Venetoclax in Combination With Intensive Induction and Consolidation Chemotherapy in Treatment Naïve AML

This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved venetoclax for this specific
disease but it has been approved for other uses.

In this research study, the investigators are combining the use of venetoclax (the
investigational drug being studied) with chemotherapy drugs daunorubicin and cytarabine. The
investigators are looking to determine the highest dose of venetoclax that can be given
safely in combination with these chemotherapy drugs.

Depending on when the participant join the study, the participant may participate in part 1
(induction with venetoclax escalation), part 2 (consolidation with venetoclax escalation), or
part 3 (an expansion cohort utilizing the maximum tolerated doses identified in parts 1 and
2). The study doctor will tell the participant which part of the study they will join.

Inclusion Criteria:

- Patients with AML who are newly diagnosed according to the WHO 2016 Classification and
previously untreated with the exception of hydroxyurea. ATRA pretreatment for
suspected APL for less than 5 days is allowed. Eligible patients with AML arising from
an antecedent hematologic disease (AHD) including MDS, may have been treated for their
prior hematologic disease (except for allogenic transplant).

- AML patients include de-novo AML, AML evolving from MDS or other AHD and AML after
previous cytotoxic therapy or radiation (secondary AML).

- For a diagnosis of AML, a bone marrow or peripheral blast count of 20% or more is
required.

- In AML with monocytic or myelomonocytic differentiation, monoblasts and
promonocytes, but not abnormal mature monocytes, are counted as blast
equivalents.

- Patients must be ≥18 and ≤75 years old.

- Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2. (See protocol
Appendix D.)

- LVEF ≥ 45% by MUGA or ECHO at screening.

- Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 50
mL/min; determined via urine collection for 24-hour creatinine clearance or by the
Cockcroft Gault formula.

- Adequate liver function as demonstrated by:

- aspartate aminotransferase (AST) ≤ 2.5 × ULN*

- alanine aminotransferase (ALT) ≤ 2.5× ULN*

- total bilirubin ≤ 1.5 × ULN*

- Unless considered due to leukemic organ involvement.

- Subjects with Gilbert's Syndrome may have a total bilirubin > 1.5 × ULN per discussion
with the overall study PI

- Male subjects must agree to refrain from unprotected sex and sperm donation from
initial study drug administration until 90 days after the last dose of study drug.

- Females of childbearing potential (i.e., not postmenopausal for at least 1 year or not
surgically sterile) must have negative results by a serum pregnancy test performed
within 7 days of day 1.

- Subject must voluntarily sign and date an informed consent, approved by an Independent
Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of
any screening or study-specific procedures.

Exclusion Criteria:

- Subject has acute promyelocytic leukemia, inversion16, t(8;21) or FLT3 mutant AML.

- Subject has known active CNS involvement with AML.

- Subject has tested positive for HIV (due to potential drug-drug interactions between
antiretroviral medications and venetoclax, as well as anticipated venetoclax
mechanism-based lymphopenia that may potentially increase the risk of opportunistic
infections). Note: HIV testing is not required.

- Subject is known to be positive for hepatitis B or C infection with the exception of
those with an undetectable viral load within 3 months. (Hepatitis B or C testing is
not required). Subjects with serologic evidence of prior vaccination to HBV [i.e., HBs
Ag-, and anti-HBs+] are allowed.

- Subject has received the following within 7 days prior to the initiation of study
treatment:

- Strong or moderate CYP3A inducers (see Appendix C)

- Strong and moderate CYP3A inhibitors (see Appendix C)

- Subject has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Star fruit within 3 days prior to the
initiation of study treatment.

- Subject has a cardiovascular disability status of New York Heart Association Class ≥
2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but
ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.

- Subject has a significant history of renal, neurologic, psychiatric, endocrinologic,
metabolic, immunologic, hepatic, cardiovascular disease, or any other medical
condition that in the opinion of the investigator would adversely affect his/her
participating in this study.

- Subject has chronic respiratory disease that requires continuous oxygen use.

- Subject has a malabsorption syndrome or other condition that precludes enteral route
of administration.

- Subject exhibits evidence of other clinically significant uncontrolled condition(s)
including, but not limited to: Uncontrolled systemic infection requiring IV therapy
(viral, bacterial or fungal).

- Subject has a history of other malignancies prior to study entry, with the exception
of:

- Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
breast;

- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
skin;

- Previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent.

- Prior malignancies treated with (surgery+/- chemotherapy+/- radiation) that have
remained disease free for at least two years after completion of therapy

- Subject has a white blood cell count > 25 × 109/L. Note: Hydroxyurea is permitted to
meet this criterion.

- Subject treated with any form of chemotherapy, immunotherapy, or investigative agent
within 1 month of enrollment.