Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812)

Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I t rial of ormaplatin administered as a 1-h infusion every 4 weeks was perform ed. Forty-one patients received 101 cycles of drug over the dose range 4-12 8 mg/m(2). The dose-limiting toxicity was reversible thrombocytopenia and g ranulocytopenia. Minimal myelosuppression was observed at dose levels less than or equal to 78 mg/m(2), while grade 3 or 4 myelosuppression (thrombocy topenia and/or granulocytopenia) was seen in 4/8 patients at 98 mg/m(2) and 4/5 patients at 123 mg/m(2). Nausea and vomiting was observed at all dose levels but was controlled with antiemetic premedication. Neurotoxicity was observed in 5/41 patients and the incidence appeared related to cumulative dose rather than to dose level or drug clearance. Platinum was measured by furnace atomic absorption spectrophotometry. Ormaplatin-derived plasma ultr afilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dos e range studied. The mean total body clearance of UF-Pt was 135 ml/min/m(2) and the mean elimination half-life (t(1/2)beta) was 13.6 h. Ormaplatin exh ibited a high degree of protein binding, with more than 70% of platinum pro tein bound by the end of the infusion. Urinary excretion of platinum accoun ted for 37% of the total dose of ormaplatin in 24 hours. A phase II dose of 98 mg/m(2) is recommended for testing in a patient population with cisplat in-refractory disease.