Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with pemetrexed in patients with advanced solid tumors
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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/m2 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/m2 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/m2 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.
KeywordsPazopanib Pemetrexed Non-small-cell lung carcinoma Maximum tolerated dose Combination therapy
The study described in this manuscript was funded by GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania. Funding for writing and editorial assistance was also provided by GlaxoSmithKline. The authors acknowledge Jane Saiers, PhD (The WriteMedicine, Inc.), for assistance with writing the manuscript, and Jerome F. Sah, PhD (ProEd Communications, Inc.), for medical editorial assistance.
This study complied with the laws of the countries in which it was conducted (United States and Italy), and the study was approved by the respective institutional ethics committees.
Conflict of interest
H.A. Burris reports that his institution, Sarah Cannon Research Institute, received a grant for this study. J.R. Infante reports that his institution, Sarah Cannon Research Institute, received consulting honoraria, travel support, and other fees related to this study. A. Huff, Q. Wang, A.B. Suttle, C.F. Xu, and L.H. Ottesen are employees and stockholders of GlaxoSmithKline. S. Novello, W.W. Ma, G.K. Dy, J.C. Bendell, R. Allen, and A.A. Adjei report no potential conflicts of interest.
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