Phase I trial of i.v. administered tirapazamine plus cyclophosphamide

Our objective was to determine the maximum tolerated doses of tirapazamine and cyclophosphamide given i.v., in combination. Eligible patients had adva nced solid tumors refractory to conventional treatment. Tirapazamine (escal ated from 80 to 390 mg/m(2)) was given i.v. over 2 h rind followed by cyclo phosphamide over 1 h, The cyclophosphamide dose was fixed at 1000 mg/m(2) u ntil the tirapazamine dose of 390 mg/m(2) was reached. Once that dose of ti rapazamine was reached, the cyclophosphamide dose was escalated to 1250 and 1500 mg/m(2), Twenty-eight patients were enrolled. The dose-limiting toxic ity was granulocytopenia. One patient had transient deafness for 2 days. Fo ur other patients had grade 1 ototoxicity, Grade 1 and 2 muscle cramps were observed at all dose levels, Other toxic effects observed included fatigue , nausea, vomiting, headache, diarrhea, drug fever, elevated transaminases and elevated creatine phosphokinase, Three patients had stable disease and the longest time to progression was 5 months. The combination of tirapazami ne and cyclophosphamide is feasible, and the dose-limiting toxicity is gran ulocytopenia. The use of growth factors could possibly allow escalation of tirapazamine doses in future phase II trials. Without growth factor support , the recommended doses of tirapazamine and cyclophosphamide when administe red in this schedule are 260 and 1000 mg/m(2), respectively. [(C) 2001 Lipp incott Williams & Wilkins.].