PHASE-I TRIAL OF TIRAPAZAMINE IN COMBINATION WITH CISPLATIN IN A SINGLE-DOSE EVERY 3 WEEKS IN PATIENTS WITH SOLID TUMORS

Purpose and Methods: Tirapazamine (SR4233, WIN 59075) is a benzotriozi ne-di-N-oxide bioreductive agent that is selectively activated to a re active DNA-damaging species in hypoxic tumors. Preclinical studies sho w that synergistic antitumor activity results from a schedule-dependen t interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tiropazamine (13 0 to 260 mg/m(2)) was administered as a 1-hour intravenous (IV) infusi on beginning 3 hours before cisplatin (75 to 100 mg/m(2)). Thirteen pa tients received 41 courses of therapy. These patients had on excellent performance status and were not heavily pretreated. The predominant d iagnosis was lung cancer. Results: The major acute side effects were n ausea and vomiting which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, wh ile with repeated dosing, anorexia and fatigue predominated. Full dose s of each agent were well tolerated in combination, although in this p reviously treated population, fatigue increased markedly after three c ycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a mi nor response occurred in a patient with mesothelioma. Tirapazamine pha rmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (C-max) of 5.97 +/- 2.25 mu g/mL and an a rea under the concentration-time curve (AUG) of 811.4 +/- 311.9 mu g/m L.min at 260 mg/m(2). These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of timpazamine are achievable inpatients based on ani mal models. The mean cisplatin AUC was 285.6 +/- 46.4 mu g/mL.min with mean C-max values of 3.38 +/- 0.43 mu g/mL at 75 mg/m(2). The clearan ce of cisplatin was unaffected by coadministration with tirapazamine. Conclusion: This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapa zamine up to 260 mg/m(2). The observation of clinical responses in thi s trial supports the phase II investigation of this regimen. (C) 1997 by American Society of Clinical Oncology.