In an early Phase I trial, AstraZeneca's Zactima (ZD6474) is showing positive objective remissions and stabilization of tumors. ZD6474 inhibits the vascular endothelial growth factor (VEGF) receptor, endothelial growth factor receptor (EGFR) and RET oncogene receptor tyrosine kinase activity.
RET transduces signals for cell growth and differentiation. RET activation is the oncogenic event, with VEGF-dependent angiogenesis and other growth factor signal transduction pathways -- including EGFR signaling -- participating in the growth and development of the tumor. Twenty-five percent of medullary thyroid cancers are caused by a mutation in the RET oncogene.
The ongoing open-label study is enrolling patients with unresectable, measurable, locally advanced or metastatic hereditary medullary thyroid carcinoma. Treatment involves once-daily oral 300-mg doses of ZD6474. The primary endpoint is objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) on Day 1 and at monthly intervals.