Testing Oral Decitabine and Cedazuridine (ASTX727) in Combination With Venetoclax for Higher-Risk Acute Myeloid Leukemia Patients
Clinical Evaluation of ASTX727 in Combination With Venetoclax All-Oral Therapy vs Standard of Care Cytarabine and Anthracycline Induction Chemotherapy for Younger FLT3WT Patients With ELN High- Risk Acute Myeloid Leukemia
4 other identifiers
interventional
5
1 country
7
Brief Summary
This phase Ib/II trial studies the effects of ASTX727 (decitabine and cedazuridine) in combination with venetoclax in treating patients with higher-risk acute myeloid leukemia patients who do not have a change in the gene called fms-like tyrosine kinase 3 (FLT3). 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 an enzyme inhibitor. It helps to increase the amount of decitabine in the body so that the medication will have a greater effect. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Venetoclax and decitabine are commonly given together for older patients with AML ASTX727 (a pill form of decitabine + cedazuridine) has been found to be equal to decitabine (given intravenously), and this part of the study is to confirm that venetoclax and ASTX727 is as safe as venetoclax and decitabine given intravenously. This study allows for lowering doses of study drugs to assure the dose chosen for the randomized study (second portion of this trial) is safe and tolerable for people. Giving ASTX727 in combination with venetoclax may help in the treatment of patients with higher-risk acute myeloid leukemia.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Feb 2022
Longer than P75 for phase_1
7 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 25, 2021
CompletedFirst Posted
Study publicly available on registry
March 26, 2021
CompletedStudy Start
First participant enrolled
February 10, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 6, 2025
CompletedStudy Completion
Last participant's last visit for all outcomes
November 5, 2026
ExpectedNovember 10, 2025
November 1, 2025
3.3 years
March 25, 2021
November 6, 2025
Conditions
Outcome Measures
Primary Outcomes (3)
Recommended safe phase 2 dose (RP2D) of decitabine and cedazuridine (ASTX727) in combination with venetoclax (Phase Ib)
The highest dose level in which at most 1 patient in 6 experiences dose-limiting toxicity (DLT).
End of each cycle (1 cycle = 28 days)
Incidence of adverse events (Phase Ib)
Will be tabulated and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Summary statistics will be provided for all adverse events reported. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percent and frequencies for categorical parameters, will be presented
Up to 2 years after completion of study treatment
Event-free survival (EFS) (Phase II)
Will be estimated using the method of Kaplan and Meier and compared among treatments and other important prognostic groups using the log-rank test.
Up to 2 years after completion of study treatment
Secondary Outcomes (7)
Complete response rate (Phase II)
Up to 2 years after completion of study treatment
Duration of response (Phase II)
Up to 2 years after completion of study treatment
Progression-free survival (PFS) (Phase II)
Time from randomization date to the date of progression or death for any reason, assessed up to 2 years after completion of study treatment
Overall response rate (Phase II)
Up to 2 years after completion of study treatment
Overall survival (OS) (Phase II)
Time from randomization to death for any reason, assessed up to 2 years after completion of study treatment
- +2 more secondary outcomes
Study Arms (3)
Arm I (decitabine and cedazuridine, venetoclax)
EXPERIMENTALPatients receive ASTX727 PO QD at the recommended phase II dose and venetoclax PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy and collection of blood samples throughout the trial.
Arm II (cytarabine, daunorubicin)
ACTIVE COMPARATORPatients receive cytarabine IV over 24 hours on days 1-7 of each cycle and daunorubicin IV over 10-30 minutes on days 1-3 of each cycle. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy throughout the trial.
Phase Ib (decitabine and cedazuridine, venetoclax)
EXPERIMENTALPatients receive ASTX727 PO QD on days 1-4 or 1-5 of each cycle and venetoclax PO QD on days 1-28 or days 1-21 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy and collection of blood samples throughout the trial.
Interventions
Undergo collection of blood samples
Undergo bone marrow aspiration and biopsy
Given IV
Given IV
Given PO
Given PO
Eligibility Criteria
You may qualify if:
- Subjects must be between 18-65 years of age at the time of signing the Informed Consent Form (ICF) and must be able to meet all study requirements. AML patients under the age of 18 are excluded as is being studied in patients under 18 years of age in different venues
- Morphologically confirmed diagnosis of AML in accordance with World Health Organization (WHO) diagnostic criteria
- Adverse risk AML per 2017 European LeukemiaNet (ELN) recommendations
- Subjects must be either treatment naive defined by =\< 1 cycle of deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi) therapy, no history of cytotoxic chemotherapy for their AML; prior treatment with lenalidomide, hydroxyurea or erythropoiesis-stimulating agents (ESAs) is allowed (prior treatment for myelodysplastic syndrome \[MDS\] with \> 1 cycle of DNMTi is not allowed)
- A bone marrow aspirate and biopsy must be performed, and tissue collected for entrance to the trial
- Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- Recovery to =\< grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia
- White blood cell count (WBC) \< 25,000 (may be reduced with leukapheresis or hydroxyurea prior to study start)
- Direct bilirubin =\< 2 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 x institutional ULN
- Creatinine clearance \>= 30 mL/min (per the Cockcroft-Gault formula)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment or have received treatment, they are eligible if they have an undetectable HCV viral load
- Tumor lysis present prior to therapy must be treated accordingly prior to start of therapy
- +3 more criteria
You may not qualify if:
- Favorable or intermediate risk AML as defined by 2017 ELN criteria
- Presence of FLT3 TKD or FLT-ITD mutations
- Inability to tolerate oral medication or keep a pill diary
- Active documented central nervous system (CNS) leukemia
- Concurrent treatment with a non-permitted concomitant medication
- Concurrent anticancer treatment, major surgery, or use of any investigational drug within 28 days before the start of trial treatment
- Other malignancy currently being treated or likely to be treated in next 6 months with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ and patients receiving hormonal therapy for prevention of hormone-sensitive cancers
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax, ASTX727, or other agents used in study
- Patient must not have received known moderate or strong CYP3A inducers within 7 days of enrollment. Patient must not have known medical conditions requiring chronic therapy of moderate CYP3A inducers. 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
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations (including substance abuse) that would limit compliance with study requirements
- Pregnant women are excluded from this study because venetoclax and ASTX727 have 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 venetoclax, breastfeeding should be discontinued if the mother is treated with venetoclax. These potential risks may also apply to other agents used in this study
- Previous exposure to either venetoclax or \> 1 cycle of DNMTi (e.g. azacitidine, decitabine, ASTX727, CC486)
- Active, uncontrolled infection as determined by the investigator. Patients with infection under active treatment and controlled with antibiotics are eligible
- Any condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (7)
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233, United States
Yale University
New Haven, Connecticut, 06520, United States
Roswell Park Cancer Institute
Buffalo, New York, 14263, United States
Montefiore Medical Center-Einstein Campus
The Bronx, New York, 10461, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232, United States
University of Virginia Cancer Center
Charlottesville, Virginia, 22908, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Michael R Savona
Yale University Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 25, 2021
First Posted
March 26, 2021
Study Start
February 10, 2022
Primary Completion
June 6, 2025
Study Completion (Estimated)
November 5, 2026
Last Updated
November 10, 2025
Record last verified: 2025-11
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.