A phase I and pharmacokinetic study of 1843U89, a noncompetitive inhibitorof thymidylate synthase, in patients with advanced solid malignancies

This study was performed to assess the feasibility of administering 1843U89 , a potent, noncompetitive inhibitor of thymidylate synthase that does not require polyglutamation for activity, as a 2-min i.v. infusion daily for 5 days every 3 weeks, to determine whether folic acid supplementation amelior ates the toxic effects of 1843U89 and permits further dose escalation, and to recommend doses of 1843U89 administered without and with folic acid for further clinical evaluations. The study also sought to characterize the pha rmacokinetic behavior of 1843U89 and to seek preliminary evidence of antica ncer activity. Patients with advanced solid malignancies were treated with escalating doses of 1843U89 as a 2-min i.v, infusion daily for 5 days every 3 weeks. Initially, patients were treated in the absence of high-dose foli c acid until dose-limiting toxicity was consistently noted. Next, patients were treated with escalating doses of 1843U89 preceded by 1000 mg of folic acid administered p.o. 30 min before each of the 5 daily doses of 1843U89, Patients (32) received 101 total courses of 1843U89 at doses ranging from 1 to 6 mg/m(2)/day with and without folic acid. At the 2 mg/m(2)/day dose le vel without folic acid, 2 of 7 new patients experienced dose-limiting toxic ity, principally neutropenia, mucositis, and malaise in 3 of 11 courses. 18 43U89 doses were further increased with folic acid to 6 mg/m2/day, but repe titive treatment was not feasible at this dose level because of an unaccept able high incidence of severe neutropenia and mucositis, Other toxicities i ncluded thrombocytopenia, rash, and fever. In contrast, repetitive treatmen t at the 5 mg/m2/day dose level was feasible. The pharmacokinetics of 1843U 89 were neither dose dependent nor affected by folic acid. On day 1, cleara nce, terminal half-life, and steady-state volume of distribution values ave raged 47.1 +/- 21.7 ml/min/m(2), 7.72 +/- 4.09 h, and 16.7 +/- 8.8 liter/m( 2)/h, respectively. The results of the study indicate that the administrati on of 1843U89 as a 2-min infusion daily for 5 days every 3 weeks without an d with folic acid is feasible at 1843U89 doses as high as 2 and 5 mg/m2/day , respectively. Because folic acid pretreatment results in no diminution of the antitumor activity of 1843U89 in preclinical studies and ameliorates t he toxic effects of 1843U89 in both preclinical models and cancer patients, the therapeutic index of 1843U89 may be enhanced by folic acid pretreatmen t and, therefore, the development of 1843U89 with folic acid is warranted. However, the question of whether to administer 1843U89 at a dose of 2 mg/m( 2)/day with folic acid, which is associated with negligible toxicity, or at its highest feasible dose with folic acid, 5 mg/m2/day, should be addresse d in appropriately designed trials.