Liposome-encapsulated Daunorubicin-Cytarabine and Venetoclax in Treating Participants With Relapsed, Refractory or Untreated Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To assess the efficacy (complete remission [CR], complete remission without blood count
recovery [CRi], complete remission without platelet recovery [CRp]) of liposome-encapsulated
daunorubicin-cytarabine (CPX-351) in combination with venetoclax in patients with acute
myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To assess safety of CPX-351 in combination with venetoclax in patients with AML.

II. To assess the event free survival (EFS) and overall survival (OS) in patients with AML.

EXPLORATORY OBJECTIVES:

I. To explore biomarkers of response and resistance in AML treated with CPX-351 and
venetoclax.

OUTLINE:

INDUCTION: Participants receive liposome-encapsulated daunorubicin-cytarabine intravenously
(IV) over 90 minutes on days 1, 3, and 5 of course 1 and on days 1 and 3 of course 2.
Participants also receive venetoclax orally (PO) once daily (QD) on days 2-21. Treatment
repeats every 28 days for up to 2 courses in the absence of disease progression or
unacceptable toxicity.

CONSOLIDATION: Participants receive liposome-encapsulated daunorubicin-cytarabine IV over 90
minutes on days 1 and 3 and venetoclax PO QD on days 2-21. Treatment repeats every 28 days
for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- For the lead in phase: Patients >= 18 years of age with a diagnosis of relapsed and/or
refractory AML will be eligible

- For the dose expansion cohort A (relapsed/refractory [R/R] AML): Patients >= 18 years
of age with a diagnosis of relapsed and/or refractory AML will be eligible

- For the dose expansion cohort B (de novo AML): Patients >=18 years to 59 years of age.
Patients in this cohort must have received no prior therapy for AML and have no prior
history of an antecedent hematologic disorder (eg. myelodysplastic syndrome,
myeloproliferative neoplasm, or aplastic anemia)

- Prior therapy with hydroxyurea, hematopoietic growth factors, or tretinoin (ATRA) (for
emergency use for stabilization) is allowed with no washout. A cumulative dose of
ara-C of up to 3 g for emergency stabilization in patients with rapidly proliferating
disease is also allowed provided it was administered > 48 hrs prior to enrollment

- Bilirubin =< 2 mg/dL

- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x upper
limit of normal (ULN) or < 5 x ULN if related to leukemic involvement

- Creatinine =< 1.5 x ULN

- Known cardiac ejection fraction of > or = 45% within the past 3 months

- 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. A woman of childbearing
potential is defined as a woman who has not been naturally postmenopausal for at least
12 consecutive months, or who had no previous surgical sterilization

- 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 active uncontrolled
infection, symptomatic congestive heart failure (New York Heart Association [NYHA]
class III or IV), unstable angina pectoris, clinically significant 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

- Patients with acute promyelocytic leukemia (M3) or core-binding factor AML

- Patients with active central nervous system (CNS) leukemia are excluded since the
antileukemia activity of the treatment components against CNS leukemia are not known

- 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 treatment with CPX-351 or venetoclax