PHASE-I PHARMACOKINETIC STUDY OF THE HYPOXIC CELL SENSITIZER ETANIDAZOLE WITH CARBOPLATIN AND CYCLOPHOSPHAMIDE IN THE TREATMENT OF ADVANCEDOVARIAN-CANCER

Purpose: A Phase I study was undertaken to determine the maximum toler ated dose of the hypoxic cell sensitizer etanidazole which could be ad ministered with carboplatin and cyclophosphamide, to determine whether adequate serum levels of etanidazole were achieved to allow for alkyl ating agent sensitization, and whether pretreatment with etanidazole a ltered carboplatin pharmacokinetics. Methods and Materials: Patients r eceived 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. Pa tients received an additional two cycles of carboplatin and cyclophosp hamide without etanidazole. Results: Two patients who received a total of 24 g/m(2) of etanidazole developed Grade 1 neurotoxicity, and ther efore etanidazole doses were not escalated further. The grade of granu locytopenia was worse after cycles with etanidazole than after those w ithout (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. Pharmacokineti c data suggested t(1/2 alpha), and t(1/2 beta) for carboplatin were pr olonged after pretreatment with etanidazole. Conclusion: Etanidazole, 2 g/m(2) followed by 4 g/m(2) 90 min later, is safe and results in ade quate serum levels for alkylating agent sensitization. Neurotoxicity a ppears to prevent dose escalation of etanidazole, and an interaction b etween etanidazole and carboplatin may have enhanced neurotoxicity in these patients.