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

Jeffrey R. Infante, Silvia Novello, Wen Wee Ma, Grace K. Dy, Johanna C. Bendell, Anne Huff, Qiong Wang, A. Benjamin Suttle, Robert Allen, Chun Fang Xu, Lone H. Ottesen, Howard A. Burris, Alex A. Adjei

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Summary: 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 B 12 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.

Original languageEnglish (US)
Pages (from-to)927-936
Number of pages10
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
StatePublished - Aug 2013

Keywords

  • Combination therapy
  • Maximum tolerated dose
  • Non-small-cell lung carcinoma
  • Pazopanib
  • Pemetrexed

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Infante, J. R., Novello, S., Ma, W. W., Dy, G. K., Bendell, J. C., Huff, A., Wang, Q., Suttle, A. B., Allen, R., Xu, C. F., Ottesen, L. H., Burris, H. A., & Adjei, A. A. (2013). Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with pemetrexed in patients with advanced solid tumors. Investigational New Drugs, 31(4), 927-936. https://doi.org/10.1007/s10637-012-9900-0