Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies

Summary Background A previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods A standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3–7, 10–14; (2) 200 mg twice daily, days 3–6, 10–13; and (3) 200 mg twice daily, days 3–7, 10–14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days. Results Fifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3–6, 10–13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control >12 months. Conclusions The MTD of this regimen is sorafenib 200 mg twice daily, days 3–6, 10–13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies.