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Invest New Drugs. 2013 Aug;31(4):927-36. doi: 10.1007/s10637-012-9900-0. Epub 2012 Nov 22.

Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with pemetrexed in patients with advanced solid tumors.

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1
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA.

Abstract

INTRODUCTION:

We sought to define the maximum tolerated dose (MTD) and evaluate the safety, pharmacokinetics, and preliminary clinical activity of pazopanib plus pemetrexed in patients with solid tumors.

METHODS:

This dose-escalation study used a standard 3 + 3 design to evaluate once daily pazopanib (400-800 mg) plus pemetrexed (400-500 mg/m(2) on Day 1 of each 21-day cycle). Eight additional patients were enrolled into an expansion cohort.

RESULTS:

Twenty-five patients were enrolled. Pazopanib 800 mg plus pemetrexed 500 mg/m(2) was the MTD. The most common adverse events at all dose levels included fatigue, neutropenia, diarrhea, and thrombocytopenia. The frequencies of non-hematologic adverse events were consistent with those of the individual agents. The rates of all-grade and Grade 4 hematologic toxicities (reversible neutropenia with median duration of 4 days) were higher with the combination regimen than with either monotherapy. Exploratory analyses revealed no association between the plasma levels of 3 biomarkers of vitamin B12 metabolism (cystathionine, homocysteine, and methylmalonic acid) and the risk of Grade 4 neutropenia and Grade 3 febrile neutropenia. Of 20 patients evaluated for efficacy, 2 (10 %) had a partial response. Pazopanib did not affect pemetrexed clearance, but increased pemetrexed maximal concentration by 22 %. In exploratory pharmacogenetic analyses, allelic variants of the VEGFA gene demonstrated weak correlation with development of severe neutropenia.

CONCLUSIONS:

Concomitant administration of pazopanib 800 mg once daily plus pemetrexed 500 mg/m(2) once every 21 days is feasible, albeit associated with a high frequency of brief, reversible neutropenia. Preliminary activity was observed in non-small-cell lung cancer.

PMID:
23179337
DOI:
10.1007/s10637-012-9900-0
[Indexed for MEDLINE]

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