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.

Keywords: Antiangiogenic agent; BRAF; Metastatic melanoma; Metronomic paclitaxel; Pazopanib.

Conflict of interest statement

Conflict of interest

Research support: Glaxo Smith Kline, Inc. and Novartis, Inc. JP Fruehauf has received financial support from Novartis for speaking at educational symposia and for developing slide decks for educational symposia. No other authors have conflicts of interest.

Ethical standards

This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The IND for this FDA approved trial is held by JP Fruehauf and UC Irvine.

Informed consent

This trial was carried out with the approval of the UC Irvine IRB and all patients were required to provided informed consent prior to their participation.

Figures

Fig. 1

Maximum percentage change in target lesion size, based on response evaluation criteria 1.1 in solid tumors (n = 54; six were invaluable for response). BRAF mutation-positive cases shown in red bars

Fig. 2

Kaplan–Meier estimates (± 95% CI) of a progression-free survival in all patients (n = 60); and b overall survival (n = 60); and c comparison of OS between BRAF WT/unknown (n = 46) and BRAF mutation-positive patients (n = 14)

Fig. 3

Correlation coefficient between pazopanib pre-dose blood levels on C2D1 and maximum percent change in target lesions