Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia.

Abstract

7007 Background: Treatment options for older patients (pts) with acute myelogenous leukemia (AML) unfit for intensive chemotherapy are limited. Expected complete remission rates for low-dose cytarabine (LDAC) are about 10% in this population. Targeting the pro-survival molecule BCL-2 has demonstrated clinical efficacy as a therapeutic strategy in various hematologic malignancies. Venetoclax (VEN), a selective BCL-2 inhibitor, shows synergy with cytarabine in several AML cell lines and primary samples. Methods: This is a non-randomized, open-label phase 1/2 dose-escalation/expansion study of VEN + LDAC, in treatment-naïve AML pts ≥ 65 years not eligible for intensive chemotherapy. Pts receive oral VEN once daily (QD) on days 1‒28 and subcutaneous LDAC 20 mg/m2 QD on days 1‒10 of each 28-day cycle. VEN dose escalation follows a 3 + 3 design; dose-limiting toxicities (DLTs: grade 4 toxicity, platelet count < 25,000/μL, or absolute neutrophil count < 500/μL within 14 days of last VEN dose) areassessed during cycle 1, up to day 42. Primary objectives include safety and preliminary efficacy evaluations. Results: As of Oct 1 2015, 18 pts (66.7% male; median age 74 years) have received LDAC + VEN in the phase 1 portion (VEN 600 mg target dose [n = 8]; VEN 800 mg target dose [n = 10]). Median time on study is 127.5 (range 30‒272) days; 9 pts (50%) remain on study. DLTs of Grade 4 thrombocytopenia lasting > 42 days without evidence of residual leukemia occurred in 2 pts in the VEN 800 mg dose group. The recommended phase 2 dose is 600 mg. Adverse events (AEs; ≥ 30% prevalence) were nausea (77.8%), anemia (55.6%), febrile neutropenia, neutropenia, fatigue (each 38.9%), vomiting, diarrhea and hypokalemia (each 33.3%). The most common serious AE was febrile neutropenia (33.3%). No clinically significant tumor lysis syndrome was observed. The overall response rate in phase 1 was 44% (complete remission, n = 4; complete remission without complete marrow recovery, n = 4; resistant disease, n = 8; death before evaluation, n = 2). Conclusions: Initial findings suggest that VEN + LDAC has acceptable tolerability and promising clinical activity in older, treatment-naïve AML pts. Available phase 2 updates will be presented. Clinical trial information: NCT02287233.