Abstract
Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.
Similar content being viewed by others
References
Dexter DL, Hesson DP, Ardecky RJ, Rao GV, Tiffett DL, Dusak BA, Paull KD, Plowman J, Delarco BM, Narayanan VL, Forbes M: Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1, 1'-biphenyl-4-YL)-3-methyl-4-quinolinecarboxylic acid sodium salt], against experimental tumors. Cancer Res 45: 5563-5568, 1985.
Chen S-F, Ruben RL, Dexter DL: Mechanism of action of the novel anticancer agent 6-fluoro-2-(2'-fluoro-1, 1'-biphenyl-4-YL)-3-methyl-4-quinolinecarboxylic acid sodium salt (NSC 368390): inhibition of de novopyrimidine nucleotide biosynthesis. Cancer Res 46: 5014-5019, 1986.
Peters GJ, Sharma SL, Laurensse E, Pinedo HM: Inhibition of pyrimidine de novosynthesis by DUP 785 (NSC 368390). Invest New Drugs 5: 235-244, 1987.
Schwartsmann G, Peters GJ, Laurensse E, de Waal F, Loonen A, Leyua A, Pinedo H: DUP 785: Schedule-dependency of growth inhibitory and antipyrimidine effects. Biochem Pharmacol 37: 3257-3266, 1988.
de Forni M, Chabot GG, Armand JP, Fontana X, Recondo G, Domenge C, Carde P, Barbu M, Gouyette A: Phase I and pharmacokinetic study of brequinar (DUP 785; NSC 368390) in cancer patients. Eur J Cancer 29A: 983-988, 1993.
Schwartsmann G, Dodion P, Vermorken JB, ten Bokkel Huinink W, Joggi J, Winograd B, Gall H, Simonetti G, Van der Vijgh W, Van Hennick M: Phase I study of brequinar sodium (NSC 368390) in patients with solid malignancies. Cancer Chemother Pharmacol 25: 345-351, 1990.
Bork E, Vest S, Hansen HH: A phase I clinical and pharmacokinetic study of brequinar sodium (DUP 785; NSC 368390), using a weekly and a bi-weekly schedule. Eur J Cancer Clin Oncol 25: 1403-1411, 1989.
Currie V, O'Hehir M, Baltzer L, Slavik W, Yaldaei S, Bertino J: Phase I trial of DUP 785 given on a single weekly intravenous dosing schedule. Proc Am Soc Clin Oncol 4: 76, 1988.
Fischer DS, Tish Knobf M, Durivage HJ: The Cancer Chemotherapy Handbook Ed4. Mosby Yearbooks, St. Louis, 1993, pp 79-82.
Braakhuis BJ, van Dongen GA, Bagnay M, van Walsum M, Snow GB. Preclinical chemotherapy on human head and neck cancer xenografts in athymic mice. Head and Neck 11(6): 511-515, 1989.
Chen S-F, Dexter DL: Preclinical studies with brequinar sodium: A novel anticancer agent. In: Valeriote FA, Corbett TH, Baker LH (eds) Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development. Kluwer Academic Publ, Norwell, MA, 1992, pp 261-280.
Arteaga C, Brown T, Kuhn J, Shen H: Phase I clinical and pharmacokinetic trial of brequinar sodium (DUP 785; NSC 368390). Cancer Res 49: 4648-4653, 1989.
Gibaldi M: Biopharmaceutics and Clinical Pharmacokinetics, Ed. 3. Lea and Febiger, Philadelphia, 1984, pp 17-18.
Lamm FC, Hung CT, Perrier DG: Estimation of variance for harmonic mean half-lives. J Pharm Sci 74: 229-231, 1985.
Chen JJ, Jones ME: The cellular location of dihydroorotate dehydrogenase: relation to de novo biosynthesis of pyrimidines. Arch Biochem Biophys 176: 82-90, 1976.
Jones ME: Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis. Annu Rev Biochem 49: 253-279, 1980.
Peters GJ, Schwartsmann G, Nadal JC, Laurensse EJ, Van Groeningen CJ, Van der Vijgh WJF, Pinedo HM: In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP 785; NSC 368390) in mice and patients. Cancer Res 50: 4644-4649, 1990.
Pizzormo G, Wiegand RA, Lentz SK, Handschumacher RE: Brequinar potentiates 5-fluorouracil antitumor activity in a murine model colon 38 tumor by tissue-specific modulation of uridine nucleotide pools. Cancer Res 52: 1660-1665, 1992.
Buzaid AC, Pizzorno G, Marsh JC, Ravikumar TS, Murren JR, Todd M, Strair RK, Poo WJ, Hait WN: Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study. Cancer Chemother Pharmacol 36(5): 373-378, 1995.
Noe DA, Rowinsky EK, Shen HSL, Clarke BV, Grochow LB, McGuire WB, Hantel A, Adams DB, Abeloff MD, Ettinger DS, Donehower RC: Phase I and pharmacokinetic study of brequinar sodium (NSC 368390). Cancer Res 50: 4595-4599, 1990.
Dodion PF, Wagener T, Stoter G, Drozd A, Lev LM, Skovsgaard T, Renard J, Cavalli F: Phase II trial with brequinar (DUP 785; NSC 368390) in patients with metastatic colorectal cancer: A study of the early clinical trials group of the EORTC. Ann Oncol 1: 79-80, 1990.
Cody R, Stewart M, de Forni M, Moore M, Dallaire B, Azarnia N, Gyves J: Multicenter phase II study of brequinar sodium in patients with advanced breast cancer. Am J Clin Oncol 16(6): 526-528, 1993.
Moore M, Maroun J, Robert F, Natale R, Neidhart J, Dallaire B, Sisk R, Gyves J: Multicenter phase II study of brequinar sodium in patients with advanced gastrointestinal cancers. Invest New Drugs 11(1): 61-65, 1993.
Natale R, Wheeler R, Moore M, Dallaire B, Lynch W, Carlson R, Grillo-Lopez A, Gyves J: Multicenter phase II trial of brequinar sodium in patients with advanced melanoma. Ann Oncol 3: 659-660, 1992.
Maroun J, Ruckdeschel J, Natale R, Morgan R, Dallaire B, Sisk R, Gyves J: Multicenter phase II study of brequinar sodium in patients with advanced lung cancer. Cancer Chemother Pharmacol 32(1): 64-66, 1993.
Urba S, Doroshow J, Griffs C, Robert F, Velez-Garcia E, Dallaire B, Adams D, Carlson R, Grillo-Lopez A, Gyves J: Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck. Cancer Chemother Pharmacol 31: 167-169, 1992.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Burris, H.A., Raymond, E., Awada, A. et al. Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies. Invest New Drugs 16, 19–27 (1998). https://doi.org/10.1023/A:1016066529642
Issue Date:
DOI: https://doi.org/10.1023/A:1016066529642