Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy.

7009 Background: Venetoclax (VEN) is a potent, orally bioavailable BCL-2 inhibitor with single-agent activity in relapsed/refractory acute myeloid leukemia (AML) patients (pts), displaying synergistic activity with hypomethylating agents in preclinical studies. This trial evaluates VEN plus decitabine (DEC) or azacitidine (AZA) in treatment (Tx)-naive AML pts ≥ 65 y (NCT02203773). Methods: Tx-naive pts (ECOG PS ≤ 2, ≥ 65 y, intermediate- or poor-risk karyotype) not eligible for standard induction therapy received DEC (Arm A: 20 mg/m2 iv) daily on days (D) 1−5 or AZA (Arm B: 75 mg/m2; subcutaneous or iv) daily on D 1−7 of each 28-D cycle in combination with once-daily continuous oral VEN. VEN dose escalation follows a 3+3 design; 1200 mg is the final dose level. Objectives include safety, preliminary efficacy, and biomarker evaluations. Results: As of 11/28/15, 39 pts (49% male; median age 74 y [65–85 y]) have been enrolled in Arm A (n = 20) and Arm B (n = 19). Median time on study is111 D (6−375 D); 16 pts (41%) remain on therapy. Biomarker analysis and response evaluations have been completed in 34 pts with 400-mg and 800-mg VEN doses. As of 9/19/15, overall response rate (ORR; complete response [CR]/CR with incomplete marrow recovery [CRi]/partial remission [PR]) within this population was 76% (CR: 13/CRi: 11/PR: 2; 26/34 pts). Poor-risk cytogenetics and IDH1/2 mutations were reported in 24% (8/34) and 32% (11/34) of pts; ORR was 88% (7/8) and 82% (9/11), respectively. Median time to CR/CRi was 29.5 D (24−112 D). Most common TEAEs were nausea (54%), febrile neutropenia (41%), diarrhea (44%), decreased appetite (33%), and peripheral edema (31%). No dose-limiting toxicity was reported. Febrile neutropenia (41%) and neutropenia (33%) were the most common Grade 3/4 TEAEs. Most frequent serious AE was febrile neutropenia (28%). Four relapses occurred, all on Arm A. Six deaths occurred (3 disease progression, 1 sepsis, 1 respiratory failure, 1 bacteremia). MTD has not been reached. Conclusions: Tx with VEN plus DEC or AZA shows a tolerable safety profile, with high response rates observed in Tx-naive AML pts ≥ 65 y, including those with adverse biologic disease features. Clinical trial information: NCT02203773.