Phase I trial of the novel epothilone sagopilone (ZK-EPO) in combination with cisplatin as first-line therapy in patients with extensive-disease small-cell lung cancer (ED-SCLC)

Abstract

19081 Background: Sagopilone, a novel epothilone, has shown preclinical activity against SCLC cell lines. A completed Phase I trial with sagopilone in various solid tumors has demonstrated single-agent administration to be well tolerated with peripheral neuropathy as the major dose-limiting toxicity (DLT). Early signals of clinical efficacy, including objective responses, have been observed. This study aimed to determine the maximum tolerated dose (MTD) of sagopilone combined with cisplatin (P) as 1st-line treatment in patients (pts) with ED-SCLC. Methods: Pts with chemotherapy-naïve ED-SCLC and measurable disease were included. Treatment consisted of a 3-h infusion of sagopilone followed by a fixed dose of P (75 mg/m2 1-h infusion) d1 q3w. Dose escalation of sagopilone included 12 mg/m2 (1st cohort), 16 mg/m2 (2nd cohort), and 22 mg/m2 (3rd cohort). At each dose level (DL) 6 pts were planned. Dose escalation would be stopped in the event of >1 DLT per cohort. Results: Until 12/2007, 16 pts were treated (12 male, 4 female): 6 pts at 1st DL (12 mg/m2 sagopilone, 75 mg/m2 P), 7 pts at 2nd DL, and 3 pts at 3rd DL. The median age was 60 years (range 43–72). Complete data are currently available for 13 pts. A median of 5 cycles per pt has been administered. So far, MTD has not been reached: no DLTs were observed at DL 1 or 2. One pt experienced DLT at 22 mg/m2 (grade 3 bone pain). The most commonly observed drug-related side effect was peripheral sensory neuropathy (7/13 patients): 1 pt, grade 1; 5 pts, grade 2; 1 pt, grade 3. Other drug-related toxicities (all grades ≥10%) were nausea (54%), vomiting (54%), pain extremities (38%), anemia (31%), fatigue (31%), anorexia (23%), pain other (23%), vertigo (23%), constipation (15%), and headache (15%). Preliminary efficacy analysis showed objective responses in 6/12 (50%) evaluable pts (all partial responses). Conclusions: In ED-SCLC, a combination of 75 mg/m2 P and sagopilone up to a dose of 16 mg/m2 can be safely administered. Final results of the 3rd cohort at 22 mg/m2 will be available at the meeting. The combination of P and sagopilone has shown promising clinical activity in pts with ED-SCLC. Further Phase II evaluation of this combination in ED-SCLC appears to be warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Schering Pharma AG Bayer Schering AG Bayer Schering AG Bayer Schering AG Bayer Schering Pharma AG Roche Pharma AG