Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): A North Central Cancer Treatment Group Trial

Evanthia Galanis, S. Keith Anderson, Jackie M. Lafky, Joon H. Uhm, Caterina Giannini, Shaji K. Kumar, Teresa K. Kimlinger, Donald W. Northfelt, Patrick J. Flynn, Kurt A. Jaeckle, Timothy J. Kaufmann, Jan C. Buckner

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Purpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity. Experimental Design: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1-5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B). Results: Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5-24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7-8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P < 0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell-derived factor-1 was associated with PFS6 success (P = 0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome. Conclusions: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.

Original languageEnglish (US)
Pages (from-to)4816-4823
Number of pages8
JournalClinical Cancer Research
Volume19
Issue number17
DOIs
StatePublished - Sep 1 2013

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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