Hoff P M, Saad E D, Ravandi-Kashani F, Czerny E, Pazdur R
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Anticancer Drugs. 2001 Jul;12(6):499-503. doi: 10.1097/00001813-200107000-00002.
Our objective was to determine the maximum tolerated doses of tirapazamine and cyclophosphamide given i.v. in combination. Eligible patients had advanced solid tumors refractory to conventional treatment. Tirapazamine (escalated from 80 to 390 mg/m(2)) was given i.v. over 2 h and followed by cyclophosphamide over 1 h. The cyclophosphamide dose was fixed at 1000 mg/m(2) until the tirapazamine dose of 390 mg/m(2) was reached. Once that dose of tirapazamine was reached, the cyclophosphamide dose was escalated to 1250 and 1500 mg/m(2). Twenty-eight patients were enrolled. The dose-limiting toxicity was granulocytopenia. One patient had transient deafness for 2 days. Four 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 tirapazamine and cyclophosphamide is feasible, and the dose-limiting toxicity is granulocytopenia. 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 administered in this schedule are 260 and 1000 mg/m(2), respectively.
