TIRAPAZAMINE-CISPLATIN - THE SYNERGY

Tirapazamine is a novel bioreductive agent with selective cytotoxicity against hypoxic tumour cells. Synergy with cisplatin and other chemot herapeutic agents has been shown in preclinical trials. Pharmacokineti c studies of tirapazamine have revealed that exposure increases with d ose over the range of 18-450 mg m(-2) for a single dose and of 9-390 m g m-2 for multiple doses. Plasma clearance is high. Tirapazamine has b een clinically tested in combination with cisplatin at escalating dose s in a phase I trial and at therapeutic doses in three separate phase II trials in patients with advanced non-small-cell lung cancer (NSCLC) in If study centres. Limiting toxicity for tirapazamine at an intrave nous dose of 390 mg m-2 was acute, reversible hearing loss. Other freq uently observed side-effects included muscle cramping and gastrointest inal symptoms. Tirapazamine did not cause myelosuppression, and no tox ic deaths were reported in these trials. The anti-tumour efficacy agai nst previously untreated, advanced NSCLC was evaluated by cumulative i ntent-to-treat analysis of 132 patients. The objective response rate ( confirmed by two independent measurements) was 25% [confidence interva l (Cl) 17.8-33.33], with a median survival of 38.9 weeks (CI 29.4-49.9 ). The efficacy of tirapazamine plus cisplatin shown in these trials w as better than that of historical controls with cisplatin monotherapy. Two large-scale international trials have been conducted, involving m ore than 70 centres, to confirm these results. The CATAPULT I trial co mpares tirapazamine plus cisplatin with cisplatin and has finished acc rual with 446 patients. The CATAPULT Il trial, which is comparing tira pazamine plus cisplatin with etoposide plus cisplatin, had enrolled 55 0 patients by June 1997. Follow-up is ongoing. Tirapazamine is the pro mising first drug from a new class of cytotoxic agents with a novel me chanism of action. It can be effectively combined with cisplatin, and possibly with other agents, because of its safety profile and lack of overlapping dose-limiting toxicity, such as myelosuppression. The comb ination of tirapazamine and cisplatin appears to be safe and effective in the treatment of NSCLC.