * Known history of HIV.
• * Active Hepatitis B or Hepatitis C (virus detectable by PCR) - chronic asymptomatic viral hepatitis is allowed.
• * Positive test results from chronic hepatitis B infection (defined as positive HBsAg serology) and/or positive test results for hepatitis C (HCV antibody serology test).
• * Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer currently in complete remission, or any other cancer from which the patient has been disease-free for 1 year
• * Active central nervous system (CNS) malignancy or symptoms of CNS spread or administration of IT chemotherapy within 14 days prior to Day 1.
• * Extramedullary disease causing symptoms and/or involving the CNS or spinal canal - asymptomatic extramedullary disease outside the CNS and spinal canal is eligible provided the marrow has measurable disease.
• * Known autoimmune disease requiring active treatment or persons with a condition requiring systemic treatment with steroids (/> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days before Cycle 1 Day 1. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• * The potential risk of QT/QTc prolongation is unknown in humans receiving
• TriKE therefore either of the following is an exclusion criteria:
• * QTc interval /> 480 msec at screening
• * A family history of long QT syndrome
• * Psychiatric illness/social situations that, in the judgement of the enrolling Investigator, would limit compliance with study requirements.
• * Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study.

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

Why Is This Research Study Being Conducted?

* The study wants to find out why people with a type of blood cancer called myelodysplastic syndromes (MDS) are more likely to have heart problems like heart disease and stroke.
* Researchers also want to see if certain proteins related to inflammation in the body can help predict these heart issues in MDS patients.
* By understanding this better, researchers hope to find new ways to detect and manage heart disease risks in people with MDS

Критерии включения

• * Age ≥18 years
• * Histologically confirmed diagnosis of MDS by bone marrow biopsy morphology, using the 2022 World Health Organization (WHO) classification for myeloid neoplasms
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤3
• * Expected survival of at least 6 months
• * Ability to provide consent

Критерии исключения

• * Cases meeting 2022 WHO criteria of MDS with excess blasts 2 as initial diagnosis
• * Hematopoietic stem cell transplantation expected within 6 months

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 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)

Описание

The primary objective of this study is to describe the frequency and characteristics of pregnancy outcomes and maternal complications among participants exposed to Ultomiris and to describe the frequency and characteristics of selected fetal/neonatal/infant outcomes in utero, at birth, and through 1 year of age after exposure in utero or via breastmilk.

Критерии включения

• * Female participant must have a medically confirmed qualifying pregnancy (prospectively or retrospectively identified).
• * Participant informed consent (written or e-consent per local regulations or ethics committee requirements) must be obtained prior to the participant`s enrollment. If the participant is a minor, consent must be obtained from the parent or legal guardian, with assent from the minor (as locally appropriate).
• * Willing to provide contact information for the participant.
• * Willing to authorize HCP(s) to release maternal and infant medical information to the study, upon request, if applicable to current local regulations.
• * Diagnosed with an indication for which Ultomiris is approved, based on HCP or medical records.
• * Exposed to Ultomiris at any point during the defined exposure window based on HCP or medical record documentation. (If exact exposure dates are unknown, the reporter must be able to specify or estimate trimester or timing of exposure /[prior to conception as LMP+14 days, or during breastfeeding/].)
• * Use of Ultomiris per local product information (i.e., United States Prescribing Information /[USPI/] or summary of product characteristics /[SmPC/])

Критерии исключения

• * Participants who are unable to provide consent or assent (as locally appropriate) (e.g., diagnosed with severe psychiatric conditions or severe intellectual disabilities) will be excluded from this study

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