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Phase I and Pharmacokinetic Study of Ormaplatin (Tetraplatin, NSC 363812) Administered on a Day 1 and Day 8 Schedule

Departments of Medical Oncology [R. J. S., F. P. L., R. P. P., S. W. J., J. M. B., S. N., C. M., T. C. H., R. C. Y., R. F. O., P. J. O'D.] and Biostatistics [A. R.], Fox Chase Cancer Center, Philadelphia 19111-2497, and Jeanes Hospital, Philadelphia 19111-2499 [D. R.], Pennsylvania

Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin 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 chemotherapy, and the median performance status was 1. Nausea/vomiting (grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m² were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) 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 clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.

¹ To whom requests for reprints should be addressed.

² Present address: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Pharmaceutical Research Institute, Syracuse, NY 13221-4755.

Received 7/28/93. Accepted 11/30/93.

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