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Phase I Clinical Trial of Carbetimer¹

Departments of Medicine/Oncology [A-R. H., G. M. C., T. J. M., G. S. H., J. B. C., J. M. K., D. L. K., B. K., G. A. S., D. D. V. H.] and Medicine/Hematology [D. B.], The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284, and Department of Research and Development, G. D. Searle Company [G. O., D. W. A., E. P.], Skokie, Illinois 60077

Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1–2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m². The dose-limiting toxicity was hypercalcemia (serum calcium >12.5 mg/dl) noted in two of three patients at a dose of 8500 mg/m². Serum calcium levels between 10.5 and 12.5 mg/dl were noted in an additional three patients treated at doses 1600 mg/m². Calcium balance studies in three patients treated at 6500 mg/m² revealed an increase in urinary cyclic AMP and phosphate excretion after treatment accompanied by a mild elevation of serum parathyroid hormone. Immunological studies in these patients revealed a statistically significant increase in the percentage of peripheral T-helper cells. An increase in the T-helper/suppressor cell ratio was observed in two of the three patients studied. Interleukin 2 production by phytohemagglutinin-stimulated peripheral mononuclear cells was increased in two of three patients. One patient with a renal cell carcinoma showed a mixed response. The recommended dose for phase II trials as assessed from this study is 6500 mg/m² as a single dose every 28 days.

¹ This study was supported by a grant from the Monsanto Company, St. Louis, MO; NIH Grant RR-01346, USPHS; National Research Service Award CA 09434 from the National Cancer Institute; DFG Grant Ha 1347/1-1; and a grant from the Freundesgesellschaft der Medizinischen Hochschule, Hannover, West Germany.

² To whom requests for reprints should be addressed, at Department of Medicine/Oncology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284.

Received 6/22/87. Revised 5/ 6/88. Accepted 6/21/88.

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