A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia
Trial Status: Complete
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.
- 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)
- 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.
University of Kansas Clinical Research Center
University of Kansas Cancer Center
University of Kansas Hospital-Westwood Cancer Center
University of Michigan Comprehensive Cancer Center
University of Pittsburgh Cancer Institute (UPCI)
Vanderbilt University / Ingram Cancer Center
Fred Hutch / University of Washington Cancer Consortium
Trial Phase Phase I/II
Trial Type Treatment
- Primary ID M14-387
- Secondary IDs NCI-2015-00216, 2014-002610-23
- Clinicaltrials.gov ID NCT02287233