Phase I Trial Using Patupilone (Epothilone B) and Concurrent Radiotherapy for Central Nervous System Malignancies

Purpose: Based on preclinical data indicating the radiosensitizing potential of epothilone B, the present study was designed to evaluate the toxicity and response rate of patupilone, an epothilone B, with concurrent radiotherapy (RT) for the treatment of central nervous system malignancies. Methods and Materials: The present Phase I study evaluated the toxicities associated with patupilone combined with RT to establish the maximal tolerated dose. Eligible patients had recurrent gliomas (n = 10) primary (n = 5) or metastatic (n = 17) brain tumors. Dose escalation occurred if no dose-limiting toxicities, defined as any Grade 4-5 toxicity or Grade 3 toxicity requiring hospitalization, occurred during treatment. Results: Of 14 patients, 5 were treated with weekly patupilone at 1.5 mg/m², 4 at 2.0 mg/m², 4 at 2.5 mg/m², and 1 at 4 mg/m². Of 18 patients, 7 were treated in the 6-mg/m² group, 6 in the 8-mg/m² group, and 5 in the 10-mg/m² group. Primary central nervous system malignancies received RT to a median dose of 60 Gy. Central nervous system metastases received whole brain RT to a median dose of 37.4 Gy, and patients with recurrent gliomas underwent stereotactic RT to a median dose of 37.5 Gy. One dose-limiting toxicity (pneumonia) was observed in group receiving 8-mg/m² every 3 weeks. At the subsequent dose level (10 mg/m²), two Grade 4 dose-limiting toxicities occurred (renal failure and pulmonary hemorrhage); thus, 8 mg/m² every 3 weeks was the maximal tolerated dose and the recommended Phase II dose. Conclusion: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone was well tolerated and safe, with a maximal tolerated dose of 8 mg/m² every 3 weeks.