Using only histology, liver cirrhosis was significantly underestimated. In our cohort, severity of CHC was not clearly affected by race when alcohol use and features of the metabolic syndrome were taken into consideration. However, there was a trend for African Americans to have lower cirrhosis rates.

TPS8602 Background: Vemurafenib induces transient objective responses in half of BRAFV600E mutant melanoma patients and a median PFS of 5.3 months (NEJM. 2011;364:2507-2516). BRAF mutations are not sufficient to cause melanoma, but the combination of BRAFV600E mutation and PTEN loss is sufficient to recapitulate the malignant melanoma phenotype in vivo (Nat. Genet. 2009;41:544-552). PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause acquired resistance to BRAF inhibitors (Cancer Cell. 2010;18:683-695). This phase I/II study is the first trial to test the safety and efficacy of combining a potent BRAF inhibitor, vemurafenib, with a potent PI3K inhibitor, BKM120, in patients with metastatic BRAF mutant melanoma. Methods: Design: Phase I patients receive a single dose of oral BKM120 (d -7) then vemurafenib twice daily with BKM120 daily (starting on c1d1). PK analysis is performed for BKM120 alone and for both drugs in combination. Doses of both drugs will be escalated in 3+3 scheme. Phase II patients receive continuous dosing of vemurafenib twice daily and BKM120 daily. Serial biopsies for PD and mRNA expression analyses are required for patients with visible or palpable tumors. Reimaging will be performed every 8 weeks.Eligibility: This study is enrolling BRAFV600E/K mutant metastatic melanoma patients with no prior exposure to BRAF inhibitors or PI3K inhibitors, ECOG PS ≥ 2 and adequate organ function. Endpoints: The primary endpoint for phase 1 is the recommended phase 2 dose of the combination. The primary endpoint for phase II is the 6 month PFS rate. Secondary endpoints include median PFS and OS. Baseline PTEN expression and changes is pS6 protein levels will be examined as predictors of efficacy, and changes in gene expression profiles will be assessed. Summary: This is the first trial examining the safety and efficacy of combined BRAF/PI3K inhibition in BRAF mutant melanoma patients.

TPS2623 Background: PAZ is a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT, approved for metastatic RCC and refractory sarcoma based on phase III data showing prolonged PFS (JCO 2010;28:1061-8 and Lancet 2012;379:1879-86). PCI is a potent pan-HDAC inhibitor (pan-HDACi), observed in cell lines to change regulation of genes involved in cell signaling, apoptosis, proliferation, differentiation, and angiogenesis (Anticancer Res 2011;31:1115-23). Pre-clinical models suggest epigenetic modification with an HDACi potentiates PAZ’s efficacy by causing chromatin instability and gene expression changes involved in drug resistance (Can Res 2005;65:3815-22 and BJC 2009;100:758-63). We therefore designed a Phase Ia/b clinical trial combining PCI with PAZ in pts with advanced solid tumors, with an expansion cohort for preliminary efficacy in RCC and sarcoma. Methods: Primary objective of this phase Ia/b study is to evaluate the safety and tolerability of the combination of PAZ and PCI to determine the MTD and RP2D. In phase Ia, we utilized an accelerated phase I design. The phase Ib portion will include up to 20 pts per expansion cohort, for up to 32-70 pts enrolled. In phase 1a, pts receive run-in PCI alone on C1D-7 to D-4. Starting with C1D1, pts receive oral PCI on D1-5, 8-12, 15-19 BID 4 hrs apart and PAZ daily (D1-28) q28D cycle. CORRELATIVES: Pre- and post-treatment (Tx) H3 & H4 acetylation and HDAC activity in PBMCs. In phase Ib, these will also be studied in tumor biopsies. We will measure expression of VEGF, VEGFR, RAD51, HIF, Ki67; and analyze SNPs through genomic profiling. We will correlate response with pre- and post-Tx tumor thymidine uptake using 18F-fluorothymidine (FLT-PET) PET. Current Status: This is the 1st trial exploring the combination of an HDACi with PAZ in RCC and sarcoma, where there is an unmet need for new tolerable therapies. It will study FLT-PET, an imaging correlate that captures tumor proliferation and may have a role as a predictive biomarker. We are currently in phase Ia. Enrollment in the 3rd cohort exploring higher doses of PAZ will begin in Feb 2013. Clinical trial information: NCT01543763.