PHASE-I AND PHARMACOKINETIC STUDY OF ORMAPLATIN (TETRAPLATIN, NSC-363812) ADMINISTERED ON A DAY-1 AND DAY-8 SCHEDULE

Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that i s active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cispl atin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior ch emotherapy, and the median performance status was 1. Nausea/vomiting ( greater-than-or-equal-to grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grad e 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 p retreatment). No toxicity limited the dose given during the first cour se. With repeated drug administration delayed severe neurotoxicity dev eloped in 4 patients, manifested as a. sensory polyneuropathy in 3 pat ients and a possible autonomic neuropathy in one. Prospective nerve co nduction studies did not detect subclinical neuropathy prior to the on set of symptoms. Patients who received cumulative doses above 200 mg/m 2 were at increased risk for developing neurotoxicity. Plasma eliminat ion of ultrafilterable platinum (measured by atomic absorption spectro metry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal cleara nce accounted for 16% of total clearance suggesting that extensive pro tein/tissue binding was responsible for the majority of platinum clear ance. Approximately 60% of the platinum is protein bound (one-half irr eversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictiv e of neurotoxicity than the cumulative ormaplatin dose. A phase II dos e cannot be recommended on this schedule because severe and unpredicta ble neurotoxicity precludes the administration of more than three cycl es at the three highest doses levels tested.