Phase 3, randomized, double-blind, placebo-controlled study of venetoclax combined with azacitidine versus azacitidine in treatment-naïve patients with acute myeloid leukemia.

Abstract

TPS7069 Background: Elderly acute myeloid leukemia (AML) is a biologically and clinically distinct disease with a diminished response to chemotherapy, low remission rates, and short disease-free and overall survival. Venetoclax (VEN) is a potent, selective small-molecular inhibitor of BCL-2. In preclinical models, venetoclax has been shown to kill AML cells as a single agent with demonstrated synergistic activity in combination with the DNA methyltransferase inhibitor azacitidine (AZA). Early clinical data from a phase 1b study (NCT02203773) showed that VEN plus AZA had an acceptable safety profile and promising efficacy in treatment-naïve elderly patients with AML. The current phase 3 study continues to evaluate the combination for this AML population. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT02993523) is designed to assess VEN plus AZA compared with placebo plus AZA in treatment-naïve elderly and adult patients with AML who are not eligible for standard induction therapy due to age or comorbidities. Primary objectives of the study are to evaluate if VEN with AZA will improve overall survival (OS) and composite complete remission rate (CR+CRi) versus placebo with AZA. Secondary objectives include event-free survival, CR+CRi rate at the end of Cycle 1, and if combining VEN plus AZA reduces fatigue and improves global health status/quality of life based on patient reported outcomes versus placebo with AZA. Exploratory objectives are to evaluate biomarkers predictive of VEN activity including minimal residual disease negativity rate, and BCL-2 expression and outcome measures of overall survival and complete remission rate, as well as the impact of VEN on additional quality of life measures. Patients will be randomized 2:1 to VEN plus AZA (arm A) or placebo plus AZA (arm B). Patients on arm A will receive once daily 400 mg VEN orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days in a 28-day cycle. Patients on arm B will receive once daily placebo orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days on a 28-day cycle. Study recruitment began in February 2017, with target enrollment of 400 patients. Clinical trial information: NCT02993523.