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Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C ß-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer

Authors' Affiliations: ¹ Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute; ² Department of Clinical Pharmacy, Slotervaart Hospital, Amsterdam, the Netherlands; ³ Department of Medical Oncology and Laboratory of Experimental Oncology, University Medical Center Utrecht; ⁴ Faculty of Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands; and ⁵ Eli Lilly and Co., Indianapolis, Indiana

Requests for reprints: Jeany M. Rademaker-Lakhai, Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands. E-mail: jeanyrademaker{at}quicknet.nl.

Purpose: Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin.

Experimental Design: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m² and cisplatin doses were either 60 or 75 mg/m². Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers.

Results: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation.

Conclusions: Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m² gemcitabine, and 75 mg/m² cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.

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