Updated interim analysis of UCI 09-53: A phase II, single arm study of pazopanib and paclitaxel as first-line treatment for subjects with unresectable advanced melanoma.

Abstract

9082 Background: Metastatic melanoma lacks effective therapy. Pazopanib is an 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, 31 patients are 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 800mg 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 VEGFR-2, 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 1.1 criteria were used to define treatment response (SD criteria was a minimum interval of 8 weeks). Results: For the 31 evaluable patients treated to date the following results were seen: 1 CR, 9 PR’s, 13 SD’s and 8 PD’s. The overall RR (CR+PR) was 32%. Total disease control rate was 74% (CR+PR+SD). The most common AEs/lab abnormalities were diarrhea (66%) nausea (60%), hypertension (63%), fatigue (63%) and vomiting (29%). Grade 3-4 AEs included hypertension (26%), transaminitis (23%) and neutropenia (17%).One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 15 patients and for paclitaxel in 4 patients. Conclusions: Updated interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 32% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients. Clinical trial information: NCT01107665.