A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC)

Abstract

3522 Background: XL184 is an orally bioavailable inhibitor of RET, MET & VEGFR2. XL184 strongly inhibits cell proliferation in MTC cell lines harboring activated RET, & pharmacodynamic studies showed substantial inhibition of RET & MET phosphorylation in TT (MTC model) xenograft tumors. Methods: Pts received XL184 QD on Days (d) 1–5 of each 14 d cycle (5&9 schedule), or continuous QD dosing. Dosing changed from mg/kg (Cohorts [C] 1–9) to flat dosing in C10. The formulation changed from suspension to capsules in C12. Response, PK & pharmacodynamic parameters are assessed. Results: 55 pts (13 w/MTC) have been treated at 13 dose levels: 0.08 - 11.52 mg/kg, 5&9 (C1–9); 175 mg/d (C10), 265 mg/d (C11), 175 mg/d (C12), & 250 mg/d (C13). 6 DLTs include 1 report each of grade (G) 3 palmar/plantar erythema, & G 3 AST, ALT & lipase elevations at 11.52 mg/kg 5&9, and G 2 & 3 mucositis at 265 mg/d resulting in dose reduction. Prominent non-DLT toxicities include diarrhea & hypopigmentation of the hair. As of 12/3/2007...