PHASE-I AND PHARMACOKINETIC STUDY OF KRN8602 ALONE AND WITH FILGRASTIM IN PATIENTS WITH ADVANCED CANCER

Purpose: To determine the recommended dose, toxicity profile, and phar macokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthra cycline with potent cytotoxicity against anthracycline-sensitive and r esistant experimental tumors in vitro and in vivo. patients and Method s: KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (D LT) was observed in three or more of five patients treated in a dose l evel. Because neutropenia was dose limiting, further escalation was in vestigated with filgrastim support. Results: Fifty-six assessable pati ents completed at least one cycle of chemotherapy. The recommended dos e of KRN8602 alone was 40 mg/m(2). Dose escalation was limited by neut ropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m(2 ), and limiting toxicities were neutropenia, diarrhea, and vomiting. T he most commonly experienced nonhematologic toxicity was nausea and vo miting. Alopecia and mucositis were infrequent and mild. Pharmacokinet ic parameters showed substantial variation, although the area under th e plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokineti c parameters and toxicity. Conclusion: KRN8602 at doses of 40 mg/m(2) when administered alone and 70 mg/m(2) when administered with filgrast im appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is curr ently being tested in phase II studies. (C) 1998 by American Society o f Clinical Oncology.