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 several solid tumors. Preclinical data suggested that methotrexate prior 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 and methods: Patients with solid tumors previously treated with no more than two prior chemotherapy regimens were given methotrexate intravenously on day 1, followed by paclitaxel, as a 24-hour infusion on day 2. The starting dose (level '0') was 40 mg/m² for methotrexate and 135 mg/m² for paclitaxel. Results: After achieving a maximum tolerated dose, additional patients were enrolled with the addition of G-CSF 5 μg/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 mg/m² and paclitaxel 110 mg/m², neutropenic fever occurred in 7 of 10 patients during the first course. At dose level -2, methotrexate 23 mg/m² and paclitaxel 85 mg/m², neutropenic fever occurred in 1 of 7 patients. To abrogate the neutropenia we explored the same combination with the addition of G-CSF. Neutropenic fever remained the only dose-limiting toxicity. At dose level '0' with G-CSF, 1 of 7 patients developed dose-limiting toxicity. At dose level 1 plus G-CSF, methotrexate 40 mg/m² and paclitaxel 170 mg/m², dose-limiting neutropenic fever occurred in 4 of 6 patients. Partial responses occurred in 4 of 41 patients entered on this study. Pharmacokinetic data suggested that methotrexate did not increase paclitaxel levels. Conclusion: The combination of methotrexate and paclitaxel is feasible, but neutropenic fever, even with the addition of G-CSF prevents further escalations of paclitaxel beyond 135 mg/m² following methotrexate.