Phase I trial and pharmacokinetic analysis of ifosfamide in cats with sarcomas

Abstract

Objective - To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of ifosfamide in tumor-bearing cats. Animals - 38 cats with resected, recurrent, or metastatic sarcomas. Procedure - The starting dosage of ifosfamide was 400 mg/m2 of body surface area, IV, and dosages were increased by 50 to 100 mg/m2 in cohorts of 3 cats. To protect against urotoxicosis, mesna was administered at a dosage equal to 20% of the calculated ifosfamide dosage. Diuresis with saline (0.9% NaCl) solution before and after administration of ifosfamide was used to minimize nephrotoxicosis. Samples for pharmacokinetic analysis were obtained after the MTD was reached. Results - 38 cats were entered into this phase I study and were administered a single dose of ifosfamide at various dosages. The MTD was 1,000 mg/m2, and neutropenia was the DLT. Seven of 8 episodes of neutropenia were on day 7 after treatment, and 1 cat developed severe neutropenia on day 5. Adverse effects on the gastrointestinal tract were generally mild and self-limiting, the most common of which was nausea during ifosfamide infusion. One cat had signs consistent with a drug-induced hypersensitivity reaction. There were no episodes of hemorrhagic cystitis or nephrotoxicosis. Correlations between pharmacokinetic variables and ifosfamide-associated toxicoses were not found. Preliminary evidence of antitumor activity was observed in 6 of 27 cats with measurable tumors. Conclusions and clinical relevance - The dosage of ifosfamide recommended to treat tumor-bearing cats is 900 mg/m2 every 3 weeks. This dosage should be used in phase II clinical trials.