Phase 1b Study of Venetoclax in Combination with Intensive Induction and Consolidation Chemotherapy in Treatment Naïve Subjects with Acute Myelogenous Leukemia

Protocol # :
Acute Myeloid Leukemia
Disease Sites
Myeloid and Monocytic Leukemia
Principal Investigator
Stone, Richard, M

Trial Description

This research study is studying the combination of venetoclax and chemotherapy as a possible
treatment for acute myelogenous leukemia (AML).

The drugs involved in this study are:

- Venetoclax

- Daunorubicin

- Cytarabine

Eligibility Requirements

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

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

- Patients must be ≥18 and ≤60 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 as
described below. Contact PI with questions.

- Inversion 16 and t(8;21): CBF chromosomal abnormalities may be assessed by
molecular (PCR), metaphase cytogenetics, or FISH

- FLT3: ITD or a point mutation in the TKD loop of variant allele fractions ≥5% by
PCR, capillary electrophoresis, or NGS panel capable of defining FLT3 allelic

- 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

- 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.

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

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

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

- 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.