A Phase I study of pazopanib in combination with gemcitabine in patients with advanced solid tumors

Ruth Plummer, Ayman Madi, Melinda Jeffels, Heike Richly, Bahar Nokay, Stephen Rubin, Howard A Ball, Steve Weller, Jeffrey Botbyl, Diana M Gibson, Max E Scheulen, Ruth Plummer, Ayman Madi, Melinda Jeffels, Heike Richly, Bahar Nokay, Stephen Rubin, Howard A Ball, Steve Weller, Jeffrey Botbyl, Diana M Gibson, Max E Scheulen

Abstract

Purpose: Pazopanib plus gemcitabine combination therapy was explored in patients with advanced solid tumors.

Methods: In a modified 3 + 3 enrollment scheme, oral once-daily pazopanib was administered with intravenous gemcitabine (Days 1 and 8, 21-day cycles). Three protocol-specified dose levels were tested: pazopanib 400 mg plus gemcitabine 1,000 mg/m(2), pazopanib 800 mg plus gemcitabine 1,000 mg/m(2), and pazopanib 800 mg plus gemcitabine 1,250 mg/m(2). Maximum-tolerated dose was based on dose-limiting toxicities during treatment Cycle 1. In the expansion phase, six additional patients were enrolled at the highest tolerable dose level.

Results: Twenty-two patients were enrolled. At the highest dose level tested (pazopanib 800 plus gemcitabine 1,250), patients received >80% of their planned dose and the regimen was deemed safe and tolerable. The most common treatment-related adverse events included fatigue, neutropenia, nausea, and decreased appetite. Neutropenia and thrombocytopenia were the most common events leading to dose modifications. Pharmacokinetic interaction between pazopanib and gemcitabine was not observed. One objective partial response at the highest dose was observed in a patient with metastatic melanoma. Prolonged disease stabilization (>12 cycles) was reported in three patients (metastatic melanoma, cholangiocarcinoma, and colorectal carcinoma).

Conclusion: Combination pazopanib plus gemcitabine therapy is tolerable, with an adverse event profile reflective of that associated with the individual agents. There was no apparent pharmacokinetic interaction with pazopanib plus gemcitabine co-administration, although patient numbers were limited. Further investigation of combined pazopanib plus gemcitabine is warranted.

Trial registration: ClinicalTrials.gov NCT00678977.

Figures

Fig. 1
Fig. 1
Median pazopanib, gemcitabine, and dFdU concentration–time profiles from patients in the cohort-expansion phase: gemcitabine (1,250 mg/m2 by 30-min infusion) was administered alone on Cycle 1 Day 1 (C1D1) and in combination with oral pazopanib (800 mg) on Cycle 2 Day 1 (C2D1); pazopanib was administered once daily beginning on C1D2, and gemcitabine was administered on Days 1 and 8 of the 21-day cycle

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Source: PubMed

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