Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors

Purpose: Patients with refractory solid tumors were treated with the combin ation of fractionated radiation therapy and multiple-dose intravenous tirap azamine to determine the toxicities and maximum tolerated dose of tirapazam ine when given concurrently with radiation therapy. Methods: Patients received radiation therapy in accordance with standard tr eatment practice in relation to fraction size and number of fractions for t heir particular cancer. In all cases, the course of radiation therapy excee ded the time of tirapazamine administration. Initially, tirapazamine was ad ministered 5 days per week for 2 weeks for a total of 10 doses. After the f irst 8 patients, the schedule was changed to 3 times per week (Monday, Wedn esday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6 patient s were treated at each dose level, Results: A total of;43 patients were treated in the study between 1991 and 1995, All patients were 18 years old or older, had a Karnofsky performance status of greater than or equal to 60% and had adequate hematologic, hepati c, and renal function. Dose escalation began at 9 mg/m(2)/dose and was incr eased using a modified Fibonacci schema, The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m(2) because of other da ta that became available suggesting 330 mg/m(2) was associated with dose-li miting toxicity (1, 2), Conclusion: Tirapazamine in doses of up to 260 mg/m(2) times 12 doses can b e given safely with fractionated radiation therapy. This dose appears to re sult in adequate plasma exposure (2) for radiation sensitization, and this schedule is being tested in a Phase II trial by the Radiation Therapy Oncol ogy Group to determine if tirapazamine is a radiation enhancer in the clini c, (C) 1999 Elsevier Science Inc.