Phase Ib/II dose-escalation trial evaluating the safety and tolerability of EPO906 plus capecitabine in patients with advanced cancer

Abstract

2093 Background: EPO906, a novel epothilone, is a microtubule stabilizer that causes growth arrest in a wide variety of human tumor cell lines. EPO906 has demonstrated clinical cytotoxic activity in taxane-sensitive, -resistant, and -refractory tumors and is associated with a low incidence of hematologic toxicity. Data from a phase I study indicated that EPO906 in combination with capecitabine may be active in patients (pts) with advanced cancers. We conducted a phase Ib/II study to determine the maximum tolerated dose (MTD) of EPO906 and evaluate the safety and tolerability of EPO906 in combination with capecitabine. Methods: Eligible pts had advanced cancer, evaluable disease, and a performance status ≤ 2. Pts received EPO906 starting at 0.5 mg/m2 via 5-min IV infusion once weekly for 3 wks and concurrent capecitabine 1,250 mg/m2 orally twice daily during wks 2 and 3, followed by 1 wk of rest. EPO906 doses were increased by 0.5-mg/m2 increments to 2.5 mg/m2 or until the MTD was reached. Results: To date, 24 pts have been enrolled in 4 cohorts treated with EPO906 0.5 mg/m2 (n = 7), 1.0 mg/m2 (n = 8), 1.5 mg/m2 (n = 5), and 2.0 mg/m2 (n = 4). Median age was 54 yrs (range, 31 - 75 yrs). Dose-limiting toxicity (DLT) was experienced by only 1 of 6 evaluable pts treated at 1.0 mg/m2 (diarrhea, stomatitis), thus the dose was increased to 2.0 mg/m2. At this dose, 3 of 4 pts experienced DLT (diarrhea, nausea, anorexia, small bowel obstruction), indicating that 2.0 mg/m2 exceeded the MTD. Pts were enrolled in a cohort with an intermediate dose of 1.5 mg/m2. Two of 4 evaluable pts treated at 1.5 mg/m2 experienced DLT; this dose is the MTD. Most common adverse events (any grade) were nausea and diarrhea (experienced by 75% and 62.5% of pts, respectively). Only 3 pts (12.5%) experienced a grade 3 or 4 hematologic event. Preliminary tumor assessment shows 10 pts with stable disease (SD), and 2 pts each with rectal and renal cancer had SD with durations of 3 or 4+ and 3+ or 14+ months, respectively. Conclusion: EPO906 in combination with capecitabine is generally safe and well tolerated. Preliminary data suggest that this regimen may be active in pts with advanced cancers. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Anormed, Inc.; Novartis Pharma AG; Novartis Pharmaceuticals Corp. Gilead; Novartis Pharma AG; Novartis Pharmaceuticals Gilead; Novartis Pharma AG; Novartis Pharmaceuticals Corp. Ross Communications Novartis; Amgen; Aventis; Roche; Schering-Plough; PharmaMar; Pfizer