Study of GemOx and Vandetanib in Advanced Solid Malignancy

This is a Phase I, open-label, dose-escalating, non-randomized study of the safety and tolerability of vandetanib in combination with a fixed dose of gemcitabine and oxaliplatin (GemOx) in the treatment of patients with advanced solid malignancy. EGFR is an important target for therapeutic drug development. It is widely expressed in most cancers and has a vital role in the regulation of proliferation signals. EGFR is expressed in a high degree (\>80%) of pancreatic tumors and is a rational target for therapy. Vandetanib selectively inhibits EGFR tyrosine kinase activity and VEGF-2 receptor. It has good oral bioavailability and has growth inhibitory activity in a wide variety of human cell lines including cells with acquired resistance to other EGFR inhibitors. The growth inhibitory property of vandetanib in vivo correlates more with its anti VEGF property, especially in cell lines with acquired resistance to EGFR inhibition. The combination of gemcitabine and oxaliplatin (GEMOX) is a well-established regimen that has demonstrated encouraging antitumor activity in pancreaticobiliary cancers in phase II studies. Recent clinical trials have also shown activity in hepatobiliary and germ cell tumors. The combination of vandetanib and gemcitabine has potential advantages and may result in an additive or synergistic effect. The GEMOX regimen is well tolerated, and toxicity does not overlap with the most common toxicity of rash or diarrhea observed with vandetanib. Thus, the combination of vandetanib and GEMOX is expected to be a well tolerated, and an easily administered regimen with improved efficacy and no overlapping toxicities.