Phase I trial of sunitinib and gemcitabine in patients with advanced solid tumors

Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy. We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale. Two different MTDs were determined. The schedule of gemcitabine 800 mg/m2 on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m2 on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m2 on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily. This combination is well-tolerated and has significant clinical activity.