A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia (AML)

This study consists of three portions: The first portion- Phase 1, or dose-escalation
portion, that will evaluate the safety and pharmacokinetic profile of venetoclax in
combination with low-dose cytarabine (LDC), define the maximum tolerated dose (MTD), and
generate data to support a recommended Phase 2 dose (RPTD) in treatment-naïve subjects with
Acute Myelogenous Leukemia (AML). Second portion, initial Phase 2 that will evaluate if the
RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the
combination therapy. Subsequently, Phase 2 Cohort C, will evaluate the overall response rate
(ORR) for subjects allowed additional supportive medications (strong CYP3A inhibitors) if
medically indicated.

Eligibility Criteria

Inclusion Criteria:

- Subject must be greater than or equal to 65 years of age in Phase 1 and 2. Subjects
enrolled in Cohort C must be either:

- greater than or equal to 75 years of age; OR

- greater than or equal to 60 to 74 years will be eligible if the subjects has at
least one of the following co-morbidities, which make the subject unfit for
intensive chemotherapy:

- ECOG Performance Status of 2 - 3;

- Cardiac history of CHF requiring treatment or Ejection Fraction less than or equal to
50% or chronic stable angina;

- DLCO less than or equal to 65% or FEV1 less than or equal to 65%;

- Creatinine clearance greater than or equal to 30 mL/min to less than 45 ml/min
(calculated by Cockcroft-Gault formula)

- Moderate hepatic impairment with total bilirubin greater than 1.5 to less than or
equal to 3.0 × ULN

- Any other comorbidity that the physician judges to be incompatible with intensive
chemotherapy must be reviewed and approved by the study medical monitor before study
enrollment

- Subject must have a projected life expectancy of at least 12 weeks.

- Subject must have histological confirmation of AML and be ineligible for treatment
with a standard cytarabine and anthracycline induction regimen due to co-morbidity or
other factors.

- Subject must have received no prior treatment for AML with the exception of
hydroxyurea, allowed through the first cycle of study treatment. Note: Subject may
have been treated for prior Myelodysplastic Syndrome.

- Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status;

- of 0 to 2 for subjects greater than equal to 75 years of age

- of 0 to 3 for subjects greater than equal to 60 to 74 years of age, if 0 - 1
another co-morbidity is required to make subject eligible.

- Subject must have adequate renal function as demonstrated by a creatinine clearance
greater than or equal to 30 mL/min; determined via urine collection for 24-hour
creatinine clearance or by the Cockcroft Gault formula.

Note: Investigators should consider measuring a 24-hour creatinine clearance for subjects
who are morbidly obese, have fluctuating renal function, or who in the investigator's
clinical judgment may yield a more accurate clearance when measured than when calculated.

- Subject must have adequate liver function as demonstrated by:

- aspartate aminotransferase (AST) less than or equal to 2.5 × upper limit of
normal (ULN)*

- alanine aminotransferase (ALT) less than or equal to 2.5 × ULN*

- bilirubin less than or equal to 1.5 × ULN for all subjects age 75 and older*
Subjects who are less than 75 years of age must have a bilirubin of less than
3.0 × ULN * Unless considered due to leukemic organ involvement. Note: Subjects
with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per
discussion between the investigator and AbbVie medical monitor.

- Male subjects must agree to refrain from unprotected sex and sperm donation from
initial study drug administration until 180 days after the last dose of study drug.

- 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.

- If female, subject must be either:

- Postmenopausal defined as no menses for 12 or more months without an alternative
medical cause OR

- Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).

Exclusion Criteria:

- Participant has received treatment with cytarabine for a pre-existing myeloid
disorder.

- Participant has acute promyelocytic leukemia (French-American-British Class M3 AML).

- Participant has known active central nervous system (CNS) involvement with AML.

- Participant has tested positive for human immunodeficiency virus (HIV).

- Participant has received the following within 7 days prior to the initiation of study
treatment: strong and moderate CYP3A inducers such as rifampin, carbamazepine,
phenytoin, and St. John's wort.

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

- Participant has a cardiovascular disability status of New York Heart Association
Class greater than 2.

- Participant 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.

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

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

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

- Participant has a history of other malignancies prior to study entry, with the
exception of: adequately treated in situ carcinoma of the breast or cervix uteri;
basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; or
previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent.

- Participant has a white blood cell count greater than 25 × 10^9/L. Hydroxyurea is
permitted to meet this criterion.

- Participant is a candidate for a bone marrow or stem cell transplant within 12 weeks
after study enrollment.

- Subject has a history of myeloproliferative neoplasm (MPN) including polycythemia
vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.

Principal Investigator

John Hayslip, MD

Study Contact

AbbVie_Call Center, MS, abbvieclinicaltrials@abbvie.com, 847-283-8955

Estimated Completion Date

Saturday, September 1, 2018

ClinicalTrials.gov #

NCT02287233
04/11/2017