Clinical development of iproplatin (CHIP).

The clinical development of the second generation platinum complex iproplatin (CHIP) is reviewed. The compound was virtually non-nephrotoxic in preclinical toxicology studies and had myelosuppression as its dose-limiting toxicity in rats and dogs. A phase I study of 20-350 mg/m2 given every 3-4 weeks showed the compound to have myelosuppression as its dose-limiting toxicity in humans, with thrombocytopenia being the most prominent feature. Nausea and vomiting were almost universal, but were less severe than with cisplatin. Diarrhoea and skin rash were also noted but nephrotoxicity, neurotoxicity and ototoxicity were not seen. The maximum tolerated dose was 350 mg/m2, with or without pretreatment hydration. In pharmacokinetic studies three platinum-containing species were measured: total Pt, non-protein bound Pt and unchanged iproplatin. Plasma decay of total Pt was biphasic with a beta-phase half-life of 69.3 h. Plasma decay of unchanged iproplatin was monophasic with a half-life of about 1.17 h. Plasma decay of filterable Pt followed a monophasic pattern at low doses and a biphasic pattern at high doses. Urinary excretion of Pt was widely variable and incomplete. Early data from phase II studies indicate a high degree of activity in small-cell lung cancer; high activity in ovarian carcinoma has been reported by others.