Acute Myeloid Leukemia Clinical Trial
Testing Oral Decitabine and Cedazuridine (ASTX727) in Combination With Venetoclax for Higher-Risk Acute Myeloid Leukemia Patients
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 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.
I. To determine the recommended safe phase 2 dose of venetoclax + decitabine and cedazuridine (ASTX727) defined as the highest dose level in which one or fewer dose limiting toxicities (DLTs) are experienced among six patients. (Phase Ib) II. To determine and compare the preliminary efficacy of venetoclax +ASTX727 versus (vs.) standard anthracycline induction therapy ('7+3') with a primary endpoint of event-free survival (EFS). (Phase II)
I. To observe and record anti-tumor activity. (Phase Ib) II. To determine the complete response (complete response [CR] + complete response with incomplete bone marrow recovery [CRi]) rate in patients with treatment naive FLT3 wild type (WT) acute myeloid leukemia (AML) treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3'). (Phase II) III. To determine the duration of response (DoR) in patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3'). (Phase II) IV. To determine the progression free survival (PFS) of patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3'). (Phase II) V. To determine the overall response rate (ORR) in patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3'). (Phase II) VI. To determine the overall survival (OS) of patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3'). (Phase II) VII. To determine the proportion of patients receiving stem cell transplantation (SCT) in patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3'). (Phase II) VIII. To identify mutational burdens in venetoclax +ASTX727 sensitive vs. resistant AML leukemia initiating cells (LICs). (Phase II)
I. To identify transcriptomic signatures in venetoclax +ASTX727 sensitive vs. resistant AML LICs.
II. Determine the utility of high-throughput phenotype-based assessment of drug efficacy for predicting patient response to venetoclax +ASTX727.
III. Determine if treatment failure is a function of therapy sequence or results in resistance to the alternative therapy by conducting a co-clinical trial via patient-derived xenograft (PDX).
IV. To characterize the pharmacokinetics of venetoclax. V. To determine the morphologic leukemia-free state (MLFS) rate in patients with treatment naïve FLT3WT AML treated with venetoclax and ASTX727 vs. 7+3 therapy.
OUTLINE: This is a phase Ib dose de-escalation study followed by a phase II randomized study.
PHASE Ib: Patients receive ASTX727 (decitabine and cedazuridine) orally (PO) once daily (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.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients 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: Patients receive cytarabine intravenously (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.
After completion of study treatment, patients are followed up every 3 months for up to 5 years.
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 leukopheresis 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
The effects of venetoclax and ASTX727 on the developing human fetus are unknown. For this reason and because BCL2 inhibitor and DNMTi agents as well as other therapeutic agents used in this trial (cytarabine and daunorubicin) are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal method of birth control or abstinence) prior to study entry and for the duration of study participation, and for 6 months following completion of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception (latex or synthetic condom or abstinence) prior to the study, for the duration of study participation, and 3 months after completion of venetoclax and ASTX727 administration
Ability to understand and the willingness to sign a written informed consent document
Adequate cardiac systolic function as measured by ejection fraction (EF) >= 50%
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
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