Phase Ib Study of the Combination of Pazopanib, an Oral VEGFR Inhibitor, and ARQ 197 (Tivantinib), an Oral MET Inhibitor, in Patients With Refractory Advanced Solid Tumors

Background:

• Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) signal transduction pathways have synergistic effects on promoting angiogenesis and growth factor expression. Hypoxia caused by treatment with VEGF inhibitors results in the upregulation of mesenchymal-epithelial transition factor (c-MET), the receptor for HGF. In a mouse model, combined blockade of VEGFR and c-MET significantly prolonged survival compared with inhibition of either target alone.
• We hypothesize that co-administration of the putative hepatocyte growth factor receptor (MET) inhibitor ARQ 197 (Tivantinib) will prevent the adaptive response to hypoxia resulting from treatment with the VEGFR inhibitor pazopanib, and conversely, that co-administration of pazopanib will prevent the effect of increased VEGF and reduced thrombospondin 1 in tumors after treatment with ARQ 197. Therefore, the combination of these agents may result in improved antitumor effects.

Objectives:

• Establish the safety and tolerability of the combination of pazopanib with ARQ 197 in patients with refractory advanced solid tumors.
• Establish the maximum tolerated dose (MTD) of the combination of pazopanib with ARQ 197 in patients with refractory advanced solid tumors.
• Evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ 197 in patients with refractory advanced solid tumors.
• Determine the pharmacokinetics (PK) of pazopanib and ARQ 197.
• Determine and compare levels of total MET, phospho MET, Hypoxia-Inducible Factor (HIF)-1, and epithelial-mesenchymal transition markers (e-cadherin, beta catenin) in tumor biopsy samples prior to and following administration of the study drugs.
• Determine and compare levels of circulating levels of hepatocyte growth factor (HGF), soluble MET (sMET), vascular endothelial growth factor A (VEGF-A), and soluble vascular endothelial growth factor receptor 2 (VEGFR2) (sVEGFR2) prior to and following administration of the study drugs.
• Determine polymorphisms in the cytochrome P450 2C19 (CYP2C19) and correlate these with the observed toxicities, and the pharmacokinetics (PK) of ARQ 197.
• Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with refractory advanced solid tumors.

Eligibility: