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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.

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.

SUBMITTER: Galanis E

PROVIDER: S-EPMC6788934 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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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 E Anderson S Keith SK Twohy Erin L EL Carrero Xiomara W XW Dixon Jesse G JG Tran David Dinh DD Jeyapalan Suriya A SA Anderson Daniel M DM Kaufmann Timothy J TJ Feathers Ryan W RW Giannini Caterina C Buckner Jan C JC Anastasiadis Panos Z PZ Schiff David D

Cancer 20190710 21

<h4>Background</h4>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.<h4>Methods</h4>After the completion of the phase 1 component, the phase 2 trial (C ...[more]

PMID: 31290996

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Project description:BackgroundMitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma.MethodsPatients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi.ResultsThe MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients.ConclusionsThe limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Project description:BackgroundFor treating recurrent glioblastoma, for which there is no established treatment, the antiangiogenic antibody, bevacizumab, is used alone or with irinotecan. This study was aimed at comparing the survival of patients with recurrent glioblastoma receiving bevacizumab monotherapy and those receiving bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset.MethodsPatients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database. From January 2008 to November 2021, patients who underwent surgery or biopsy and subsequent standard concurrent chemoradiation with temozolomide were included. Among them, those who received bevacizumab monotherapy or B+I were selected. Demographic characteristics, inpatient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups.ResultsEight hundred and forty-six patients who underwent surgery or biopsy and received concurrent chemoradiotherapy with temozolomide were included. Of these, 450 and 396 received bevacizumab monotherapy and B+I, respectively. The corresponding median overall survival from the initial surgery was 22.60 months (95% confidence interval [CI], 20.50-24.21) and 20.44 months (95% CI, 18.55-22.60; P = 0.508, log-rank test). The B+I group had significantly more bevacizumab prescriptions (median 5 times; BEV group: median 3 times). Cox analysis, based on the postsurgery period, revealed that male sex (hazard ratio [HR], 1.28; P = 0.002), older age (HR, 1.01; P = 0.042), and undergoing biopsy instead of surgery (HR, 1.79; P < 0.0001) were significantly associated with decreased survival. Fewer radiotherapy cycles correlated with improved survival outcomes (HR, 0.63; P = 0.001). Cox analysis, conducted from the start of chemotherapy including bevacizumab, showed that male sex was the only variable significantly associated with decreased survival (HR, 1.18; P = 0.044).ConclusionWe found no significant difference in overall survival between the bevacizumab monotherapy and B+I groups. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for treating recurrent glioblastoma.

Dataset Information

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.

Publications

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.

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