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Phase I Clinical and Pharmacokinetic Trial of Brequinar Sodium (DUP 785; NSC 368390)¹

The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7884 [C. L. A., T. D. B., J. G. K., D. D. V. H., G. R. W.]; Brooke Army Medical Center, Fort Sam Houston, Texas 78234 [T. D. B., T. J. O., K. B.]; and DuPont Pharmaceuticals, Wilmington, Delaware 19898 [H-S. L. S., H. J. B.]

Brequinar sodium is a 4-quinolinecarboxylic acid analogue that inhibits dihydroorotate dehydrogenase and subsequent de novo pyrimidine biosynthesis. It has shown dose-dependent antineoplastic activity against several mouse and human tumor models. This trial evaluated Brequinar given as a single daily i.v. bolus over a 5-day period repeated every 28 days. One hundred seven courses of treatment at dosages ranging from 36 to 300 mg/m²/day x 5 were administered to 45 patients (31 male and 14 female) with refractory solid tumors; median age was 58 years (range 30–74); median Southwest Oncology Group performance status was 1 (range, 0–3). Thirty patients had prior cytotoxic chemotherapy. Dose-limiting toxicities were thrombocytopenia and a severe desquamative maculopapular dermatitis. Two of 5 good risk patients at 300 mg/m² and 3 of 6 poor risk patients at 170 mg/m² developed a platelet count <25 x 10³/µl. Two of 5 good risk patients at 300 mg/m² and 1 of 6 poor risk patients at 170 mg/m² developed a severe desquamative dermatitis. Moderate to severe mucositis was usually associated with the thrombocytopenia and/or the dermatitis. Nonhematological drug-related toxicities included nausea and vomiting, malaise, anorexia, diarrhea, phlebitis, reversible transaminase elevation, and mucositis. Other hematological toxicities were anemia, granulocytopenia, and leukopenia. There were no drug-related deaths. There were no objective tumor responses. Plasma and urine levels of Brequinar were quantified by high pressure liquid chromatography in 28 patients. Plasma levels and areas under the curve increased proportionally with increased dose. Brequinar had a harmonic mean terminal t of 8.1 ± 3.6 h with a model-independent determined apparent volume of distribution at steady state of 9.0 ± 2.9 liters/m² and a total body clearance of 19.2 ± 7.7 ml/min/m². Renal excretion was a minor route of elimination for Brequinar. The maximally tolerated dose of Brequinar on a daily x 5 i.v. schedule was 250 mg/m² for good risk patients. For the daily x 5 i.v. schedule, the recommended dose of Brequinar for phase II evaluation is 250 mg/m² for good risk patients and 135 mg/m² for poor risk patients.

¹ This work was supported by a grant from E. I. DuPont de Nemours, Inc., Wilmington, DE; General Clinical Research Grant RR-01346, NIH, DHHS; and the clinical and support services of the Audie L. Murphy Memorial Veterans Administration Hospital, San Antonio, TX. Presented in part at the Annual Meeting of the American Society of Clinical Oncology in New Orleans, LA, May 1988.

² To whom requests for reprints should be addressed.

Received 10/11/88. Revised 5/ 5/89. Accepted 5/16/89.

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