This is a single-center randomized phase 2 open-label clinical trial.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Decitabine-cedazuridine (DEC-C) dosage per protocol taken by mouth once weekly plus Venetoclax (VEN) 400 milligrams (mg), taken by mouth once weekly
Azacitidine (AZA) 75 milligrams per meters squared (mg/m2) taken per institutional practice, plus venetoclax (VEN) standard ramp-up
Virginia Commonwealth University
Richmond, Virginia, United States
RECRUITINGCompare 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
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)
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)
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
Event free survival (EFS) defined as time from treatment initiation to relapse, disease progression, or death from any cause
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
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.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
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
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)
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
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.
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
overall survival (OS) defined as time from treatment initiation to death from any cause.
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
A ssess short-term survival by the 30-day and 60-day mortality in the R/R AML cohort.
Time frame: 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.
Time frame: 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
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
Proportion of patients proceeding to allogeneic hematopoietic cell transplantation (allo-HCT)
Time frame: Start of treatment, up to 2 years following last dose of study treatment