A phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer.

TPS3117 Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway, especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the development of many different types of cancers, including breast, colorectal, melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, but there is currently no approved therapy for advanced radioiodine-resistant disease. In DTC xenograft models, vertical inhibition of this pathway, achieved by targeting the vascular endothelial growth factor receptor (VEGFR) and MEK, has shown greater clinical efficacy than with either agent alone. Pazopanib (P) is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infan...