a study evaluating venetoclax in combination with low-dose cytarabine in treatment-naïve participants with acute myelogenous leukemia

Conditions: Acute Myelogenous Leukemia; AML

Summary: 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.

Keywords: myelogenous leukemia treatment naive aml untreated aml