Phase II trial of sagopilone (ZK-EPO), a novel synthetic epothilone, with significant activity in metastatic melanoma

Abstract

9031 Background: Sagopilone (ZK-Epothilone) is a novel, fully synthetic epothilone with promising preclinical activity in several cancer models. This phase II study aims to define the efficacy and safety of sagopilone in patients with metastatic melanoma, as well as perform pharmacokinetic evaluation of this dose and schedule. Methods: Patients with unresectable stage III or IV malignant melanoma, with up to 2 prior chemotherapy and any prior immunotherapy regimens with measurable disease were eligible. Sagopilone was administered at 16 mg/m2 as a 3-hour IV infusion every 21 days. The primary end point of the trial was response rate, and secondary endpoints included time to progression, overall survival, and tolerability. Pharmacokinetic analysis was done on the first 10 patients. A total of 37 patients were to be accrued to have 33 evaluable patients. The trial had a 0.90 power and assumed α of 0.03. Results: Thirty four patients have been enrolled to date. Sagopilone appears to be well tolerated: The most common side effects seen have been sensory neuropathy, (55%, 19/34, 5 Grade 2, 14Grade 1) motor neuropathy (23%, 8/34, All Grade 1); anemia (26 %, 9/34) neutropenia (14%, 5/34 1 Grade 2, 4 Grade 1) thrombocytopenia (14%, 5/34) and fatigue (38%, 13/34). Two patients have shown grade 3 events (syncope and mental status changes, respectively, possibly related to therapy), both of which resolved and an additional patient had a pulmonary embolism which was considered unlikely to be related to therapy. Responses have been seen in 4 patients (3 RECIST confirmed PR, 1 unconfirmed PR). Stable disease was seen for at least 12 weeks in an additional 10 patients for a clinical benefit rate (CR+PR+SD) of 44%. No grade 4 events have been reported. Conclusions: Unlike the epothilone analogs patupilone or ixabepilone, sagopilone appears to be an active drug in advanced melanoma. The side effect profile seen to date at 16 mg/m2 given over 3 hours repeated every 3 weeks appears to be notably free of myelosuppression indicating that it could be combined with other drugs active in melanoma. Pharmacokinetic studies show a prolonged terminal half life, probably due to release from deep tissue compartments. [Table: see text]