A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia

This study consists of two parts: A Phase 1 dose-escalation part that will evaluate the safety and pharmacokinetic profile of venetoclax in combination with low-dose cytarabine (LDAC), define the maximum tolerated dose (MTD), and generate data to support a recommended Phase 2 dose (RPTD) in treatment-naïve participants with acute myelogenous leukemia (AML); and a Phase 2 part that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy.


Eligibility Criteria:
Inclusion Criteria:

* Participant must be greater than or equal to 65 years of age in Phase 1 and 2. Participants 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 participants has at least one of the following co-morbidities, which make the participant unfit for intensive chemotherapy:

    * Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 - 3;
    * Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction less than or equal to 50% or chronic stable angina;
    * Diffusion capacity of carbon monoxide (DLCO) less than or equal to 65% or forced expiratory volume in one second (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 × upper limit of normal (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
* Participant must have a projected life expectancy of at least 12 weeks.
* Participant 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.
* Participant must have received no prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Participant may have been treated for prior Myelodysplastic Syndrome.
* Participant must have an ECOG performance status:

  * of 0 to 2 for participants greater than equal to 75 years of age
  * of 0 to 3 for participants greater than equal to 60 to 74 years of age, if 0 - 1 another co-morbidity is required to make participant eligible.
* Participant 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.
* Participant must have adequate liver function as demonstrated by:

  * aspartate aminotransferase (AST) less than or equal to 2.5 × ULN
  * alanine aminotransferase (ALT) less than or equal to 2.5 × ULN
  * bilirubin less than or equal to 1.5 × ULN for all participants age 75 and older

    * Participants who are less than 75 years of age must have a bilirubin of less than 3.0 × ULN.

Note: Participants with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.

* Male participants 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.
* Participant 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, participant 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 intravenous (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;
  * 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. Note: 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.
* Participant has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.