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

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)

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

Study Overview

• Status: Not yet recruiting
• Conditions: High Risk Myelodysplastic Syndrome; Relapsed / Refractory AML; High Risk Myeloproliferative Neoplasms
• Intervention / Treatment: Drug: Decitabine-cedazuridine plus venetoclax (DEC-C+VEN); Drug: Azacitidine plus venetoclax (AZA+VEN)

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Massey IIT Research Operations; Phone Number: 804-628-6430; Email: masseyepd@vcu.edu

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
      • Principal Investigator: Keri Maher, DO
      • Contact: Acute Leukemia/Myeloid Malignancies CTO Team; Phone Number: 804-628-6430; Email: masseyhiit@vcu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Metronomic decitabine-cedazuridine (DEC-C) plus venetoclax (VEN)	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
Active Comparator: Arm B: Azacitidine (AZA) plus venetoclax (VEN)	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare safety and tolerability of the arms	Incidence of Grade 3 or greater treatment related adverse events per the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 Treatment-related hematologic toxicity will be defined as a worsening from baseline CTCAE grade accompanied by clinically significant consequences, including new transfusion requirement, clinically significant bleeding, hospitalization, dose interruption/reduction, growth factor support, or investigator determination of clinically significant change from baseline	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

Outcome Measure	Measure Description	Time Frame
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	Incidence of prolonged cytopenias defined as absolute neutrophil count (ANC) ≤ 500/microliter (µL) and/or platelets ≤ 50,000/µL for greater than 28 days and febrile neutropenia, serious infection (requiring intravenous (IV) antibiotics or hospitalization) or serious bleeding events (requiring hospitalization or procedural intervention)	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	Event free survival (EFS) defined as time from treatment initiation to relapse, disease progression, or death from any cause	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	Minimal residual disease (MRD) negativity defined as <0.1% by multiparameter flow cytometry or next generation sequencing (NGS)-based MRD negativity when available (below assay-specific detection threshold). Multiparameter flow cytometry or NGS-MRD analyzes patient's genetic material, deoxyribonucleic acid (DNA), from bone marrow or peripheral blood to detect patient-specific genetic sequences associated with cancer cells.	Baseline and end of Cycle 2, each cycle is 28 days.
Estimate best response rates in acute myeloid leukemia (AML) for both arms	Best response defined as <0.1% by multiparameter flow cytometry or next generation sequencing (NGS) based MRD negativity when available (below assay-specific detection threshold)	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	Duration of response (DoR) defined from first documented complete response (CR), or complete remission with incomplete hematologic recovery (CRi). CRi means that while the cancer is gone, the patient's blood cell counts have not yet returned to normal, or Morphologic Leukemia-Free State (MLFS). MLFS indicates the absence of detectable leukemic blasts to relapse or death.	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	overall survival (OS) defined as time from treatment initiation to death from any cause.	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	A ssess short-term survival by the 30-day and 60-day mortality in the R/R AML cohort.	Day 30 and Day 60 after start of protocol treatment
Estimate health care utilization metrics for both arms	Health care utilization metrics including the number of red blood cell (RBC) and platelet transfusions per patient in Cycles 1-4 (transfusion independence, defined as no transfusions for 4 and 8 consecutive weeks) and unplanned hospitalizations attributable to disease or treatment related complications.	Cycles 1 through 4, about 112 days
Estimate of quality of life (QoL) metrics for both arms	Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ C30), a 30-item questionnaire to capture the subjective experiences of cancer patients, including physical, emotional, and social well-being. Items are scored on a 1-4 Likert scale (except global health status, scale 1-7) and scores are linearly transformed to a 0-100 scale, where higher scores on functional scales signal better functioning, higher scores on symptoms scales signal higher symptom burden, and higher scores on global health status signify better overall quality of life	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	Proportion of patients proceeding to allogeneic hematopoietic cell transplantation (allo-HCT)	Start of treatment, up to 2 years following last dose of study treatment

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Investigators: Principal Investigator: Keri Maher, DO, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2026
• Primary Completion (Estimated): September 30, 2031
• Study Completion (Estimated): December 31, 2033

Study Registration Dates

• First Submitted: July 7, 2026
• First Submitted That Met QC Criteria: July 13, 2026
• First Posted (Actual): July 17, 2026

Study Record Updates

• Last Update Posted (Actual): July 17, 2026
• Last Update Submitted That Met QC Criteria: July 13, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: High Risk Myelodysplastic Syndrome; Relapsed / Refractory AML; High Risk Myeloproliferative Neoplasms
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax; decitabine and cedazuridine drug combination
• Other Study ID Numbers: MCC-26-23119

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to share individual patient data. Datasets are available on reasonable request to the author.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No