OncoTrials - мониторинг клинических исследований

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

To find a recommended dose of the combination of alpelisib and pembrolizumab that can be given to patients with metastatic breast cancer or melanoma.

Критерии включения

• 1. Patients must be 18 years or older.
• 2. Patients must be willing and able to provide informed consent.
• 3. In the dose escalation, patients must have histologically documented locally advanced, unresectable, or metastatic melanoma or TNBC that has progressed on treatments that are known to prolong survival or for which no standard treatment is available or refused such therapy. Presence of active brain metastases is not required. Patients with active metastases as defined below can be eligible in the dose escalation.
• 4. In the dose expansion, patients must have histologically documented locally advanced, unresectable, or metastatic melanoma or TNBC that has progressed on treatments that are known to prolong survival or for which no standard treatment is available or refused such therapy.
• 1. Melanoma patients without brain metastases who have progressed on an anti-PD-1 or anti-PD-L1-based regimen.
• 2. Melanoma patients with active and untreated brain metastases who have progressed on an anti-PD-1 or anti-PD-L1-based regimen.
• 3. TNBC patients (defined as ER /<1%, HER2 0, 1+, 2+, and fluorescence in situ hybridization negative) with active untreated brain metastases. Prior treatment with anti-PD-1/anti-PD-L1 is not required.
• 5. All patients must have had a brain magnetic resonance imaging (MRI) scan in the previous 28 days to confirm eligibility for the following cohorts:
• 1. Dose escalation and dose expansion Cohort 1: Confirmed absence of untreated brain metastases in patients with histologically confirmed advanced melanoma. Prior surgery for brain metastases must have been completed at least 4 weeks prior study treatment initiation, whole brain radiation therapy must have been completed at least 3 weeks prior to study treatment initiation, and stereotactic radiosurgery must have been completed within 7 days prior to study treatment initiation.
• 2. Dose escalation and dose expansion Cohorts 2 and 3: At least one confirmed measurable untreated brain lesion ≥ 0.5 cm and /< 3.0 cm in the longest axis.
• 6. Has measurable disease based on the RECIST v1.1.
• 7. Has adequate organ function as defined in Table 2:
• 8. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 4).
• 9. Has a life expectancy of at least 12 weeks.
• 10. Able to swallow and retain orally administered medication.
• 11. In the dose expansion, patients with EC disease must be willing to provide tissue from a newly obtained, safely accessible core or excisional biopsy lesion at pre-treatment and at least one time point while on study treatment. Correlative biopsies will be optional in the dose escalation portion of the study. Newly obtained biopsy is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of study treatment on Day 1 without intervening systemic therapy.
• 12. Women of childbearing potential (WOCBP) should have a negative urine pregnancy test within 72 hours prior to receiving the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• 13. Alpelisib and pembrolizumab can cause fetal harm when administered to a pregnant woman. Therefore, WOCBP must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of screening through 4 months after the last dose of study treatment. Refer to Pregnancy Assessment Policy MD Anderson Cancer Center (MDACC) Institutional Policy # CLN1114. This includes all female patients between the onset of menses and 55 years unless the patient presents with an applicable exclusionary factor such as one of the following:
• 1. Postmenopausal (no menses in ≥ 12 consecutive months)
• 2. History of hysterectomy or bilateral salpingo-oophorectomy
• 3. Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range and have received whole pelvic radiation therapy)
• 4. History of bilateral tubal ligation or another surgical sterilization procedure
• 14. Approved methods of birth control are as follows: hormonal contraception (i.e., birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation or hysterectomy, patient/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the study and the study treatment 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.
• 15. Male patients with partner(s) of childbearing potential must agree to use adequate contraception from the time of screening through 4 months after the last dose of study treatment.

Критерии исключения

• 1. Has a history of or active autoimmune disease, as follows: history of inflammatory bowel disease, history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis /[scleroderma/], systemic lupus erythematosus, autoimmune vasculitis /[e.g., Wegener`s granulomatosis/]), motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré syndrome and myasthenia gravis), or history of autoimmune thyroiditis (patients may be eligible if their current thyroid disorder is treated and stable with replacement or other medical therapy).
• 2. Has active infection or had a serious general medical condition(s) (such as vascular accident) in the past 6 months.
• 3. Any unresolved /> Grade 1 toxicity (per CTCAE v5.0) from previous anticancer therapy or previously administered agent at the time of enrollment, except for alopecia and Grade 2 anemia (if hemoglobin is /> 9 g/dL). Note: If the patient received major surgery, he/she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• 4. Patients who received chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to starting study treatment.
• 5. Presence of any clinically significant gastrointestinal abnormality or other condition(s) (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) that may alter absorption such as malabsorption syndrome or major resection of the stomach or substantial portion of the small intestine based on investigator discretion.
• 6. Previous major surgery within 14 days prior to enrollment.
• 7. Evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease).
• 8. Established diagnosis of diabetes mellitus type I or uncontrolled type II (based on fasting blood glucose and HbA1c /[see inclusion criteria #4/]).
• 9. History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
• 10. History of severe cutaneous reaction, such as SJS, erythema multiforme (EM), TEN, or drug reaction with eosinophilia and systemic symptoms (DRESS).
• 11. Based on average of triplicate 12-lead electrocardiogram (ECG), a mean resting QTc interval using Fridericia formula /> 450 msec for males and /> 470 msec for females at screening or a history of congenital long QT syndrome or QTc /> 480 msec for patients with a bundle branch block.
• 12. History or evidence of cardiovascular risk including any of the following:
• 1. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting within 6 months prior to enrollment.
• 2. Class III or IV heart failure as defined by the New York Heart Association functional classification system.
• 3. Known left ventricular ejection fraction /< 50%.
• 4. Known cardiac metastases.
• 13. Poorly controlled hypertension (defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure />100 mmHg based on a mean of three measurements taken at approximately 2-minute intervals).
• Note: Initiation or adjustment of antihypertensive medication(s) is permitted if done 30 or more days prior to enrollment.
• 14. For dose expansion Cohorts 2 and 3 with active brain metastases:
• 1. Patients must not have any of the following on the screening brain MRI:
• * Any untreated brain lesions /> 3.0 cm in size.
• * Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to the patient (e.g., brainstem lesions). Patients who undergo local treatment for such lesions may still be eligible for the study.
• 2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of dexamethasone (or equivalent) /> 4 mg.
• * Poorly controlled (/> 1/week) generalized or complex partial seizures, or manifestation of neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
• 15. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• 16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient`s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
• 17. Has known psychiatric or substance abuse disorder that in the opinion of the treating physician or principal investigator (PI) would interfere with cooperation with the requirements of the trial.
• 18. Known history of hepatitis B or C or positive test for human immunodeficiency virus.
• 19. Has received a live vaccine within 30 days of planned start of study treatment.
• Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; COVID-19 vaccines are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• 20. Current use of or anticipated requirement during the study of any prohibited medication(s) (See Section 5.5.2).
• 21. History of allergic reactions attributed to compounds of similar chemical or biologic composition to alpelisib and pembrolizumab.
• 22. Pregnant or nursing.

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/CMML 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. Advanced MPN is defined as bone marrow blast percentage />/=10%.
• 3. 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.
• 2. Participants must have a documented IDH1 mutation
• 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
• 9. 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
• 10. 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. 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
• 5. Participants with white blood cell count /> 25 x109/L Note: hydroxyurea use is permitted to meet this criterion
• 6. Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care

Описание

Adult patients with refractory or relapsed CD123+ hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or blastic plasmocytoid dentritic cell neoplasm will be recruited in the trial. CART123 cells will be manufatured from blood of each patient. During the production of CAR123 cells, patients may receive appropriate bridging therapy. After cells are produced, participants will undergo a single course of lymphodepleting chemotherapy and receive a single dose of CAR123 T cells. The trial will establish the recommended dose for further studies, either the Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD). Patients must be eligible for hematopoietic stem cell transplantation in order to participate in the trial.

Критерии включения

• 1. Patients with AML, MDS-IB2, BPDCN or ALL positive for CD123 antigen, who meet one of disease specific criteria below:
• a) Patients with AML will be eligible if they meet one of the following criteria:
• i) Patient with refractory AML defined as failure to achieve CR or CRi after at least 2 cycles of induction chemotherapy or 1 cycle of high dose salvage regimen or 4 cycles of venetoclax with azacytidine OR
• ii) Second or subsequent relapse of AML OR
• iii) Relapse after allogeneic HSCT.
• b) Patients with ALL will be eligible if they meet one of following criteria:
• i) disease refractory to or relapsed after CAR-19 cell therapy OR
• ii) CD19 negative relapse ineligible for treatment with TKI inhibitors and inotuzumab ozogamicin.
• c) Patients with BPDCN will be eligible if they meet following criteria:
• i) Refractory or relapsing after chemotherapy with or without allogeneic stem cell transplantation.
• d) Patients with MDS-IB2 will be eligible if they meet one of following criteria:
• i) Disease refractory to at least four cycles of azacytidine or progression on azacytidine-based therapy OR
• ii) Disease refractory to induction chemotherapy OR
• iii) Relapse after haematopoietic stem cell transplantation.
• 2. CD123 expression on malignant cells confirmed by flow cytometry or by immunohistochemistry.
• 3. Age between 18 and 70 years.
• 4. Patient has a suitable donor for allogeneic hematopoietic stem cell transplantation. Workup and clearance of the donor must be completed before IMP administration.
• 5. Patient able to understand and sign informed consent.
• 6. Women of child-bearing potential: negative pregnancy test at enrolment (PSV) and at Visit 1.
• 7. Patient for whom there are no standard-of-care treatments available or such treatment options have been exhausted.

Критерии исключения

• 1. Known hypersensitivity to any component of the IMP.
• 2. Allogeneic HSCT within 3 months prior to IMP administration.
• 3. Severe, uncontrolled active infection.
• 4. Life expectancy /< 8 weeks.
• 5. Respiratory insufficiency (need for oxygen therapy).
• 6. Significant liver impairment: bilirubin /> 50 µmol/L, AST or ALT /> 4 times normal upper limit.
• 7. Acute kidney injury with serum creatinine /> 180 µmol/L, oliguria or need for acute dialysis.
• 8. Heart failure with LVEF /< 50% by echocardiography.
• 9. Presence of active grade 3 - 4 acute GvHD or severe chronic GvHD.
• 10. Serious uncontrolled neurological comorbidity.
• 11. Vaccination with live virus vaccines in the 4 weeks before IMP administration and within 90 days after the IMP dose.
• 12. Women: pregnancy or breast-feeding.
• 13. Subjects of fertile age, unless permanent sexual abstinence is their lifestyle choice:
• 1. female patients of childbearing potential not willing to use a highly effective method of contraception during the study,
• 2. male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception during the study.

Описание

The primary objective of this study is to describe the response to treatment with biosimilar EPO alpha in MDS patients who had already been treated with "originator" EPO alpha and were responsive, and in patients who started treatment with biosimilar EPO alpha

Критерии включения

• MDS patients with symptomatic anemia (pre-treatment hemoglobin /< 10g/dL) who started treatment with biosimilar EPO alpha, diagnosed according to the WHO 2016 classification, and characterized by very low, low, or intermediate IPSS-R risk and a pre-treatment serum EPO level /< 500 U/L, who started treatment with biosimilar EPO alpha at the U. O. of Hematology of IRCCS AOUBO during the period from 01/06/2018 to 31/12/2021.
• * Age ≥ 18 years at the time of enrollment
• * Acquisition of informed consent to study participation and data processing

Критерии исключения

• * - Presence of other possible contributory causes of anemia (e.g., anemia from chronic inflammatory disease, hemolysis, hemorrhage)
• * Poor compliance with treatment
• * Very impaired general clinical condition (ECOG performance status /> 3)
• * Concomitant treatment with antineoplastic cytotoxic drugs

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 phase I trial tests the safety, side effects, and best dose of SM08502 (cirtuvivint) alone and in combination with ASTX727 in treating patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Cirtuvivint may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. ASTX727 is a combination of two drugs, decitabine and cedazuridine. 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. 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. Giving cirtuvivint alone or in combination with ASTX727 may be safe, tolerable, and/or effective in treating patients with AML and MDS.

Критерии включения

• * In Cohorts I and II, patients must have R/R AML and MDS (venetoclax naïve or venetoclax exposed)
• * Relapsed AML is defined as the appearance of 5% or greater myeloblasts in the bone marrow or peripheral blood after achieving a complete remission (CR), CR with partial hematologic recovery (CRh), or CR with incomplete hematologic recovery (CRi). Patients with mutations in FLT3, IDH1 or IDH2 must have failed or been intolerant of a Food and Drug Administration (FDA) approved FLT3, IDH1 or IDH2 inhibitor before enrolling on study
• * Refractory AML is defined as failure to achieve a CR, CRh, or CRi after one of the following regimens: (i) Two cycles of intensive induction chemotherapy with a cytarabine containing regimen (e.g., 7+3, mitoxantrone, etoposide, cytarabine /[MEC/], high-dose cytarabine /[HIDAC/], etc.) or, (ii) Two cycles of hypomethylating agent (HMA)/venetoclax or low-dose cytarabine (LDAC)/glasdegib or, (iii) Four cycles of HMA monotherapy
• * Relapsed MDS is defined as: (i) Intermediate, high, or very high-risk disease by International Prognostic Scoring System-Revised (IPSS-R) and, (ii) Any relapse after achieving any 2023 IWG MDS defined response
• * Refractory MDS is defined as: (i) Intermediate, high, or very high-risk disease by IPSS-R and /> 5% blasts in the bone marrow or peripheral blood, (ii) Failure to achieve a response (as per IWG 2006 criteria) after four cycles of HMA monotherapy, or (iii) Two cycles of HMA + venetoclax
• * In Cohort III, patients must have prior untreated high-risk MDS
• * MDS with /> 5% blasts in the bone marrow or peripheral blood AND
• * IPSS-R high or very high-risk disease OR
• * Molecular International Prognostic Scoring System (IPSS-M) high or very high-risk disease
• * No prior use of deoxyribonucleic acid methyltransferase inhibitor (DNMTi) therapy with the exception of one single cycle of DNMTi. Prior use of erythropoiesis stimulating agents (ESA), thrombopoietin agonists, lenalidomide, and luspatercept are allowed
• * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of SM08502 (cirtuvivint) in combination with ASTX727 in patients /< 18 years of age, children are excluded from this study
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3
• * Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (unless bilirubin rise is due to Gilbert`s syndrome or of non-hepatic origin; in that case a cut off of ≤ 4 × institutional ULN will be used)
• * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase /[SGPT/]) ≤ 3 x institutional ULN (unless considered due to organ involvement by the patient`s myeloid malignancy; in that case a cut off of ≤ 5 x institutional ULN will be used)
• * Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73m/^2
• * If female, patient must be either:
• * Postmenopausal (surgically sterile or age /> 55 years with no menses for 12 or more months without an alternative medical cause or age equal to 55 or less with no menses for 12 or more months without an alternative medical cause and a follicle stimulating hormone /[FSH/] level /> 40 IU/L); or
• * Of children bearing potential. These patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. 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. Patient must agree to have a negative urine or serum beta-human chorionic gonadotropin (HCG) test result during screening and repeated within 7 days prior to study drug (local labs are allowed) to be eligible
• * The effects of SM08502 (cirtuvivint) and ASTX727 on the developing human fetus are unknown. For this reason, and because these agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and during the treatment therapy. Women of childbearing age should agree to use adequate contraception for 7 months after completion of SM08502 (cirtuvivint) administration. For ASTX727, adequate contraception must continue for at least 6 months after last dose of ASTX727. 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 and for the duration of the study and at least 4 months after the last dose of SM08502 (cirtuvivint) and 3 months after last dose of ASTX727. Women who are lactating must refrain from breastfeed during the study and at least for two weeks after last dose of ASTX727
• * 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 are eligible for this trial
• * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Критерии исключения

• * Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities /> grade 1) with the exception of alopecia or abnormal blood counts
• * Patients who are receiving any other investigational agents
• * Systemic anti-leukemic therapy within 14 days of first day of study treatment. If on venetoclax, then a wash-out period of at least five times the half-life of the treatment. Exceptions: No wash-out required for intrathecal chemotherapy, hydroxyurea, cytarabine (Ara-C), or palliative radiation therapy to painful sites of leukemic disease
• * Patient is receiving known inhibitors or activators of flavin-containing monooxygenases (FMO1 or FMO3), and these cannot be stopped at least 5 days prior to SM08502 (cirtuvivint) treatment start. Known inhibitors of FOMO are chlorpromazine and imipramine
• * Patient is receiving strong inhibitors or strong inducers of CYP3A4/5 and these cannot be stopped at least 5 days prior to SM08502 (cirtuvivint) treatment start
• * Strong inhibitors include grapefruit juice or grapefruit/grapefruit related citrus fruits (e.g., Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance
• * Strong inducers include phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, and St. John`s Wort. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance.
• * While moderate inhibitors or moderate inducers of CYP3A4/5 are not an exclusion criterium for the trial, it is preferred that moderate inhibitors or moderate inducers of CYP3A4/5 be replaced prior to the first dose of SM08502 (cirtuvivint) and during study conduct where this is possible.
• * Moderate inhibitors include erythromycin, ciprofloxacin, verapamil, diltiazem, atazanavir, fluconazole, darunavir, delavirdine, amprenavir, fosamprenavir, aprepitant, imatinib, tofisopam, and cimetidine. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance
• * Moderate inducers include bosentan, efavirenz, etravirine, modafinil, and nafcillin. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to SM08502 (cirtuvivint) or ASTX727
• * Chronic, active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: patients with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface /[HBs/] antigen negative, anti-HBs antibody positive and anti-hepatitis B core /[HBc/] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. Patients who had prior HCV that has been definitively treated with negative HCV viral load prior to study initiation and no evidence of cirrhosis, are allowed to participate. If there is no known history of HBV infection no HBV studies need to be obtained. If there is no known history of HCV infection, no HCV studies need to be obtained
• * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• * Pregnant and lactating women are excluded from this study because SM08502 (cirtuvivint) is a small molecule inhibitor of CLK DYRK with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SM08502 (cirtuvivint), breastfeeding should be discontinued if the mother is treated with SM08502 (cirtuvivint). These potential risks may also apply to other agents used in this study
• * Patients with acute promyelocytic leukemia
• * Subject has symptomatic central nervous system (CNS) involvement with AML
• * Patient has immediate life-threatening, severe complications of their myeloid malignancy such as uncontrolled bleeding and/or uncontrolled infection
• * Patient has significant active cardiac disease within 6 months prior to the start of study treatment, including uncontrolled New York Heart Association (NYHA) class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke
• * Left ventricular ejection fraction (LVEF) /< 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 30 days prior to the start of study treatment
• * Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Patient needs to be able to swallow pills
• * Patient 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)
• * Subject has corrected QC (QTc) interval (i.e., Fridericia`s correction /[QTcF/]) ≥ 480 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening

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 multicenter, single-arm, non-interventional study (NIS) with a central registration system and an all-case surveillance system. The observation period is 48 weeks after the start of treatment with Fabhalta.

Критерии включения

• All patients who received Fabhalta.
• ·

Критерии исключения

• Patients receiving Fabhalta for an unapproved indication under the Clinical Trials Act or GCP.

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

A study of the efficacy and safety of HRS-5965 capsules compared to eculizumab for 24 weeks in patients with PNH.

Критерии включения

• 1. Diagnosis of PNH confirmed by flow cytometry with clone size /> 10%.
• 2. Have not received complement inhibitor therapy;
• 3. LDH /> 1.5/*ULN at screening.
• 4. Hemoglobin level /< 10 g/dL at screening.

Критерии исключения

• 1. Known or suspected hereditary or acquired complement deficiency;
• 2. Patients with laboratory evidence of bone marrow failure (reticulocytes /<100x109/L; platelets /<30x109/L; neutrophils /<0.5x109/L);
• 3. Presence or suspicion of a systemic active bacterial, viral, or fungal infection (based on judgment of the investigator) within 2 weeks prior to the first dose of HRS-5965;
• 4. History of infection with capsular bacteria (e.g., meningococcus, pneumococcus, etc.)
• 5. Positive of HIV, HBsAg or HCVAb.

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/II trial tests the best dose of axatilimab and effectiveness of axatilimab with or without azacitidine for the treatment of patients with advanced phase myeloproliferative neoplasms (MPN), myeloproliferative neoplasm/myelodysplastic syndrome (MPN/MDS) overlap or high risk chronic myelomonocytic leukemia (CMML). Axatilimab is an antibody that is cloned from a single white blood cell that is known to be able to recognize cancer cells and block a protein on the surface of the white blood cells that may be involved in cancer cell growth. By blocking the proteins, this may slow or halt the growth of the cancer. Azacitidine is in a class of medications called antimetabolites. It works by stopping or slowing the growth of cancer cells. Giving axatilimab with or without azacitidine may be safe and effective in treating patients with advanced phase MPN, MPN/MDS overlap or high risk CMML.

Критерии включения

• * Signed informed consent must be obtained prior to participation in the study
• * Age ≥ 18 years at the date of signing the informed consent form (ICF)
• * Morphologically confirmed diagnosis of the following based on 2016 World Health Organization (WHO) classification (Arber et al 2016): Phase 1b, patients with relapsed or refractory of any of the following; phase 2, patients with newly diagnosed of any of the following:
• * Chronic myelomonocytic leukemia (CMML), classified as intermediate-2, OR high-risk per the CMML Specific Prognostic Scoring System (CPSS) Molecular Model
• * Atypical chronic myelocytic leukemia (aCML)
• * MDS/MPN unclassified (MDS/MPN-U)
• * Myeloproliferative neoplasm accelerated phase (MPN-AP)
• * MPN-AP requires a previous diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF) with intermediate-2 or high risk disease according to International Prostate Symptom Score (IPSS) as well as progression on or failure to respond to at least one line of therapy.
• * Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) or MDS/MPN with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T).
• * Not suitable for immediate myeloablative/intensive chemotherapy based on investigator assessment of age, comorbidities, local guidelines, institutional practice (any or all of these)
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
• * Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome)
• * Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m/^2 (estimation based on Modification of Diet in Renal Disease /[MDRD/] formula, by local laboratory)
• * Patient is able to communicate with the investigator and has the ability to comply with the requirements of the study procedures
• * Women of childbearing potential and men, if not surgically sterilized, should use adequate contraception from 14 days prior to study entry and until 90 days after the last follow-up visit. Adequate contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom

Критерии исключения

• * Previous treatment for MPN or MDS/MPN overlap with chemotherapy or other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine or INQOVI (oral decitabine) (patients who had up to 2 cycles of hypomethylating agents /[HMAs/] can be included). However, previous treatment with hydroxyurea and/or ruxolitinib is permitted
• * Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary AML based on WHO 2016 classification (Arber et al 2016)
• * Patients who are candidates for myeloablative or intensive chemotherapy treatment or who do not provide consent for this treatment
• * History of organ transplant or allogenic hematopoietic stem cell transplant
• * Participants with prior malignancy, except:
• * Participants with history of adequately treated malignancy for which no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study.
• * Participants who are receiving adjuvant therapy such as hormone therapy are eligible. However, participants who developed therapy related neoplasms are not eligible
• * Previous known allergy/sensitivity to components of axatilimab
• * History of acute or chronic pancreatitis
• * History of myositis

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

This phase 2 study aims to confirm the efficacy seen in the prior phase 1 trial, and further contribute to this effort through the collection of leukemia cells pre- and post- in vivo IFN-γ therapy. As in the previously conducted phase 1 trial, this trial will test whether leukemia blasts were responsive to IFN-γ in vitro and in vivo, with single-cell RNA sequencing (scRNAseq) conducted to understand the transcriptomic changes induced by IFN-γ in leukemia cell subsets, including those with stem cell characteristics.

Критерии включения

• * Recipients of an alloSCT for AML or MDS from an HLA-matched donor
• * AML/MDS relapsed post-alloSCT with measurable residual disease defined by at least 5% of more myeloblasts based on bone marrow biopsy morphology by pathologist review. Abnormal myeloblasts cannot not exceed 30% overall
• * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
• * A DLI is available, or the donor is available and agrees to undergo apheresis to collect lymphocytes for infusion
• * If salvage therapy for post-alloSCT relapse was received, the therapy is limited to 1 cycle of the following:
• 1. For hypomethylating agents, venetoclax, and targeted therapies (e.g., tyrosine kinase inhibitors, IDH1/IDH2 inhibitors, or FLT3 inhibitors), the last dose must be /> 2 week prior to the initiation of IFN-γ
• 2. For cytotoxic chemotherapy agents, the last dose must be />2 weeks prior to start of treatment for the present study
• 3. For investigational agents, the last dose must be ≥ 4 weeks or 5 half-lives (whichever is longer) prior to the start of treatment for the present study
• * Provision of signed and dated informed consent form
• * Stated willingness to comply with all study procedures and availability for the duration of the study
• * For female subject, who is /< 55 years old without hysterectomy, oophorectomy or documented menopause, willingness to use two forms of contraception including one form of highly effective contraception (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study
• * For male subject, willingness to use highly effective contraception methods including male condoms by male subject and one form of highly effective contraception by his female partner (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study

Критерии исключения

• * Primary engraftment failure after alloSCT
• * Grade 3 or 4 aGVHD per Mount Sinai Acute GVHD International Consortium (MAGIC) at the time of planned enrollment
• * History of grade 4 aGVHD per the MAGIC criteria
• * Moderate or severe cGVHD per NIH Consensus Criteria at time of planned enrollment
• * Any systemic immunosuppressive medications taken within 2 weeks before the enrollment
• * Grade 3 or higher non-hematologic toxicity related to any prior therapy at the time of enrollment
• * A contraindication to receive IFN-γ including a known hypersensitivity to IFN-γ, E. coli derived products or any other component of the product
• * Positive pregnancy test or currently breastfeeding on Day 1 of study treatment
• * Active cardiac arrhythmia not controlled by medical management or current NYHA class II or higher congestive heart failure within 2 months of enrollment unless it was due to a tachyarrhythmia which is under control at the time of enrollment
• * Active ischemic heart disease not controlled with medications within 2 months of enrollment
• * Acute or chronic pulmonary disease requiring continuous oxygen treatment
• * Seizure disorder not controlled by medications within 2 months of enrollment
• * AST or ALT /> 5x ULN or total bilirubin />3x ULN at time of enrollment
• * Renal function eGFR /<30 mL/min at time of enrollment using modified Cockcroft-Gault formula
• * Body surface area ≤ 1.5 m2 or ≥ 2.5 m2 so as to minimize variation in IFN-γ exposure based on differences in body surface area

Описание

This phase I trial tests the safety, side effects and best dose of decoy-resistant interleukin-18 (DR-18) and how well it works in treating patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has come back after a period of improvement (relapsed) or that remains despite treatment (persistent) after hematopoietic cell transplantation (HCT). HCT is the only curative therapy for most forms of AML and MDS. However, relapse occurs in a third of patients and is the most common cause of death after HCT. DR-18, a variant of the human cytokine interleukin-18, binds to IL-18 binding probein (IL-18BP) and overcomes the inhibitory effect of the IL-18BP on IL-18, which may boost the body`s immune system and may interfere with the ability of tumor cells to grow and spread. Giving DR-18 may be safe, tolerable and/or effective in treating patient with relapsed or persistent AML or MDS after HCT.

Критерии включения

• * ≥ 18 years of age (no upper age limit)
• * Documented persistent or recurrent AML or MDS after HCT (including measurable residual disease /[MRD/] or overt leukemia). Nota bene (NB): MRD (/< 5% malignant blasts) must be detected with flow cytometry testing at University of Washington Medical Center (UWMC)/Fred Hutchinson Cancer Center (Fred Hutch) clinical laboratory
• * No Food and Drug Administration (FDA)-approved targeted therapy for the subject`s AML or MDS is available, or if such therapy is available, that class of drugs previously failed for the subject or the subject was intolerant of the therapy
• * No history of grade 3 or 4 acute GvHD after the most recent HCT
• * No history of moderate or severe chronic GvHD after the most recent HCT
• * No active acute or chronic GvHD or other immunologic phenomenon (e.g., immune cytopenias, cryptogenic immunologic pneumonia) in last month requiring systemic therapy (Hydrocortisone or prednisone for adrenal insufficiency at ≤ 10 mg/day prednisone-equivalent is permitted.)
• * Stable or reducing immune suppression in the preceding 4 weeks without GvHD flares
• * The most recent HCT was from a 10/10 human leukocyte antigen (HLA)-matched related or unrelated donor (assessed at HLA-A, B, C, DR, DQ)
• * Evidence of blood count recovery at any time post-HCT defined as absolute neutrophil count (ANC) ≥ 0.5 x 10/^9/L for ≥ 3 consecutive days and platelets ≥ 30 x 10/^9/L (independent of granulocyte colony-stimulating factor /[G-CSF/] or platelet transfusions for 5 days). (Blood count recovery may not be sustained.)
• * No cellular immunotherapy or new targeted therapy in the 4 weeks prior to enrollment
• * Karnofsky performance status (KPS) ≥ 80%
• * Not pregnant/breastfeeding
• * Agrees to use a suitable method of contraception for 4 months after the last dose of DR-18
• * Capable of providing informed consent
• * At least 60 days have elapsed since the HCT donor cell infusion (HCT day 0). (There is no upper limit to the time elapsed since HCT.)

Критерии исключения

• * Active moderate-severe thrombotic microangiopathy (TMA) as evidenced by any of the following: /> 10 schistocytes per high-power field, or required anti-C5 or other anti-complement therapy for TMA in the prior 4 weeks, any of the following manifestations if attributed to TMA in the prior 4 weeks: hypertension, worsening or new renal insufficiency, ≥ 2+ proteinuria, hematochezia, seizure, transient or ongoing neurologic deficits
• * Renal insufficiency: Estimated glomerular filtration rate (eGFR) (calculated per the performing laboratory`s standard formula) or measured 24 hour (hr.) creatinine clearance /< 30 mL/min
• * Hemodialysis in the prior 4 weeks
• * Major cardiac event requiring evaluation in the emergency room (ER) or hospitalization in the past 4 weeks
• * New York Heart Association (NYHA) class II or higher congestive heart failure (CHF) in the past 4 weeks
• * Uncontrolled cardiac arrhythmias, including atrial fibrillation
• * Left ventricular ejection fraction (LVEF) /< 35%. LVEF may be established with echocardiogram or MUGA scan, and left ejection fraction must be ≥ 35%
• * Liver dysfunction: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) /> 5 x upper limit of normal (ULN) or bilirubin /> 3 x ULN
• * Active uncontrolled infection. NB: Examples of controlled infections:
• * Bacterial infection may be still requiring antibiotics at the time of enrollment, but clinical signs and symptoms of the infection should be improving. If the subject had bloodstream infection, negative blood cultures off antibiotics must be documented prior to initiating DR-18 treatment. For urinary tract infection, a repeat urine culture must be sterile prior to initiating DR-18. Radiographic improvement of bacterial pneumonia may lag behind clinical improvement so is not mandatory prior to DR-18 initiation
• * Fungal infection may be still requiring antifungal medication at the time of enrollment, but evidence of clinical response to antifungal medication (such as regression of lesions on chest CT) must be available at the time of enrollment
• * Asymptomatic shedding of respiratory viruses after cessation of antiviral therapy, or if not specifically treated with antiviral therapy, is permitted
• * Cytomegalovirus (CMV) viremia or organ infection meeting institutional criteria for CMV treatment with antiviral therapy such as ganciclovir, valganciclovir or foscarnet must be on maintenance phase of treatment or must have completed treatment and must not be in the induction treatment phase at the time of enrollment. Low-level CMV viremia not meeting institutional criteria for antiviral therapy is permitted, including low-level viremia in patients receiving CMV prophylaxis with letermovir
• * Any of the following: Pulmonary dysfunction requiring supplemental oxygen, even intermittently, in the past 2 weeks; corrected diffusion capacity of the lung for carbon monoxide (DLCO) or forced expiratory volume in 1 second (FEV1) /< 60% predicted; bronchiolitis obliterans syndrome; prior diagnosis of idiopathic pulmonary fibrosis; prior diagnosis of drug-induced pneumonitis; cryptogenic organizing pneumonia under active treatment
• * Seizure in the past 4 weeks or significant underlying neurologic disease: Study participants must not have significant active underlying neurologic disease, such as Parkinson`s disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, prior symptomatic ischemic or hemorrhagic stroke, or transient ischemic attack, unless approved by principal investigator (PI). Peripheral neuropathy related to diabetes or prior chemotherapy is acceptable
• * Other medical, social, or psychiatric factor that interferes with medical appropriateness and/or ability to comply with study, as determined by the PI
• * Known allergic reactions to any of the components of study treatments
• * Concurrent use of other investigational anti-cancer agents
• * Peripheral blood T cell chimerism /< 40%

Описание

The goal of this phase 1/2 trial is to test the safety and efficacy of Venetoclax Plus Azacytidine Conditioning Regimen Allo-HSCT in treating patients with higher-risk MDS.

Критерии включения

• * The patient should, in the investigator`s opinion, be able to meet all clinical trial requirements.
• * The patient is willing and able to adhere to the study visit schedule and other protocol requirements.
• * The patient should be diagnosed with higher risk MDS according to the standard criteria of the World Health Organization (WHO).

Критерии исключения

• * Active or uncontrolled infections requiring systemic treatment within 14 days before enrollment.
• * Any instability of systemic disease, including but not limited to severe cardiac, liver, kidney, or metabolic disease need therapy.

Описание

There are 2 possible treatments for the treatment of Acute Myelogenous Leukemia (AML), high-risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukemia (CMML): intensive curative chemotherapy , and for over-aged or co-morbid patients , non-intensive palliative chemotherapy with a hypomethylating agent (Azacytidine) associated or not with venetoclax.

Pro-inflammatory cytokines and in particular IL-6 (Interleukin 6) seem to play a key role in the chemoresistance of solid cancers and AML : it would be associated with a poor prognosis of AML , would promote the proliferation of leukemic blasts , and would promote the progression of MDS to AML .

In AML treated with intensive chemotherapy, researchers demonstrated that a particular kinetic profile of the FLT3 ligand and IL6 at day 22 could very significantly predict the survival of patients with AML .

It therefore seems interesting to study the plasma cytokine profiles in patients with AML, HR-MDS or CMML treated non-intensively, and to see if researchers observe the same prognostic correlation as during intensive chemotherapy.

Критерии включения

• * Age />=18 years
• * AML or SMD-HR or CMML in first line or in relapse receiving a hypomethylating agent +/- another molecule or a hypomethylating agent in combination with venetoclax +/- another molecule.
• * Patient having agreed to participate in the study (information note signature) and having signed the biocollection consent

Критерии исключения

• * No social security or any other regime
• * Pregnant women or patient unable to take contraception in case of fertility
• * Breastfeeding women
• * Minors
• * Adults under guardianship, curators or safeguard of justice

Описание

This phase I trial tests the safety, side effects, and best dose of eltanexor in combination with venetoclax for the treatment of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Eltanexor works by trapping "tumor suppressing proteins" within the cell, thus causing the cancer cells to die or stop growing. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving eltanexor together with venetoclax may be safe, tolerable and/or effective in treating patients with relapsed or refractory MDS or AML.

Критерии включения

• - Age />/= 18 years at the time of signing the Informed Consent Form (ICF); must voluntarily sign an ICF; and must be able to meet all study requirements.
• For Myelodysplastic Syndrome (MDS):
• Morphologically confirmed diagnosis of MDS with increased blasts (/>/= 5%), with a prior DNA methyltransferase inhibitor (DNMTi) treatment and progression after 2 cycles or stable disease after 4 cycles
• For Acute Myeloid Leukemia (AML):
• Morphologically confirmed diagnosis of AML in accordance with WHO diagnostic criteria that is relapsed or refractory following />/= 1 line(s) of therapy.
• * WBC must be less than 25,000/ul prior to study start (hydroxyurea allowed).
• * A bone marrow aspirate must be performed, and tissue collected for entrance to the trial unless circulating blasts />/= 5% in which case, peripheral blood can be used.
• * Eastern Cooperative Oncology Group Performance Status of 0 - 2.
• * Must have adequate hepatic and renal function as demonstrated by the following:
• ALT(SGPT) and/or AST (SGOT) /</= 3x upper limit of normal (ULN); Direct bilirubin /</= 1.5 x ULN; or Total bilirubin /</= 2.5x ULN (known Gilbert`s Syndrome as cause of elevated bilirubin is allowed); Calculated creatinine clearance /> 50 ml/min (per the Cockroft-Gault formula).
• - Willingness to abide by all study requirements, including contraception, maintenance of a pill diary, and acceptance of recommended supportive care medications.

Критерии исключения

• * Anticancer therapy, including investigational agents /</= 2 weeks or /</= 5 half-lives of the drug, whichever is shorter, prior to C1D1. (Use of hydroxyurea is permitted).
• * Inadequate recovery from toxicity attributed to prior anti-cancer therapy to /</= Grade 1 (NCI CTCAE v5.0), excluding alopecia or fatigue.
• * Prior treatment with SINE compounds or other inhibitors of XPO1.
• * History of allogeneic hematopoietic stem cell transplant (HCT), or other cellular therapy product, within 3 months.
• * Active acute or chronic GVHD requiring calcineurin inhibitors or steroid dosing />/= 10mg/day or patients within 4 weeks of stopping calcineurin inhibitors for GVHD.
• * Radiation therapy or major surgery within 3 weeks.
• * Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible. Prophylaxis, even if parenteral, is acceptable.
• * Inability to swallow oral medications.
• * Active documented central nervous system leukemia.
• * Second active malignancy within past 2 years except for basal or squamous cell carcinoma of the skin, ductal carcinoma of breast in situ or cervical carcinoma in situ.
• * Women of childbearing age or potential must have negative pregnancy test and must not be actively breastfeeding to enroll on the study
• * Clinically significant cardiovascular disease with major event or cardiac intervention within the past 6 months (e.g. percutaneous intervention, coronary artery bypass graft, documented cardiac heart failure) as determined by the investigator.
• * Any condition not listed but deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents.

Описание

This research is being done to investigate the safety and effectiveness of Darzalex Faspro (daratumumab and hyaluronidase-fihj) (a monoclonal antibody that targets plasma cells that make antibodies) and whether it can lower donor specific antibodies (DSA) levels to low enough levels to permit patients to proceed with allogeneic peripheral blood transplant (alloBMT). Those being asked to participate have high DSA levels that puts those being asked to participate at high risk of rejecting the available donor`s blood stem cells and making those being asked to participate ineligible to receive a stem cell transplant.

Критерии включения

• 1. Participates must meet all other institutional criteria for the planned reduced intensity conditioning allogeneic peripheral blood stem cell transplant (RIC alloHSCT) as defined in Johns Hopkins BMT Policy; all potential non-cord blood donor sources are included: matched related, haploidentical, matched unrelated, mismatched unrelated.
• 2. Participants must be ≥18 years of age.
• 3. Participants must have adequate organ function for undergoing RIC allogeneic peripheral blood stem cell transplant, and for undergoing a clinical trial.
• a. Hematologic. i. White blood cell (WBC). ANC ≥ 500/mm3 (growth factor support allowed). ii. Hemoglobin. No specific cut-off. (PRBC transfusion allowed). iii. Platelets. Platelets ≥ 10,000/mm3 (platelet transfusion allowed). b. Liver. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert`s syndrome or hemolysis), and Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) /< 5x Upper limit of normal (ULN) c. Renal. Serum creatinine ≤ 2.0 mg/dL. d. Cardiac. Left ventricular ejection fraction ≥ 35%. e. Pulmonary. FEV1 ≥ 50%.
• 4. Subjects are eligible if there are high levels of Donor Specific Antibody levels based on protocol specific scoring system regardless of prior attempts at standard desensitization.
• 5. Participants must have a no other readily available suitable alternative donor.
• 6. All potential Participants must be pre-approved by BMT faculty consensus.
• 7. Participants must have adequate willingness to participate in a clinical trial.

Критерии исключения

• 1. Previous exposure to Daratumumab-SC or other anti-CD38 therapy
• 1. Exposure to Daratumumab-SC or other anti-CD38 therapies (unless a re-treatment study)
• 2. Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.
• 3. Focal radiation therapy within 14 days prior to beginning of planned RIC allogeneic peripheral blood stem cell transplant regimen with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma
• 2. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) /< 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is /< 50% of predicted normal.
• 3. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
• 4. Known hypersensitivity or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or the excipients
• 5. Diagnosis of multiple myeloma or Amyloid light-chain (AL) amyloidosis
• 6. A planned myeloablative alloBMT or the planned use of bone marrow or cord blood as a stem cell source
• 7. History of HIV infection at any time in past.
• 8. Seropositive for hepatitis B (HBV) (defined by a positive test for hepatitis B surface antigen /[HBsAg/] positive, or antibodies to hepatitis B surface and/or core antigens /[antiHBs or antiHBc, respectively/] with hepatitis B virus /[HBV/]- DNA quantitation positive). Patients who are positive for antiHBs and/or antiHBc must have a negative polymerase chain reaction (PCR) for HBV-DNA quantitation result during screening. Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded.
• 9. Seropositive for hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)
• 10. Clinically significant cardiac disease, including:
• 1. Myocardial infarction within 6 months before RIC alloHSCT or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
• 2. Uncontrolled cardiac arrhythmia

Описание

Observational study to evaluate changes in quality of life (QoL) in patients diagnosed with low risk MDS who are red blood cell (abc) transfusion dependent.

Changes in QoL will be correlated with patient cardiorespiratory function. Cardiac biomarkers and plasma cytokines will also be evaluated.

Критерии включения

• Subjects must meet all of the following inclusion criteria:
• 1. They must be able to understand the study procedures, comply with them, and consent in writing prior to any specific study procedure.
• 2. Must be able to understand the study procedures, comply with them, and give written informed consent prior to any study-specific procedure.
• 3. Adult subjects ≥ 18 years of age with a diagnosis of myelodysplastic syndrome.
• 4. Very low, low or intermediate IPSS-R risk category.
• 5. Subject requires are red blood cell transfusion dependent with the following criteria: requires an average of 2 to 6 units of CH on average over an 8-week period.
• 6. ECOG 0-3.

Критерии исключения

• 1. Subject undergoing any of the following treatments: azacitidine, decitabine, venetoclax, cytotoxic chemotherapy, radiotherapy, arsenic trioxide, interferon or interleukin.
• 2. High or very high IPSS-R risk category.
• 3. Subject diagnosed with any active neoplasm except:
• * epidermoid or basal cell carcinoma,
• * carcinoma in situ of the uterine cervix
• * Carcinoma in situ of the breast
• 4. Subjects with a score on the New York Heart Association Scale IV.
• 5. Subjects with major surgery within 8 weeks prior to study inclusion. Subjects must have fully recovered from any previous surgery prior to inclusion in the study.
• 6. Subject with known clinically significant anaemia due to iron, vitamin B12 or folate deficiencies or autoimmune or hereditary haemolytic anaemia or uncontrolled hypothyroidism or known clinically significant haemorrhage or sequestration or subject with drug induced anaemia.
• 7. New onset or uncontrolled seizures.
• 8. Subjects with uncontrolled systemic fungal, bacterial or viral infections (defined as ongoing signs or symptoms related to the infection without improvement despite appropriate antibiotics or antimicrobial therapy).
• 9. Pregnant or breastfeeding women.
• 10. The subject has any condition, including the presence of laboratory abnormalities that would place the subject at unacceptable risk if he/she were to participate in the study.
• 11. The subject has any condition or receives concomitant medication that confounds the ability to interpret the study data.

Описание

Recruitment on the RAV pole in consultation or day hospital. Competitive recruitment of subjects /> 60 years of age respecting a male/female ratio = 1.

Критерии включения

• * Men and women over 60 years of age.

Критерии исключения

• * Inability to Understand Consent,
• * Non-Security Beneficiaries
• * social, subjects protected by law, subjects deprived of liberty,
• * history of breast cancer,
• * brain tumor,
• * melanoma,
• * colon cancer,
• * lung cancer,
• * prostate cancer,
• * lymphoma,
• * myeloma,
• * syndrome myelodysplastic/myeloproliferative,
• * leukemia,
• * history of radiation therapy.

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

Описание

This study will evaluate orally administered RVU120, a novel small molecule Cyclin-dependent Kinase (CDK) 8/19 inhibitor, in terms of erythroid hematologic improvement (HI-E) and safety in participants with lower-risk myelodysplastic syndrome (MDS). Responding patients are eligible to continue treatment until loss of response/disease progression.

Критерии включения

• 1. Written informed consent provided prior to any study-related procedure
• 2. Age ≥18 years
• 3. Diagnosis of de novo myelodysplastic neoplasms (MDS) according to World Health Organization (WHO) 2022 criteria.
• Diagnosis will be confirmed during screening assessment.
• 4. Very low, low or intermediate risk disease MDS with up to 3.5 points according to International Prognostic Scoring System Score Revised (IPSS-R) classification (to be confirmed during screening assessment).
• Patients with del(5q) and max. one further abnormality (excluding monosomy 7, del(7q), TP53mut) are eligible.
• 5. Symptomatic anemia: Symptomatic anemia (all non transfusion dependent (NTD), low transfusion burden (LTB), or high transfusion burden (HTB)) has to be documented in the 16 weeks baseline period ending on the day of inclusion.
• Patients should be registered only if it is expected at time of registration that
• * a valid and complete Hb (at least five measurements in the period of 16 weeks before the first dose of IMP) and transfusion history will be available at inclusion AND
• * the Hb Mean over the baseline period will be less than 10 g/dL OR three or more red blood cell (RBC)-transfusions will have been given during the baseline period documenting transfusion dependence.
• 6. No available option of an approved MDS therapy according to decision of the treating physician and based on the following:
• Patients must be
• * ESA exposed (and refractory or intolerant) or ESA naïve and serum erythropoietin level />200 U/L AND/OR
• * Luspatercept exposed (and refractory or intolerant) or luspatercept naïve and not eligible for treatment (e.g. not approved) AND/OR
• * Lenalidomide exposed (and refractory or intolerant) or lenalidomide naïve and not eligible for treatment (e.g. due to non-presence of del(5q))
• 7. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
• 8. Patients must have been off anti-cancer treatment for 2 weeks or 5 half-lives, whichever is longer
• 9. Clinical laboratory parameters as follows:
• * Peripheral white blood cell (WBC) count, no upper or lower limit at screening, but must be /<10 x 109/L prior to first dose of study drug
• * Platelets count />25,000/μL
• * Serum albumin ≥ 30 g/L (3.0 g/dL)
• * Normal coagulation (elevated International Normalized Ratio (INR), prothrombin time or activated partial thromboplastin time (APTT) /<1.3 x ULN acceptable)
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x the upper limit of normal (ULN)
• * Total bilirubin ≤1.5 x ULN
• * Creatinine clearance ≥60 mL/min
• * Urine protein /< 2+ (as measured by dipstick) or ≤1000 mg/24 hours urine
• 10. Adequate cardiac function confirmed by left ventricular ejection fraction (LVEF) ≥40% as per echocardiography or MUGA (Multiple Gated Acquisition) scan
• 11. For females of childbearing potential (FCBP), a negative serum pregnancy test must be confirmed before enrolment. FCBP must commit to use of highly effective method of contraception during study participation and until 28 weeks (6.5 months) after the last dose of study drug. Females must also refrain from donating blood or egg (ovum) during the same time-period.
• 12. For males, an effective barrier method of contraception must be used during study participation until 28 weeks (6.5 months) after the last dose of study drug, if the patient is sexually active with a FCBP. Males must also refrain from donating blood or sperm during the same time-period.
• 13. Investigator considers the patient to be suitable for participation in the clinical study by assessing that they:
• * Understand the requirements of the clinical study and can give informed consent.
• * Can comply with study medication dosing requirements and all study-related procedures and evaluations; and
• * Are not considered to be potentially unreliable and/or not cooperative
• 14. Has received all Coronavirus disease-19 (COVID-19) vaccinations per relevant national guidelines.

Критерии исключения

• 1. Inability to swallow and retain oral medications.
• 2. Patient does not accept bone marrow sampling during screening and after the treatment.
• 3. Prior treatment with azacitidine (injectable or oral) or decitabine.
• 4. The patient medically requires treatment with the following drugs that are forbidden during the trial or was exposed to one of these 14 days before the first dose of the IMP:
• * Erythropoiesis stimulating agent (ESA) or luspatercept
• * Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF)
• * Lenalidomide
• * Another investigational drug or device, or approved therapy for investigational use
• 5. Iron chelation therapy NOTE: if therapy was initiated 56 days or more prior to the first dose of the IMP, patient can be included. Recently initiated iron chelation /[/< 56 days prior to registration/] might influence interpretation of hematological response after start of trial medication.
• 6. Previous treatment with CDK8-targeted therapy(s).
• 7. Active central nervous system (CNS) involvement.
• 8. Patients who have undergone major surgery within 28 days prior to first dose of study drug.
• 9. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection and acute inflammatory conditions (including pancreatitis)
• 10. Hematopoietic stem cell transplant within 120 days prior to first dose of study drug.
• 11. Active Grade 2-4 acute graft versus host disease (GVHD), active moderate-to-severe chronic GVHD, or requirement for systemic immunosuppressive medications for GVHD.
• 12. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV).
• 13. Ongoing significant liver disease such as cirrhosis, drug-induced liver injury, active hepatitis or chronic persistent hepatitis B and/or C:
• * Positive serologic or polymerase chain reaction (PCR) test results for acute or chronic Hepatitis B virus (HBV) infection. Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation.
• * Acute or chronic Hepatitis C virus (HCV) infection. Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation
• 14. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RVU120 (e.g. active inflammatory bowel disease, ulcerative disease, malabsorption syndrome, short bowel syndrome, uncontrolled nausea, vomiting or diarrhea).
• 15. Ongoing drug-induced pneumonitis.
• 16. Concurrent participation in another investigational clinical trial.
• 17. Taking any medications, herbal supplements or other substances (including smoking) that are known to be strong inhibitors or moderate/strong inducers or sensitive substrates of CYP1A2, within less than 5 half-lives, prior to first dose of study drug. Any exception should be discussed with the Coordinating Investigator. For clarity, vaping (use of e-cigarettes) is not considered smoking.
• 18. Significant cardiac dysfunction defined as myocardial infarction within 12 months of first dose of study drug, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias, or poorly controlled angina.
• 19. Currently taking drugs that are documented, in the drug package insert, to have a risk of causing prolonged QTc or torsades de pointes (TdP) within 5 half-lives, prior to first dose of study drug.
• Any exception should be discussed with the Coordinating Investigator.
• 20. Personal or family history of serious ventricular arrhythmia, or QT interval corrected for heart rate (QTc) ≥470 ms.
• 21. Any other prior or current medical condition, intercurrent illness, surgical history, physical or electrocardiogram (ECG) findings, laboratory abnormalities, or extenuating circumstance (e.g. alcohol or drug addiction) that, in the Investigator`s opinion, could jeopardize patient safety or interfere with the objectives of the study.
• 22. Prior history of malignancies other than Acute myeloid leukemia (AML) or MDS, unless the patient has been free of the disease for 5 years or more prior to screening. Exceptions to the ≥5-year time limit include history of the following:
• * basal cell carcinoma of the skin
• * non-metastatic squamous cell carcinoma of the skin
• * carcinoma in situ of the cervix
• * carcinoma in situ of the breast
• * carcinoma in situ of the bladder
• * incidental histological finding of prostate cancer (Tumor/Node/Metastasis /[TNM/] stage of T1a or T1b).
• 23. Pregnant or breast-feeding females

Описание

This phase I trial tests the safety, side effects, and best dose of iadademstat when given together with azacitidine and venetoclax in treating patients with newly diagnosed acute myeloid leukemia (AML). Iadademstat inhibits the LSD1 protein and may lead to inhibition of cell growth in LSD1-overexpressing cancer cells. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving iadademstat with azacitidine and venetoclax may be safe, tolerable and/or effective in treating patients with newly diagnosed AML who cannot undergo intensive chemotherapy.

Критерии включения

• * Patients at least 18 years of age will be considered for inclusion without bias against gender identity, race, or ethnicity
• * Ability to comprehend the investigational nature of the study and provide written informed consent
• * Patients with previously untreated, morphologically documented AML based on World Health Organization (WHO) 2008 definitions who are ineligible for standard of care (SOC) intensive chemotherapy induction and also meet the following criteria:
• * Documented intermediate- or adverse-risk AML based on European Leukemia Network (ELN) 2022 criteria
• * Note: Cases of AML/myelodysplastic syndrome (MDS) overlap with 10-19% bone marrow (BM) or peripheral blood (PB) blasts will be considered
• * Note: Cases of acute promyelocytic leukemia (PML) and AML with BCR::ABL1 fusions will be excluded
• * Eastern Cooperative Oncology Group (ECOG) performance ≤ 2 (Patients aged ≥ 75 years, at the time of consent)
• * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Patients aged ≥ 75 years, at the time of consent)
• * High total bilirubin values may require indirect and direct bilirubin testing. Individuals with known Gilbert`s syndrome may be considered for enrollment despite high indirect (and total) bilirubin
• * Creatinine clearance (CrCl) of ≥ 60 mL/min (estimated using the Cockcroft Gault formula or measured by 24 hours urine collection) (Patients aged ≥ 75 years, at the time of consent)
• * Patients aged ≥ 18 to 74 years (ECOG performance status /[PS/] ≤ 3 is accepted) at consent must meet ≥ 1 of the following criteria defining a co morbidity:
• * ECOG PS of 2 or 3 (Note: Patients ≥ 18 to 74 years of age with PS of 0-1 must meet criteria of one of the following comorbidities.)
• * Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina
• * Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%
• * CrCl ≥ 30 mL/min to /< 45 ml/min
• * Moderate hepatic impairment with total bilirubin /> 1.5 to ≤ 3.0 × ULN;
• * High total bilirubin values may require indirect and direct bilirubin testing. Individuals with known Gilbert`s syndrome may be considered for enrollment despite high indirect (and total) bilirubin
• * Other comorbidities that the physician judges to be incompatible with intensive chemotherapy (IC). In these cases, the comorbidity must be reviewed and approved by the principal investigator (PI) before study enrollment
• * Ability to swallow oral medications
• * No ongoing anticoagulation or antiplatelet therapy within 14 days of start of treatment with IADA (i.e., cycle 0 day 1 /[C0D1/])
• * No history of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
• * No history of stroke or intracranial hemorrhage within 180 days of start of IADA
• * No major bleeding event, as defined by the International Society of Thrombosis and Hemostasis (ISTH), within 12 weeks of start of IADA
• * Uncorrected international normalized ratio (INR) or activated partial thromboplastin time (aPTT) of /< 1.5 x ULN.
• * If INR or aPTT /> 1.5 x ULN has been corrected (prior to enrollment), then history of disseminated intravascular coagulation (DIC) must be absent
• * White blood cell (WBC) /< 20 x 10/^9/L prior to study start. Cytoreduction prior to study treatment is allowed with
• * Hydroxyurea for up to 14 days and until 24 hours prior to start of IADA; or
• * Leukapheresis for up to 14 days prior to start of IADA
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase /[SGPT/]) ≤ 2.0 x institutional ULN
• * Lower hepatic function may be considered if liver enzyme abnormalities are determined by the treating MD and principal investigator (PI) to be due to leukemic infiltration
• * Willing and able to
• * Adhere to study schedule of activities and life style restrictions while on treatment;
• * Provide bone marrow (BM) aspirate and core biopsy samples; and
• * Accept supportive and prophylactic care for hematologic toxicities, infection, and immediate sequelae, including transfusions
• * Negative pregnancy test within 72 hours of start of IADA for persons of childbearing potential (PCBP)
• * Willingness to comply with study requirements for contraception, as follows: PCBP and sperm-producing participants who are sexually active with a PCBP must use study approved contraception from start of investigational product (first dose of IADA) until 6 months after the last dose of IADA. Pregnancy is exclusionary because the agents used in this study have the potential for teratogenic or abortifacient effects

Критерии исключения

• * Prior allergic response to iadademstat (IADA), venetoclax, azacitidine, or any excipients in the formulations
• * Body weight /< 50 kg
• * Investigational therapy within 5 half-lives or, if unknown, within 28 days prior to start of IADA
• * Treatment for AML within 14 days prior to start of IADA. Cytoreduction for patients with proliferative disease must meet the criteria listed in inclusion criteria
• * Radiotherapy less than 14 days prior to start of IADA
• * Recent and significant medical interventions, such as major surgery within 28 days prior to the start of IADA, or stem cell transplant within 100 days prior to the start of IADA. Patients with active treatment for graft-versus-host disease (GVHD) are excluded
• * Another active malignancy within 5 years prior to the start of IADA, or at the investigator`s discretion
• * Treatments targeting or inhibiting LSD1/KDM1A or BCL 2 within 12 months prior to the start of IADA
• * Documented dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
• * Treatment with monoamine oxidase inhibitors (e.g., tranylcypromine), if treatment is not finalized at least 3 weeks prior to the start of IADA
• * Active central nervous system involvement with AML
• * Uncontrolled infection. Participants with controlled infection must be afebrile and hemodynamically stable for at least 72 hours prior to start of IADA and must be amenable to alternate treatment if current treatment will interact with investigational regimen
• * Active hepatic disorder or documented positive hepatitis B or C virus (HBV/HCV, respectively) status, except in cases of undetectable HBV/HCV viral load for at least 3 months prior to the start of IADA. (Hepatitis B or C testing is not required for eligibility assessment.)
• * Individuals serology positive for human immunodeficiency virus (HIV) and under active treatment with highly active antiretroviral therapy (HAART) (or another therapy that may interfere with metabolism of study agents). Otherwise, enrollment may be considered in cases of HIV that is controlled with another treatment type or in cases that that acceptable modification of the patient`s HIV treatment exists
• * Use a P-gp inhibitor within 23 days prior to treatment with venetoclax
• * Use of strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half lives whichever is longer, prior to start of treatment with venetoclax
• * Unwillingness to stop breastfeeding. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided throughout the study and until at least 60 days after last dose of IADA
• * 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 C1D1 is allowed
• * Patients with poorly controlled diabetes. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) ≥ 8%; 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
• * Patients with mean of triplicate corrected QT interval (Fridericia`s correction formula /[QTcF/]) /> 450 ms at Screening based on central reading
• * Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, unstable cardiac or pulmonary function or acute insufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), or psychiatric illness or social situation that could limit compliance with study requirements, at the discretion of the investigator

Описание

This phase II MyeloMATCH treatment trial tests whether the standard approach of cytarabine and daunorubicin in comparison to the following experimental regimens works to shrink cancer in patients with high risk acute myeloid leukemia (AML): 1) daunorubicin and cytarabine liposome alone; 2) cytarabine and daunorubicin with venetoclax; 3) azacitidine and venetoclax; 4) daunorubicin and cytarabine liposome and venetoclax. "High-risk" refers to traits that have been known to make the AML harder to treat. Cytarabine is in a class of medications called antimetabolites. It works by slowing or stopping the growth of cancer cells in the body. Daunorubicin is in a class of medications called anthracyclines. It also works by slowing or stopping the growth of cancer cells in the body. 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. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. There is evidence that these newer experimental treatment regimens may work better in getting rid of more AML compared to the standard approach of cytarabine and daunorubicin.

Критерии включения

• * STEP 1 REGISTRATION:
• * Participants must have been registered to Master Screening and Re-Assessment Protocol, MYELOMATCH, prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox, prior to registration to this study.
• * Note: Pre-enrollment/diagnosis labs must have already been performed under the MYELOMATCH
• * Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) per World Health Organization (WHO) criteria
• * Participants must have high-risk (adverse) AML per European LeukemiaNet (ELN) 2017 criteria
• * Participants with therapy-related AML (t-AML), or with AML evolving from an antecedent hematologic disorder (such as myeloproliferative neoplasm), or AML with myelodysplasia-related changes (AML-MRC) are eligible
• * Acute promyelocytic leukemia is excluded
• * Participants with favorable or intermediate risk disease are excluded
• * Participants with FLT3 mutations (ITD or TKD) are excluded
• * Participants with t(9;22) translocation are excluded
• * A single dose of intrathecal chemotherapy is allowed prior to study entry
• * Prior anthracycline therapy is allowed but must not exceed a cumulative lifetime dose of 200 mg/m/^2 daunorubicin or equivalent. Prior hypomethylating agent (HMA) exposure is allowed, as long as not for AML diagnosis
• * Participants must not have received or be currently receiving any prior therapy for acute myeloid leukemia. Hydroxyurea to control the white blood cells (WBC) is allowed prior to registration and initiation of protocol-defined therapy. All trans retinoic acid (ATRA) given until a diagnosis of acute promyelocytic leukemia is ruled out is also allowed.
• * Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy
• * Participants must be between 18 and 59 years of age
• * Participants must have Zubrod performance status =/< 3 as determined by a history and physical (H/&P) completed within 14 days prior to registration
• * Participants must have a complete medical history and physical exam within 7 days prior to registration
• * Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications
• * Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at time of registration and have undetectable HIV viral load within 6 months prior to registration
• * Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to registration and be on suppressive therapy, if indicated
• * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration
• * The following tests must be performed within 14 days prior to registration to establish baseline values:
• * Complete blood count (CBC)/differential/platelets
• * Total bilirubin
• * Lactate dehydrogenase (LDH)
• * Albumin
• * Glucose
• * Fibrinogen
• * Participants must have adequate kidney function as evidenced by creatinine clearance />= 30mL/min (by Cockcroft Gault) within 28 days prior to registration
• * Participants must have adequate liver function as evidenced by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) /< 3.0 x upper limit of normal (ULN), and total bilirubin =/< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert`s disease) within 28 days prior to registration
• * Total bilirubin =/< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert`s disease) within 28 days prior to registration
• * Participants must have adequate cardiac function as determined by echocardiography or MUGA scan with an ejection fraction />= 50% within 28 days prior to registration
• * Participants with a prior or concurrent malignancy whose natural history (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. No concurrent therapies for such malignancy are allowed with the exception of hormonal therapy
• * Participants with known history of Wilson`s disease or other known copper-metabolism disorder are excluded
• * Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use 2 contraception methods. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods (e.g., hormonal contraceptives /[examples include birth control pills, vaginal rings, or patches/] associated with inhibition of ovulation for at least 1 month prior to taking study drug), "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. A barrier method should be used during this study along with hormonal contraceptives from initial study drug administration to 30 days after the last dose of study drug as drug-drug interaction with venetoclax is unknown
• * Participants must have agreed to have specimens submitted for translational medicine (MRD) under the myeloMATCH MSRP and specimens must be submitted
• * Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
• * As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution`s identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Критерии исключения