Phase I study of ethylenediamine platinum(II) malonate (NSC 146 068), a second generation platinum analogue.
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 myelo-suppression. 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.
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D004064:Digestive System / Q000187:drug effects; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C038327:ethylenediamine platinum(II) malonate