Tirapazamine-cisplatin: the synergy

Tirapazamine is a novel bioreductive agent with selective cytotoxicity against hypoxic tumour cells. Synergy with cisplatin and other chemotherapeutic agents has been shown in preclinical trials. Pharmacokinetic studies of tirapazamine have revealed that exposure increases with dose over the range of 18-450 mg m(-2) for a single dose and of 9-390 mg m(-2) for multiple doses. Plasma clearance is high. Tirapazamine has been clinically tested in combination with cisplatin at escalating doses 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 11 study centres. Limiting toxicity for tirapazamine at an intravenous dose of 390 mg m(-2) was acute, reversible hearing loss. Other frequently observed side-effects included muscle cramping and gastrointestinal symptoms. Tirapazamine did not cause myelosuppression, and no toxic deaths were reported in these trials. The anti-tumour efficacy against previously untreated, advanced NSCLC was evaluated by cumulative intent-to-treat analysis of 132 patients. The objective response rate (confirmed by two independent measurements) was 25% [confidence interval (CI) 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 was better than that of historical controls with cisplatin monotherapy. Two large-scale international trials have been conducted, involving more than 70 centres, to confirm these results. The CATAPULT I trial compares tirapazamine plus cisplatin with cisplatin and has finished accrual with 446 patients. The CATAPULT II trial, which is comparing tirapazamine plus cisplatin with etoposide plus cisplatin, had enrolled 550 patients by June 1997. Follow-up is ongoing. Tirapazamine is the promising first drug from a new class of cytotoxic agents with a novel mechanism 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 combination of tirapazamine and cisplatin appears to be safe and effective in the treatment of NSCLC.