Abstract
Summary Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination’s safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7–5.5), with 8.3 months (95 % CI, 3.7–11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-012-9850-6) contains supplementary material, which is available to authorized users.
Highlights
IntroductionEnzastaurin HCL (enzastaurin, LY317615) was developed as a selective PKCβ inhibitor [1, 2]
Enzastaurin HCL was developed as a selective PKCβ inhibitor [1, 2]
The content was presented in part at the: Ovarian Cancer Research Symposium (Rivken Conference), 2008; 44th Annual Meeting of the American Society of Clinical Oncology, 2008; 45th Annual Meeting of the American Society of Clinical Oncology, 2009; 41st Annual Meeting of the Society of Gynecologic Oncologists, 2010
Summary
Enzastaurin HCL (enzastaurin, LY317615) was developed as a selective PKCβ inhibitor [1, 2]. Enzastaurin has antiproliferative and antiapoptotic activities [2]. Enzastaurin has antiangiogenic activity [3]. Enzastaurin inhibits the AKT pathway with reduced phosphorylation of glycogen synthase kinase 3β (GSK3-β) and AKT [2]. Vascular endothelial growth factor (VEGF) is a regulator of blood vessel growth [4]. Bevacizumab is a humanized anti-VEGF monoclonal antibody [4]. Because bevacizumab and enzastaurin mechanisms of action did not appear to overlap, we hypothesized that the combination might have additive or synergistic effects on tumors
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