This is a open-label non-randomized, dose escalation and expansion Phase Ia/Ib study to
determine the safety, tolerability and maximum tolerated dose (MTD) of pazopanib in
combination with PCI-24781 in patients with advanced solid tumors.
Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor44 of VEGFR-1, -2, -3, PDGFRand
- 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-nave 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
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.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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