Phase I study of enzastaurin (ENZ) and bevacizumab (BV) in patients with advanced cancer

Abstract

3529 Background: ENZ is an oral kinase inhibitor that suppresses tumor growth through PKC and PI-3 kinase/AKT. BV is a monoclonal antibody that binds VEGF and inhibits angiogenesis. Since ENZ and BV complement each other in inhibiting angiogenesis, we conducted a Phase I study of ENZ and BV in advanced cancer patients (pts). Methods: Eligible pts had advanced cancer, adequate organ function and no co-morbidities suggesting increased risk of drug-related toxicities. Six pts were enrolled per cohort; if ≤ 1 DLT occured the next cohort opened. A treatment cycle consisted of 28 days (Dose Levels [DL] 1, 2 and 2a) or 21 days (DL 3 and 3a). A loading dose of ENZ 1125mg was given on Day 1, Cycle 1 for each cohort. DL 1 consisted of ENZ 500mg po daily and BV 5mg/kg IV on Days 1 and 15 of each cycle. Pts were then alternately assigned to DL 2 (BV 10mg/kg IV on Days 1 and 15) or DL 3 (BV 15mg/kg IV on Day 1 every 21 days). The ENZ dose remained 500mg daily. Additional pts were then alternately assigned to DL 2a (ENZ 250mg bid and BV 10mg/kg IV on Days 1 and 15) or DL 3a (ENZ 250mg bid and BV 15mg/kg IV on Day 1 every 21 days). DLT was defined as any of the following occurring in Cycle 1: Grade (G) 4 neutropenia ≥ 7 days, febrile neutropenia, G 3 thrombocytopenia with bleeding or G 4 thrombocytopenia, G 3 non-hematological toxicities, and toxicities associated with BV. Results: 24 pts (13 with ovarian cancer) are evaluable for toxicity through at least one cycle (6 each at DL 1, 2, 3 and 3 each at DL 2a and 3a). Fifteen are evaluable for response. One DLT (G 3 transaminitis) occurred after the first cycle at DL 2. This resolved after decreasing ENZ for 1 cycle, and the pt continues on study at full doses. No apparent increase in ENZ or BV toxicity was seen. One SAE (deep venous thrombosis) occurred at DL 3 after 3 cycles. Common toxicities included fatigue, chromaturia, dry/sore mouth, nausea and diarrhea. Eight pts (53%) had partial response (PR) or stable disease (SD) as best response. Seven of these pts remain on study with a range of duration of PR or SD of 8–24 weeks. Conclusions: The addition of ENZ to BV in any of the currently approved BV dosing schedules is well tolerated and clinically active in advanced cancer pts. The combination of ENZ and BV may be appropriate for further study in pts with NSCLC, colon or ovarian cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Genentech Eli Lilly