Phase I trial of a 5-day course of carbetimer

Abstract

Carbetimer (carboxyimamidate) is a low molecular weight derivative of ethylene/maleic anhydride polymer. This compound has demonstrated antitumor activity against several animal models with a daily x 5 schedule appearing most effective. A phase I clinical study of the daily x 5 schedule repeated every 28 days was therefore performed. Forty-one evaluable patients received 66 evaluable cycles of Carbetimer at daily doses ranging from 100-11000 mg/m 2. Hypercalcemia was the dose limiting toxicity with both patients at the 11000 mg/m 2 daily dose level and one patient who received 6 cycles of drug at the 4200 mg/m 2 dose level developing severe hypercalcemia not explained by the underlying malignancy. Mild nausea, concentration and rate dependent arm pain at the site of infusion, proteinuria, and coagulopathy were also seen. Calcium balance studies revealed hypercalciuria, suggesting increased mobilization of calcium rather than renal retention. In vitro coagulation studies revealed concentration dependent prolongation of the partial thromboplastin time and thrombin time. No complete or partial responses were seen. However mixed response or biochemical response (reduction in serum lactic dehydrogenase) were seen in 5 patients with melanoma or renal cancer. Due to unacceptable toxicity at the 11000 mg/m 2 daily dose level, Carbetimer 8500 mg/m 2 is the recommended dose for a 5-day treatment schedule every 28 days. Special attention should be directed toward possible activity against melanoma and renal cancer.

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

“…Analyses of parathormone levels displayed no consistent deviations from the normal range. Furthermore, careful monitoring of plasma calcium seems indicated in future studies, concomitant to any administration of Carbetimer, since this was the dose-limiting toxicity described in another study at a dose of 11,000 mg/m 2 [11].…”

Phase II study of carbetimer in non-small cell lung cancer

“…Antitumor activity has been demonstrated in vitro to various human tumor types in the human tumor cloning assay [2]. Phase one studies have found Carbetimer to have low systemic toxicity with hypercalcemia being the dose limiting toxicity [3][4][5][6]. This report presents the results of Carbetimer in the treatment of non-small cell lung cancer.…”