Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics

Nwabundo Nwankwo, Zhe Zhang, Ting Wang, Connie Collins, Lee Resta, Sabine Ermisch, Jeannette Day, Rodney Decker, Lori Kornberg, Steven Nicol, Donald Thornton, Deborah K Armstrong, Michael A Carducci, Nwabundo Nwankwo, Zhe Zhang, Ting Wang, Connie Collins, Lee Resta, Sabine Ermisch, Jeannette Day, Rodney Decker, Lori Kornberg, Steven Nicol, Donald Thornton, Deborah K Armstrong, Michael A Carducci

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00550927.

Figures

Fig. 1
Fig. 1
Study design. Dosing of the cohorts is shown. BID, twice daily; BV, bevacizumab; DLT, dose-limiting toxicity; ENZ, enzastaurin; IV, intravenous; PO, oral; QD, once daily. * All cohorts subsequent to Dose Level 1 followed the same enrollment pattern and safety assessment schedule shown in Dose Level 1

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