Phase I dose-escalation trial investigating the safety and tolerability of EPO906 plus gemcitabine in patients with advanced cancer

Abstract

3100 Background: EPO906, a novel epothilone, is a microtubule stabilizer that has demonstrated clinical cytotoxic activity in taxane-sensitive, -resistant, and -refractory tumors and, unlike taxanes, is not associated with myelosuppression, alopecia, or infusion-related hypersensitivity. EPO906 and gemcitabine, an inhibitor of DNA synthesis, have different mechanisms of action and non-overlapping toxicity profiles and may have synergistic antitumor activity. In a phase I, multicenter trial, we evaluated the safety and tolerability of EPO906 in combination with gemcitabine for the treatment of advanced cancers. Methods: Eligible patients (pts) had stage IV disease with ≥ 1 measurable lesion and performance status grade ≤ 2. Pts received weekly EPO906 via 5-min IV infusion starting at 0.5 mg/m2, immediately followed by gemcitabine 800 mg/m2 via 30-min IV infusion, for 3 wks followed by 1 wk rest. EPO906 was escalated in subsequent cohorts by 0.5-mg/m2 increments to 2.5 mg/m2 (the probable MTD of EPO906 alone for the 3 wk on/1 wk off schedule). Results: In total, 24 pts were enrolled in 5 cohorts treated with 0.5 mg/m2 (n = 4), 1.0 mg/m2 (n = 4), 1.5 mg/m2 (n = 4), 2.0 mg/m2 (n = 6) and 2.5 mg/m2 (n = 6). Median age was 54 yrs (range, 27–75 yrs). No DLTs were reported in pts treated with EPO906 at doses up to 2.0 mg/m2. In the 2.5-mg/m2 cohort, 4 of 6 pts experienced DLTs, including grade (gr) 3 diarrhea (n = 3), nausea (n = 1), and dizziness (n = 1). Thus, the MTD of EPO906 in combination with gemcitabine is 2.0 mg/m2. Most common nonhematologic toxicities (any gr) included diarrhea (n = 15), nausea (n = 15), and fatigue (n = 12). Hematologic toxicities included gr 4 neutropenia (n = 1) and gr 3 anemia (n = 4), neutropenia (n = 3), leukopenia (n = 2), and thrombocytopenia (n = 1). After 2 cycles of therapy, RECIST tumor assessment in 16 evaluable pts showed 1 pt with a partial response and 7 with stable disease. Conclusion: These preliminary data indicate that the combination of EPO906 and gemcitabine is generally safe and well tolerated. Future studies will fully characterize the role of EPO906 in combination with gemcitabine in the treatment of advanced cancers. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Berlex; Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp. August A. Fink Memorial Foundation Novartis