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Phase I Study of Ethylenediamine Platinum(II) Malonate (NSC 146 068), a Second Generation Platinum Analogue¹

Department of Oncology, Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam [B. W., J. B. V., H. E. G., M. K. T. K., W. J. F. v. d. V., H. M. P.], and Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam [W. W. t. B. H., G. S. J. G. M.], The Netherlands

Ethylenediamine platinum(II) malonate [JM-40 (NSC 146 068)] has been selected for clinical studies because of its favorable preclinical toxicity profile as a "second generation" platinum analogue. When compared to cisplatin, JM-40 was less emetic in the ferret and less nephrotoxic in the dog, while its antitumor activity approached that of cisplatin. Twenty-nine patients received 86 courses of JM-40 as a single dose every 3-4 wk. After 13 dose escalation steps the maximum tolerable dose was reached at 1200 mg/m². The dose limiting toxicities were nausea, vomiting, and nephrotoxicity. The renal damage seemed reversible up to a dose level of 1000 mg/m² and consisted of a glomerular and tubular dysfunction. JM-40 did not cause any other dose related side effect or myelosuppression. Pharmacokinetic studies at a dose of 1000 mg/m² revealed mean terminal half-lives of 5.0 and 1.9 days for platinum in plasma and plasma ultrafiltrate, respectively. The mean cumulative excretion of platinum in urine accounted for 57% of the dose up to day 5. Two partial responses were observed in a patient with a large cell carcinoma of the lung and in one with a carcinoma of the lacrimal gland. Limited evaluation of JM-40 in phase II studies is warranted. The recommended dose is 1000 mg/m² every 4 wk and 800 mg/m² for patients pretreated with platinum analogues.

¹ Supported by grant AUKC 82-6 of the Netherlands Cancer Foundation. Presented in part at the 20th Annual Meeting of the American Society of Clinical Oncology (1).

² To whom requests for reprints should be addressed.

Received 5/14/85. Revised 10/17/85. Revised 12/23/85. Accepted 12/27/85.