A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma

Alliance/North Central Cancer Treatment Group N0872

Evanthia Galanis, S. Keith Anderson, Erin L. Twohy, Xiomara W. Carrero, Jesse G. Dixon, David Dinh Tran, Suriya A. Jeyapalan, Daniel M. Anderson, Timothy J Kaufmann, Ryan W. Feathers, Caterina Giannini, Jan Craig Buckner, Panagiotis Z Anastasiadis, David Schiff

Research output: Contribution to journalArticle

Abstract

Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P =.22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P =.93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P =.52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.

Original languageEnglish (US)
JournalCancer
DOIs
StatePublished - Jan 1 2019

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Glioblastoma
Placebos
Neoplasms
Therapeutics
National Cancer Institute (U.S.)
src-Family Kinases
Dasatinib
Bevacizumab
Terminology
Glioma
Disease-Free Survival
Up-Regulation
Survival
Incidence

Keywords

  • bevacizumab
  • dasatinib
  • phase 2 trial
  • recurrent glioblastoma
  • Src family kinase inhibitors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma : Alliance/North Central Cancer Treatment Group N0872. / Galanis, Evanthia; Anderson, S. Keith; Twohy, Erin L.; Carrero, Xiomara W.; Dixon, Jesse G.; Tran, David Dinh; Jeyapalan, Suriya A.; Anderson, Daniel M.; Kaufmann, Timothy J; Feathers, Ryan W.; Giannini, Caterina; Buckner, Jan Craig; Anastasiadis, Panagiotis Z; Schiff, David.

In: Cancer, 01.01.2019.

Research output: Contribution to journalArticle

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title = "A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872",
abstract = "Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9{\%} [95{\%} CI, 19.5{\%}-40.0{\%}] vs 18.4{\%} [95{\%} CI, 7.7{\%}-34.4{\%}]; P =.22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P =.93). The objective response rate was 15.7{\%} in arm A and 26.3{\%} in arm B (P =.52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7{\%} vs 7.9{\%}) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.",
keywords = "bevacizumab, dasatinib, phase 2 trial, recurrent glioblastoma, Src family kinase inhibitors",
author = "Evanthia Galanis and Anderson, {S. Keith} and Twohy, {Erin L.} and Carrero, {Xiomara W.} and Dixon, {Jesse G.} and Tran, {David Dinh} and Jeyapalan, {Suriya A.} and Anderson, {Daniel M.} and Kaufmann, {Timothy J} and Feathers, {Ryan W.} and Caterina Giannini and Buckner, {Jan Craig} and Anastasiadis, {Panagiotis Z} and David Schiff",
year = "2019",
month = "1",
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doi = "10.1002/cncr.32340",
language = "English (US)",
journal = "Cancer",
issn = "0008-543X",
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T1 - A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma

T2 - Alliance/North Central Cancer Treatment Group N0872

AU - Galanis, Evanthia

AU - Anderson, S. Keith

AU - Twohy, Erin L.

AU - Carrero, Xiomara W.

AU - Dixon, Jesse G.

AU - Tran, David Dinh

AU - Jeyapalan, Suriya A.

AU - Anderson, Daniel M.

AU - Kaufmann, Timothy J

AU - Feathers, Ryan W.

AU - Giannini, Caterina

AU - Buckner, Jan Craig

AU - Anastasiadis, Panagiotis Z

AU - Schiff, David

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P =.22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P =.93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P =.52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.

AB - Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P =.22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P =.93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P =.52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.

KW - bevacizumab

KW - dasatinib

KW - phase 2 trial

KW - recurrent glioblastoma

KW - Src family kinase inhibitors

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