Venetoclax, Cladribine, Low Dose Cytarabine, and Azacitidine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Venetoclax, Cladribine, Low Dose Cytarabine, and Azacitidine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Phase II Study of Venetoclax Added to Cladribine Plus Low Dose Cytarabine (LDAC) Induction Followed by Consolidation With Cladribine Plus LDAC Alternating With 5-Azacitidine With Venetoclax in Patients With Untreated AML

This phase II trial studies how well venetoclax, cladribine, low dose cytarabine, and azacitidine work in treating patients with acute myeloid leukemia that has previously not been treated. Drugs used in chemotherapy, such as venetoclax, cladribine, and low dose cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax, cladribine, low dose cytarabine induction followed by cladribine, low dose cytarabine, and azacitidine consolidation may work better in treating patients with acute myeloid leukemia.

PRIMARY OBJECTIVE: I. To assess the complete response (CR/complete response with incomplete recovery [CRi]) rate of patients with acute myeloid leukemia (AML) treated with venetoclax combined with cladribine (2-CDA) plus low-dose cytarabine (LDAC) alternating with 5-azacytidine. SECONDARY OBJECTIVES: I. To assess overall survival (OS) of patients with AML treated with venetoclax added to cladribine plus LDAC alternating with 5-azacytidine. II. To assess the disease free survival (DFS) patients with AML treated with venetoclax added to cladribine plus LDAC alternating with 5-azacytidine and achieved a complete response (CR/CRi). III. To assess the overall response rate of patients with AML treated with venetoclax added to cladribine plus LDAC alternating with 5-azacytidine. IV. To assess toxicity and induction mortality of patients with AML treated with venetoclax added to cladribine plus LDAC alternating with 5-azacytidine. EXPLORATORY OBJECTIVES: I. Evaluate and determine venetoclax pharmacokinetics (pK) in presence or absence of concomitantly administered drugs such as posaconazole, voriconazole, isafuconazole, and fluconazole. II. Investigate the correlation between venetoclax pK with toxicities and efficacy. III. Investigate the correlation of baseline cytogenetic and mutational data with likelihood of response and resistance to the regimen. IV. Evaluate the depth of response with minimal residual disease (MRD) testing and correlate with long term outcome. OUTLINE: INDUCTION: Patients receive cladribine intravenously (IV) daily over 1-2 hours on days 1-5, cytarabine subcutaneously (SC) twice daily (BID) on days 1-10, and venetoclax orally (PO) daily on days 1-21. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR or CRi after cycle 1 may receive a second induction cycle. Patients who do not achieve CR or CRi after second induction cycle may proceed to cycle 3 of consolidation per investigator. CONSOLIDATION/MAINTENANCE: Patients who achieve CR or CRi after cycle 1 of induction receive cladribine IV over 1-2 hours daily on days 1-3, cytarabine SC BID on days 1-10, and venetoclax PO once daily (QD) on days 1-21 of cycle 2. All patients receive cladribine IV daily over 1-2 hours of cycles 5-6, 9-10, 13-14, and 17-18, cytarabine SC BID on days 1-3 of cycles 5-6, 9-10, 13-14, and 17-18, venetoclax PO QD on days 1-21 of cycle 3-18, and azacitidine SC daily or IV over 30-60 minutes on days 1-7 of cycles 3-4, 7-8, 1-12, and 15-18. Treatment repeats every 28 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6-12 months for 5 years.

5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, Vidaza

.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453

The optimum two-stage design will be implemented. Will be estimated along with the 95% confidence intervals.

Kaplan-Meier method will be used to assess the OS probabilities. The median OS will be reported, along with the 95% confidence intervals.

Time interval between treatment start and the date of death or last follow-up, whichever occurred first, assessed up to 5 years

Kaplan-Meier method will be used to assess the DFS probabilities. The median DFS will be reported, along with the 95% confidence intervals.

Time interval between treatment start and the date of death or last follow-up, whichever occurred first, assessed up to 5 years

Incidence of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

The Bayesian approach will be implemented for toxicity monitoring, where toxicity is defined as any grade 3 or higher non-hematological toxicity which is at least possibly related to the treatment that occurs during the first 2 cycles of treatment. Safety data will be summarized by category, severity and frequency.

Inclusion Criteria: Patients with previously untreated acute myeloid leukemia (AML). Prior therapy with hydroxyurea, hematopoietic growth factors, HMA, all-trans retinoic acid (ATRA), or a total dose of cytarabine up to 2 g (for emergency use for stabilization) is allowed. Patients aged < 50 years who are unsuitable for standard induction therapy may be eligible after discussion with primary investigator. Bilirubin =< 2 mg/dL. Unless liver enzyme abnormalities are determined by the treating Doctor of Medicine (MD) and principal investigator (PI) to be due to leukemic infiltration. Aspartate aminotransferase (AST) and/or alanine aminotransferase (AL)T =< 3 x ULN. Unless liver enzyme abnormalities are determined by the treating MD and PI to be due to leukemic infiltration. Creatinine =< 1.5 x upper limit of normal (ULN). Eastern Cooperative Oncology Group (ECOG) performance status of =< 2. A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial. Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol. Exclusion Criteria: Pregnant women are excluded from this study because the agents used in this study have the potential for teratogenic or abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided. Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patient with documented hypersensitivity to any of the components of the chemotherapy program. Men and women of childbearing potential who do not practice contraception. Women of childbearing potential and men must agree to use contraception prior to study entry and for the duration of study participation. Prior therapy with venetoclax. Patients with a diagnosis of acute promyelocytic leukemia (AML-M3) will be excluded from this study.

Kadia TM, Reville PK, Wang X, Rausch CR, Borthakur G, Pemmaraju N, Daver NG, DiNardo CD, Sasaki K, Issa GC, Ohanian M, Montalban-Bravo G, Short NJ, Jain N, Ferrajoli A, Bhalla KN, Jabbour E, Takahashi K, Malla R, Quagliato K, Kanagal-Shamanna R, Popat UR, Andreeff M, Garcia-Manero G, Konopleva MY, Ravandi F, Kantarjian HM. Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. J Clin Oncol. 2022 Nov 20;40(33):3848-3857. doi: 10.1200/JCO.21.02823. Epub 2022 Jun 15.