A PHASE-I INVESTIGATION OF THE SEQUENTIAL USE OF METHOTREXATE AND PACLITAXEL WITH AND WITHOUT G-CSF FOR THE TREATMENT OF SOLID TUMORS

Background: Paclitaxel is a novel agent with significant activity in s everal solid tumors. Preclinical data suggested that methotrexate prio r to paclitaxel would be synergistic. To determine the qualitative and quantitative toxicity of this regimen we performed a phase I study in patients with solid tumors. Patients ann methods: Patients with solid tumors previously treated with no more than two prior chemotherapy re gimens were given methotrexate intravenously on day 1, followed by pac litaxel, as a 24-hour infusion on day 2. The starting dose (level '0') was 40 mg/m(2) for methotrexate and 135 mg/m(2) for paclitaxel. Resul ts: After achieving a maximum tolerated dose, additional patients were enrolled with the addition of G-CSF 5 mu g/kg/d on days 4-13. At the starting dose level, dose-limiting toxicity consisting of neutropenic fever occurred in 3 of 4 patients. At dose level -1, methotrexate 30 m g/m(2) and paclitaxel 110 mg/m(2), neutropenic fever occurred in 7 of 10 patients during the first course. At dose level -2, methotrexate 23 mg/m(2) and paclitaxel 85 mg/m(2), neutropenic fever occurred in 1 of 7 patients. To abrogate the neutropenia we explored the same combinat ion with the addition of G-CSF. Neutropenic fever remained the only do se-limiting toxicity. At dose level '0' with G-CSF, 1 of 7 patients de veloped dose-limiting toxicity. At dose level 1 plus G-CSF, methotrexa te 40 mg/m(2) and paclitaxel 170 mg/m(2), dose-limiting neutropenic fe ver occurred in 4 of 6 patients. Partial responses occurred in 4 of 41 patients entered on this study. Pharmacokinetic data suggested that m ethotrexate did not increase paclitaxel levels. Conclusion: The combin ation of methotrexate and paclitaxel is feasible, but neutropenic feve r, even with the addition of G-CSF prevents further escalations of pac litaxel beyond 135 mg/m(2) following methotrexate.