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 single agent activity in colorectal, nonsmall cell lung, and breast carcinomas. The recommended Phase II dose of raltitrexed administered as a single agent is 3 mg/m² every 3 weeks. Paclitaxel also has a broad spectrum of activity. A Phase I study of both agents in combination therapy was conducted. METHODS. Eligible patients had refractory solid tumors and a Cancer and Leukemia Group B performance status of 0 to 2. Cohorts of patients were treated with escalating doses of raltitrexed as a 15-minute intravenous infusion immediately followed by 175 mg/m² of paclitaxel administered over 3 hours. Dose-limiting toxicity was defined as World Health Organization Grade 4 neutropenia with fever, Grade 4 thrombocytopenia requiring platelet transfusion, a nonhematologic toxicity of Grade 3 or higher (excluding nausea, emesis, 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 escalated in increments of 0.5 mg/m², from 0.5 mg/m² to the recommended Phase II dose of 3 mg/m². Dose-limiting toxicity first was observed at a raltitrexed dose of 2 mg/m². At a dose of 3 mg/m², dose-limiting neutropenia was observed in 2 of 12 patients. Diarrhea was the other dose-limiting toxicity. Two patients achieved a partial response (one patient with carcinoma of the head and neck and another with gallbladder carcinoma). CONCLUSIONS. The authors conclude that raltitrexed and paclitaxel may be administered in combination at their respective single agent Phase II doses. Phase II testing of this combination is indicated.