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A Phase I Clinical and Pharmacokinetic Trial of Hepsulfam¹

Division of Oncology, Department of Medicine [P. M. R., K. A. H., M. V. M., T. D. B., G. R., D. D. V. H.] and Department of Pharmacology [J. M. K., J. G. K.], University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7884

Hepsulfam (1,7-heptanediol-bis-sulfamate) is one of a series of bissulfamate acid esters that was synthesized in an attempt to improve the antitumor efficacy of busulfan. Hepsulfam has shown broad antineoplastic activity in preclinical studies. This Phase I trial evaluated hepsulfam given as a single i.v. dose every 21–35 days. Twenty-nine patients with refractory solid tumors participated in this study. Twenty-six of these patients had had either prior chemotherapy or radiation therapy. Fifty-two courses of treatment were given at doses ranging from 30 to 360 mg/m²/day. The dose limiting toxicity was prolonged thrombocytopenia and granulocytopenia. This toxicity was cumulative with Grade 3 or 4 thrombocytopenia occurring in 3 of 15, 4 of 9, and 2 of 2 patients in the first, second, and third courses of 210 mg/m², respectively. This toxicity was noted in patients with 1 prior chemotherapeutic regimen, as well as in patients with >1 prior chemotherapeutic regimens. Nonhematological toxicities included Grade 1 or 2 nausea and vomiting and fatigue. There was no evidence of pulmonary toxicity. Plasma levels of hepsulfam were quantified by gas chromatography in 12 patients. The plasma and blood half-lives were 15.9 ± 4.6 and 90 ± 13 h, respectively. No objective tumor responses were seen. We conclude that the maximally tolerated dose when hepsulfam is given as a single dose every 35 days is 210 mg/m², but that there is significant risk of cumulative hematological toxicity at this level.

¹ Supported by NIH grants NO1-CM-27542 and NIH MO1-RR-01346

² To whom requests for reprints should be addressed, at Division of Oncology, The University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7884.

Received 7/ 9/91. Accepted 9/24/91.