Metronomic Decitabine-Cedazuridine and Venetoclax in R/R AML, HR-MDS, HR/AP MPN

Official title

Metronomic Decitabine-Cedazuridine and Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia R/R AML), High Risk Myelodysplastic Syndrome (HR-MDS), and High-Risk Myeloproliferative Neoplasms (HR/AP MPN)

Overview

This is a single-center randomized phase 2 open-label clinical trial.

Detailed description

Patients are randomized 1:1 to metronomic-dosed Decitabine-Cedazuridine and Venetoclax (DEC-C+VEN) vs (Azacitidine (AZA)+ Venetoclax (VEN). Patients will be stratified at randomization based on disease cohort Relapsed/Refractory Acute Myeloid Leukemia (R/R AML), High Risk Myelodysplastic Syndrome (HR-MDS), High Risk Myeloproliferative Neoplasms (HR/AP-MPN) Patients will undergo treatment indefinitely until progression, unacceptable toxicity, or allogeneic hematopoietic transplant.

Interventions

• Drug Decitabine-cedazuridine plus venetoclax (DEC-C+VEN)
  Decitabine-cedazuridine (DEC-C) dosage per protocol taken by mouth once weekly plus Venetoclax (VEN) 400 milligrams (mg), taken by mouth once weekly
• Drug Azacitidine plus venetoclax (AZA+VEN)
  Azacitidine (AZA) 75 milligrams per meters squared (mg/m2) taken per institutional practice, plus venetoclax (VEN) standard ramp-up

Primary outcome measures

• Compare safety and tolerability of the arms [Time frame: Baseline through 30 days following last dose of protocol treatment, indefinitely until progression, unacceptable toxicity, or allogeneic hematopoietic transplant, whichever comes first, assessed up to 10 years)]

Secondary outcome measures (10)

• Characterize events of special interest defined as Grade 3 or greater adverse events (AEs) with attention to prolonged cytopenias, febrile neutropenia, serious infection, and serious bleeding events for both arms [Time frame: Baseline through 30 days following last dose of protocol treatment, indefinitely until progression, unacceptable toxicity, or allogeneic hematopoietic transplant, whichever comes first, assessed up to 10 years.]
• Estimate the event free survival (EFS) for both arms [Time frame: Day 1 of protocol treatment up to 2 years following last dose of treatment]
• Estimate minimal residual disease (MRD) negativity rates in acute myeloid leukemia (AML) for both arms [Time frame: Baseline and end of Cycle 2, each cycle is 28 days.]
• Estimate best response rates in acute myeloid leukemia (AML) for both arms [Time frame: Baseline, Cycle 2 Day 28, Cycle 4 Day 28, If patient has not reached maximum response by Cycle 4 Day 28 biopsy, an additional biopsy will be performed at Cycle 7 Day 28, or at disease progression, whichever comes first, assessed up to 7 months.]
• Estimate duration of response (DoR) for both arms [Time frame: Start of protocol treatment through up to 2 years following last dose of protocol treatment. Patients will undergo treatment indefinitely until progression, unacceptable toxicity, or allogeneic hematopoietic transplant.]
• Estimate overall survival (OS) for both arms [Time frame: Start of protocol treatment through up to 2 years following last dose of protocol treatment. Patients will undergo treatment indefinitely until progression, unacceptable toxicity, or allogeneic hematopoietic transplant.]
• Estimate of early mortality rate at 30 and 60 days in the relapsed or refractory acute myeloid leukemia (R/R AML) cohort for both arms [Time frame: Day 30 and Day 60 after start of protocol treatment]
• Estimate health care utilization metrics for both arms [Time frame: Cycles 1 through 4, about 112 days]
• Estimate of quality of life (QoL) metrics for both arms [Time frame: Cycle 3 Day 1 ± 1 week (each cycle is 28 days), and Cycle 5 Day 1 ± 1 week, or end of study treatment (± 2 weeks) if occurring prior to the four-month timepoint (when feasible)]
• Estimate proportion of patients proceeding to allo-HCT for both arms [Time frame: Start of treatment, up to 2 years following last dose of study treatment]

Eligibility criteria

Inclusion criteria

• Age ≥18 years at time of enrollment
• Diagnosis of one of the following by World Health Organization (WHO) International Consensus Classification (ICC) criteria as determined by local assessment:

• Relapsed/ refractory acute myeloid leukemia (R/R AML) as defined by ≥5% marrow blasts or unequivocal, measurable extramedullary disease
• High Risk Myelodysplastic Syndrome (HR-MDS) (high/very high risk MDS by Revised International Prognostic Scoring System (IPSS-R) or Molecular International Prognostic Scoring System (IPSS-M)
• high-risk accelerated-phase myeloproliferative neoplasm (HR/AP-MPN) defined by ≥10% blasts in blood or bone marrow
• Eastern Cooperative Oncology Group (ECOG) Performance status 0-3
• White blood cell (WBC) count ≤25 × 109/Liter (L) (cytoreduction with hydroxyurea or steroids is allowed to achieve this)
• Aspartate Aminotransferase (AST)/ Alanine Aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (≤5 × ULN if due to leukemic involvement)
• Total bilirubin ≤2 × ULN (unless the elevation is due to Gilbert's or hemolysis)
• Creatinine clearance ≥ 30 milliliters / minute (mL/min)
• Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of non-childbearing potential are those who have had a hysterectomy or bilateral oophorectomy, or who have completed menopause (no menses for at least one year and age ≥65 or follicle-stimulating hormone levels in the menopausal range).
• Subjects and their partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months after the last dose of study treatment. Effective contraception includes methods such as oral contraceptives or double-barrier method.

Exclusion criteria

• Prior use of hypomethylating agent and venetoclax in combination (Note, use of hypomethylating agent and/or venetoclax separately in alternative combinations with other drugs is allowed)
• Inability to tolerate oral therapies, or medical co-morbidities that significantly impact parenteral absorption
• Acute promyelocytic leukemia myeloproliferative neoplasm (MPN) with the Philadelphia chromosome translocation (BCR:ABL) translocation
• Clinically significant cardiovascular disease as defined by unstable angina
• New York Heart Association class III/IV congestive heart failure
• Treatment with any investigational drug or therapy within 2 weeks of study treatment or 5 half-lives before the first dose of study treatment, whichever is shorter
• Known hypersensitivity to azacitidine, venetoclax, decitabine or cedazuridine
• Cytotoxic chemotherapy or prior azacitidine or decitabine within 2 weeks of first dose of study treatment
• Concurrent use of AML/MDS/MPN therapies including lenalidomide, erythropoietin, luspatercept, cytotoxic chemotherapies, targeted agents, etc Note: hydroxyurea is allowed in Cycle 1 if necessary for cytoreduction and/or cytarabine not exceeding a maximum dose of 1 gram per meter squared (g/m2) in Cycle 1 is also allowed for cytoreduction
• Uncontrolled intercurrent illness or infection (those with controlled HIV, hepatitis, or other chronic infections are eligible)
• Untreated central nervous system disease
• Pregnancy or breastfeeding
• Other active malignancy requiring systemic therapy during duration of trial or otherwise would confound endpoints (eg, second malignancy present where survival is expected to be less than 6 months)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Virginia Commonwealth University — Richmond

Identifiers

NCT: NCT07710534 · MCC-26-23119

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗