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Πέμπτη 19 Ιουλίου 2018

Phase II study of pazopanib in combination with paclitaxel in patients with metastatic melanoma

Abstract

Purpose

This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma.

Experimental design

Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m2 weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted.

Results

The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response.

Conclusions

The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted.



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