A phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors

The purpose of this study was to perform a Phase I trial of raltitrexed, a selective inhibitor of thymidylate synthase, and to determine the pharmacok inetic and toxicity profiles as a function of raltitrexed dose, Fifty patie nts with advanced solid tumors and good performance status were treated wit h raltitrexed as a 15-min i.v. infusion every 3 weeks, at doses escalating from 0.6 to 4.5 mg/m(2). Asthenia, neutropenia, and hepatic toxicity were t he most common dose-limiting toxicities in this largely pretreated patient population, but they occurred during the initial cycle in only one of nine patients treated with 4.0 mg/m(2) and in two of nine patients treated with 4.5 mg/m2. Only 2 of 13 patients treated with 3.5 mg/m(2) ultimately experi enced unacceptable toxicity after three and seven cycles, compared with 42 and 56% of patients receiving 4.0 and 4.5 mg/m(2) after medians of three an d two cycles, respectively. The maximum raltitrexed plasma concentration an d the area under the plasma concentration-time curve increased in proportio n to dose. Raltitrexed clearance was independent of dose and was associated with the estimated creatinine clearance. Asthenia, neutropenia, and hepati c transaminitis were dose-related and tended to occur more frequently when patients received three or more cycles of therapy. A 3-week treatment inter val was feasible in the majority of patients at all doses. Although 4.0 mg/ m(2) appeared to be a safe starting dose in this pretreated patient populat ion, about half who received two or more courses ultimately experienced dos e-limiting toxicity. A dose of 3.5 mg/m(2) was well tolerated in most patie nts.