Pazopanib in Combination With PCI-24781 in Patients With Metastatic Solid Tumors

Study rationale/purpose Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor44 of VEGFR-1, -2, -3, PDGFR-α and -β and c-kit approved for metastatic renal cell carcinoma based on phase III data showing a significant prolongation of progression-free survival (PFS) (5 mos in pretreated patients and 8.3 mos in treatment-naïve patients). In addition recent data was presented this year, but is not yet published, with treatment-refractory sarcoma patients that showed a PFS was significantly prolonged from a median of 20 vs. 7 weeks. As can occur with all antiangiogenic agents, resistance to pazopanib may develop. Epigenetic modification with HDAC inhibitors may overcome drug resistance by causing an increase in accessibility of DNA to chemotherapeutic agents and may therefore significantly potentiate their cytotoxicity. Combination trials with chemotherapy agents are ongoing (ClinicalTrials.gov) To our knowledge, a combination trial of HDACi with anti-angiogenesis agents has not yet been performed and represents an unmet medical need. PCI-24781 is a pan HDAC inhibitor. In cell lines tested, up-regulation and down-regulation of genes known to result in changes with signal transduction, oxidation, metabolic changes, apoptosis, proliferation, differentiation and angiogenesis were seen. In addition, ongoing single agent and combination trials have shown the drug to be effective and well-tolerated. Hypothesis: Combining an antiangiogenic agent, such as pazopanib, with an epigenetic modifier, such as histone deacetylase inhibitor (HDACi) PCI-24781, can increase the efficacy of pazopanib as well as overcome development of resistance to pazopanib.