A Phase I study of raltitrexed and paclitaxel given every 3 weeks to patients with solid tumors

BACKGROUND. Raltitrexed is a novel thymidylate synthase inhibitor with sing le agent activity in colorectal, nonsmall cell lung, and breast carcinomas. The recommended Phase II dose of raltitrexed administered as a single agen t is 3 mg/m(2) every 3 weeks. Paclitaxel also has a broad spectrum of activ ity. A Phase I study of both agents in combination therapy was conducted. METHODS. Eligible patients had refractory solid tumors and a Cancer and Leu kemia Group B performance status of 0 to 2. Cohorts of patients were treate d with escalating doses of raltitrexed as a 15-minute intravenous infusion immediately followed by 175 mg/m(2) of paclitaxel administered over 3 hours . Dose-limiting toxicity was defined as World Health Organization Grade 4 n eutropenia with fever, Grade 4 thrombocytopenia requiring platelet transfus ion, a nonhematologic toxicity of Grade 3 or higher (excluding nausea, emes is, and alopecia), or failure of toxicities to recover to Grade 1 or lower within 21 days after causing a dose delay. RESULTS. A total of 33 patients enrolled in the study. Raltitrexed was esca lated in increments of 0.5 mg/m(2), from 0.5 mg/m(2) to the recommended Pha se II dose of 3 mg/m(2). Dose-limiting toxicity first was observed at a ral titrexed dose of 2 mg/m(2). At a dose of 3 mg/m(2), dose-limiting neutropen ia was observed in 2 of 12 patients. Diarrhea was the other dose-limiting t oxicity. Two patients achieved a partial response (one patient with. carcin oma of die head and neck and another with gallbladder carcinoma). CONCLUSIONS. The authors conclude that raltitrexed and paclitaxel may be ad ministered in combination at their respective single agent Phase II doses. Phase II testing of this combination is indicated. (C) 1999 American Cancer Society.