Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II

Summary

cis-Diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA, JM8), an analogue of cisplatin showing reduced toxicity in preclinical studies, was evaluated in 60 patients. Doses were given initially every 3 weeks and escalated from 20 to 520 mg/m². Following this, doses were given every 4 weeks and escalated from 300 to 500 mg/m². The dose-limiting toxicity, thrombocytopoenia, occurred in four-fifths of patients treated at 520 mg/m², with the nadir occurring 3 weeks after treatment. Leucopoenia and anaemia also occurred but were less severe. Vomiting occurred in all patients receiving over 120 mg/m² but seldom persisted beyond 24 h. Serial measurements of ⁵¹Cr-EDTA clearances, urinary N-acetylglucosaminidase, urinary leucine aminopeptidase, and β₂-microglobulin did not reveal significant evidence of nephrotoxicity. Detriment to the audiogram has not been seen in the first 13 patients studied. Pharmacological studies showed that most of the dose of platinum was excreted in the urine, and that impairment of renal function may be associated with drug retention and an increased risk of myelosuppression. The previous therapy and age of the patient also affected the tolerance of the drug. Clinical responses were seen in patients with ovarian carcinoma receiving >120 mg/m².

A further dose escalation was performed on a 4-week schedule in patients under 65 with good renal function. The maximum dose it was possible to administer repeatedly without incurring myelosuppression was in the range 400–500 mg/m².

JM8 is not significantly nephrotoxic and is less emetic than cisplatin. It has antitumour activity in man and deserves wider evaluation, along with the other analogues under study in various centres, as an alternative to cisplatin.