PHASE-I STUDY OF TIRAPAZAMINE AND CISPLATIN IN PATIENTS WITH RECURRENT CERVICAL-CANCER

Objectives. Tirapazamine (SR 4233) is a benzotriazine compound exhibit ing substantial differential toxicity for hypoxic cells. A large enhan cement in tumor cell killing has been demonstrated in preclinical stud ies when tirapazamine was combined with cisplatin. This phase I study was undertaken to establish a safe dose combination of tirapazamine an d cisplatin when administered to patients with recurrent cervical carc inoma. Methods. Tirapazamine was administered as an intravenous infusi on over 2 hr, followed 1 hr later by cisplatin intravenously over 1 hr , every 21 days. All patients received prophylactic antiemetics consis ting of ondansetron, dexamethasone, and lorazepam. The planned dose es calation levels of tirapazamine were 195, 260, 330, and 390 mg/m(2). T he cisplatin dose was fixed at 75 mg/m(2) Results. A total of 12 patie nts were treated with 43 courses of therapy. Patients were heavily pre treated. Eleven of the 12 had prior radiotherapy and 5 of the 12 had p rior cisplatin-based chemotherapy. A maximally tolerated dose of 330 m g/m(2) was defined for this patient population. The dose-limiting toxi city was nausea and vomiting. All 12 patients were also evaluated for response. Two major responses were seen (17%). In addition, there were three minor responses (25%) and 4 patients achieved disease stabiliza tion (33%). All major and minor responses were seen at the highest dos e level tested of 330 mg/m(2). Conclusions. Tirapazamine and cisplatin is an interesting drug combination in the treatment of cervical cance r. Phase YI testing is planned. (C) 1997 Academic Press.