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

PRIMARY OBJECTIVES:

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 (AZA).

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.

OUTLINE:

INDUCTION: Participants 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. Participants who do not achieve a CR or CRi after
course 1 may receive a second induction course. Participants who do not achieve CR or CRi
after second induction course may proceed to course 3 of consolidation per investigator.

CONSOLIDATION/MAINTENANCE:

Participants who achieve CR or CRi after course 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 course 2. All participants receive cladribine IV daily over 1-2 hours of courses
5-6, 9-10, 13-14, and 17-18, cytarabine SC BID on days 1-3 of courses 5-6, 9-10, 13-14, and
17-18, venetoclax PO QD on days 1-21 of course 3-18, and azacitidine SC daily or IV over
30-60 minutes on days 1-7 of courses 3-4, 7-8, 1-12, and 15-18. Treatment repeats every 28
days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 6-12 months for 5
years.

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 < 60 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.