Phase I pharmacokinetic study of the hypoxic cell sensitizer etanidazole with carboplatin and cyclophosphamide in the treatment of advanced ovarian cancer

Abstract

Purpose : A Phase I study was undertaken to determine the maximum tolerated dose of the hypoxic cell sensitizer etanidazole which could be administered with carboplatin and cyclophosphamide, to determine whether adequate serum levels of etanidazole were achieved to allow for alkylating agent sensitization, and whether pretreatment with etanidazole altered carboplatin pharmacokinetics. Methods and Materials Patients received 2 g/m 2 of intravenous etanidazole followed by a second dose of 4 g/m 2 90 min later, followed by intravenous carboplatin (300 mg/m 2) and cyclophosphamide (600 mg/m 2) for four treatment cycles. Patients received an additional two cycles of carboplatin and cyclophosphamide without etanidazole. Results : Two patients who received a total of 24 g/m 2 of etanidazole developed Grade 1 neurotoxicity, and therefore etanidazole doses were not escalated further. The grade of granulocytopenia was worse after cycles with etanidazole than after those without ( p = 0.03), but clinical outcome was not different. Etanidazole levels were adequate for alkylating agent sensitization (> 70 ug/ml) in all patients for the majority of the 7 h of testing. Pharmacokinetic data suggested t 1 2α and t 1 2β for carboplatin were prolonged after pretreatment with etanidazole. Conclusion : Etanidazole, 2 g/m 2 followed by 4 g/m 2 90 min later, is safe and results in adequate serum levels for alkylating agent sensitization. Neurotoxicity appears to prevent dose escalation of etanidazole, and an interaction between etanidazole and carboplatin may have enhanced neurotoxicity in these patients.