This phase Ib/II trials studies the side effects of decitabine/cedazuridine (ASTX727) and venetoclax in combination with ivosidenib or enasidenib, and how well they work in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). ASTX727 is the combination of a fixed dose of 2 drugs, cedazuridine and decitabine. Cedazuridine may slow down how fast decitabine is broken down by the body, and decitabine may block abnormal cells or cancer cells from growing. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Enasidenib and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving decitabine/cedazuridine and venetoclax in combination with ivosidenib or enasidenib may help control acute myeloid leukemia.
Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (including biphenotypic or bilineage leukemia including a myeloid component or isolated extramedullary AML); OR
Patients (> 60 year old) with newly diagnosed AML not eligible for intensive chemotherapy are also eligible
Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
Severe pulmonary disorder (eg, DLCO ≤65% or forced expiratory volume in 1 second [FEV1] ≤65%).
Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
Patients with any concurrent uncontrolled clinically significant medical condition including life-threatening severe infection, or psychiatric illness, which could place the patient at unacceptable risk of study treatment
Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI)
Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
Parallel
Decitabine and Cedazuridine
DrugGiven PO
Enasidenib
DrugGiven PO
Ivosidenib
DrugGiven PO
Venetoclax
DrugGiven PO
Dose limiting toxicity (Phase Ib)
Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 by organ system.
Overall response rate (ORR) (Phase II)
Defined as complete remission (CR), CR with incomplete hematologic recovery, CR with incomplete count recovery, partial response or marrow clearance of blasts. Will estimate the ORR for the combination treatmen1t, along with the Bayesian 95% credible interval.
Incidence of adverse events (Phase II)
Assessed using Common Toxicity Criteria version 5.0. Safety data will be summarized using frequency and percentage, by category and severity.
Event-free survival (EFS)
The Kaplan-Meier method will be used to estimate the probabilities of EFS. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.
Overall survival (OS)
The Kaplan-Meier method will be used to estimate the probabilities of OS. Log-rank tests will be used to compare among subgroups of patients in terms of OS.
Duration of response
The Kaplan-Meier method will be used to estimate the probabilities and log-rank tests will be used to compare among subgroups of patients.
Minimal residual disease negative status
Will be summarized graphically and with descriptive statistics. The association between molecular and cellular markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.
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