Phase I study of enzastaurin (ENZ) and bevacizumab (BV) in patients with advanced cancer: Safety, pharmacokinetics (PK), and response assessment

Abstract

3517 Background: ENZ, an oral kinase inhibitor, suppresses tumor growth through PKC and PI-3 kinase/AKT. BV binds VEGF and inhibits angiogenesis. Since ENZ and BV are complementary in inhibiting angiogenesis, we conducted a Phase I study of ENZ / BV. Methods: Eligible patients (pts) had advanced cancer, adequate organ function and no co-morbidities for increased risk of drug-related toxicities. Six pts were enrolled per cohort; if ≤1 DLT the next cohort opened. A loading dose of ENZ 1125 mg was given on Day 1, C1. After 1 cohort combining ENZ 500 mg/QD and BV at 5mg/kg IV q 2 wks, subsequent cohorts alternated pts between BV 10 mg/kg IV q 2 wks and BV 15 mg/kg IV q 3wks with escalating doses of ENZ (500 mg/QD, 250 mg/BID, and 375 mg/BID) for a total of 7 cohorts. DLT was defined as C1: Grade (G)4 neutropenia ≥7 days, febrile neutropenia, G3 thrombocytopenia with bleeding or G4 thrombocytopenia; G3/G4 non-hematological toxicities, and toxicities associated with BV. ENZ PK was performed at steady-state on Day 1, C2. Results: 43 pts (21 with ovarian cancer) are evaluable for toxicity. Two DLTs (G3 elevated aminotransferase and intraparenchymal hemorrhage) occurred at different dose levels. No apparent increase in ENZ or BV toxicity was seen. Two SAEs (DVT and myocardial ischemia) in two pts occurred at DL 3 after 3 cycles and 13 cycles, respectively. Common toxicities included fatigue, chromaturia, dry/sore mouth, nausea and diarrhea. Nine of 43 pts (21%) had a response (CR, PR), 6 responses were in the ovarian subset (29%). Median time to progression was 3.9 mos (range 0–19.2 mos) and 7.7 mos for ovarian pts (range 0.3–19.2 mos). Overall, 43% remained on study without disease progression for >6 mos (51% of ovarian pts remained on study for >6 mos). Mean steady-state ENZ concentrations (%CV) at 500 mg/QD, 250mg/BID and 375mg/BID were 1080 nmol/L (82.8 %), 516 nmol/L (102%) and 1120 nmol/L (93.3%), respectively. 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. ENZ exposures are highly variable and comparable across the three dose groups. The combination of ENZ / BV demonstrates encouraging activity, specifically in our population of ovarian cancer pts. [Table: see text]