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AT-03PHASE I TRIAL OF ENZASTAURIN (LY 317615) IN COMBINATION WITH CARBOPLATIN IN ADULTS WITH RECURRENT GLIOMA

BACKGROUND: Enzastaurin is a selective protein kinase-C β inhibitor with antiangiogenic activity. Preclinical studies support its potential efficacy in combination with carboplatin in high-grade glioma. METHODS: The objective of this open-label phase-I study in adults with refractory high-grade glioma was to determine the maximum tolerated dose, and describe pharmacokinetics of carboplatin in combination with enzastaurin. Patients were stratified based on antiepileptic medication [Group A= nEIAED, Group B = EIAED]. A lead in period with single agent enzastaurin was administered for 7 days (loading dose of 1125 mg Day 1 + 500 mg/d x 6d (Group A); 875 mg/d x 6d (Group B). Each subsequent 28-day-cycle consisted of carboplatin (AUC 3, 4, 5, or 6 Day 1) with enzastaurin (500-875 mg/d Day 1-28). Carboplatin was dose escalated on a 4 + 8 schema. Plasma samples for enzastaurin, its active metabolite-LY326020 and total-platinum were collected at various time points. Adverse events were monitored and graded using NCI CTCAE criteria version 3.0. RESULTS: Fifty-eight patients were accrued (43 Group A;15 Group B). 12 dose limiting toxicities (DLT) occurred in 11 patients (Group-A, 8; Group B, 3). These included lymphopenia (n = 5), deep-vein thrombosis (n = 2), and thrombocytopenia (n = 2). Multi-organ failure resulted in 1 study-related death in Group A. PK analyses were available for 32 patients. Lower area under the plasma concentration time curve ( AUCt), maximum (Cmax ), and average steady-state concentration (Cav,ss) for enzastaurin and LY326020 were noted in Group B. Total platinum exposures [AUC(0-∞)] were generally lower than the targeted AUC but increased with increasing dose, and no differences were observed when given with enzastaurin. CONCLUSION: The maximum tolerated dose of carboplatin in combination with enzastaurin was not reached prior to termination of the study for poor accrual. EIAEDs significantly decreased enzastaurin and its active metabolite. No significant pharmacokinetic interactions were noted between enzastaurin and carboplatin.