A Phase Ii Single Arm Study Of Pazopanib And Paclitaxel As First-Line Treatment For Unresectable Stage Iii And Stage Iv Melanoma: Interim Analysis.

8524 Background: Metastatic melanoma lacks effective therapy. Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 20 eligible patients have been enrolled with 17 evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib at 800mg as a continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST criteria were used to define treatment response. Results: For the 17 evaluable patients treated to date the following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall RR (CR+PR) was 40%. Total disease control rate was 80% (PR+SD). The most common AEs/lab abnormalities were nausea (71%), hypertension (57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included hypertension (28%), transaminitis (21%) and neutropenia (14%). One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 5 patients and for paclitaxel in one patient. Conclusions: Planned interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 40% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients.