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 Jaeckle, Timothy J. Kaufmann, Jan C. Buckner

Research output: Contribution to journalArticle

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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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Glioblastoma
Vascular Endothelial Growth Factor A
Neoplasms
Single Nucleotide Polymorphism
Biomarkers
Therapeutics
Chemokine CXCL12
Hypoxia-Inducible Factor 1
Therapeutic Uses
Genetic Promoter Regions
Glioma
Disease-Free Survival
Disease Progression
Research Design
Endothelial Cells
Bevacizumab
sorafenib
Confidence Intervals
Survival

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Galanis, Evanthia ; Anderson, S. Keith ; Lafky, Jackie M. ; Uhm, Joon H. ; Giannini, Caterina ; Kumar, Shaji K. ; Kimlinger, Teresa K. ; Northfelt, Donald W. ; Flynn, Patrick J. ; Jaeckle, Kurt ; Kaufmann, Timothy J. ; Buckner, Jan C. / Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776) : A North Central Cancer Treatment Group Trial. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 17. pp. 4816-4823.
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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.",
author = "Evanthia Galanis and Anderson, {S. Keith} and Lafky, {Jackie M.} and Uhm, {Joon H.} and Caterina Giannini and Kumar, {Shaji K.} and Kimlinger, {Teresa K.} and Northfelt, {Donald W.} and Flynn, {Patrick J.} and Kurt Jaeckle and Kaufmann, {Timothy J.} and Buckner, {Jan C.}",
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Galanis, E, Anderson, SK, Lafky, JM, Uhm, JH, Giannini, C, Kumar, SK, Kimlinger, TK, Northfelt, DW, Flynn, PJ, Jaeckle, K, Kaufmann, TJ & Buckner, JC 2013, 'Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): A North Central Cancer Treatment Group Trial', Clinical Cancer Research, vol. 19, no. 17, pp. 4816-4823. https://doi.org/10.1158/1078-0432.CCR-13-0708

Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776) : A North Central Cancer Treatment Group Trial. / Galanis, Evanthia; Anderson, S. Keith; Lafky, Jackie M.; Uhm, Joon H.; Giannini, Caterina; Kumar, Shaji K.; Kimlinger, Teresa K.; Northfelt, Donald W.; Flynn, Patrick J.; Jaeckle, Kurt; Kaufmann, Timothy J.; Buckner, Jan C.

In: Clinical Cancer Research, Vol. 19, No. 17, 01.09.2013, p. 4816-4823.

Research output: Contribution to journalArticle

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T1 - Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776)

T2 - A North Central Cancer Treatment Group Trial

AU - Galanis, Evanthia

AU - Anderson, S. Keith

AU - Lafky, Jackie M.

AU - Uhm, Joon H.

AU - Giannini, Caterina

AU - Kumar, Shaji K.

AU - Kimlinger, Teresa K.

AU - Northfelt, Donald W.

AU - Flynn, Patrick J.

AU - Jaeckle, Kurt

AU - Kaufmann, Timothy J.

AU - Buckner, Jan C.

PY - 2013/9/1

Y1 - 2013/9/1

N2 - 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.

AB - 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.

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