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

• Status: Completed
• Trial end date: 2021-08-10
• Target enrollment: 0
• Participant gender: All

Summary

This study consists of two 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 participants 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 participants allowed additional supportive medications (strong Cytochrome P450 3A (CYP3A )inhibitors) if medically indicated.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: AbbVie
• Collaborator: Genentech, Inc.
• Treatments: Cytarabine; Venetoclax

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:

• 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 × 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 Eastern Cooperative Oncology Group (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.

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.

• Participant 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 participants age 75 and older* Participants 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: 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 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.