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 - PubMed (original) (raw)

Clinical Trial

. 2019 Nov 1;125(21):3790-3800.

doi: 10.1002/cncr.32340. Epub 2019 Jul 10.

S Keith Anderson 2, Erin L Twohy 2, Xiomara W Carrero 2, Jesse G Dixon 2, David Dinh Tran 3, Suriya A Jeyapalan 4, Daniel M Anderson 5, Timothy J Kaufmann 6, Ryan W Feathers 7, Caterina Giannini 8, Jan C Buckner 1, Panos Z Anastasiadis 7, David Schiff 9

Affiliations

Clinical Trial

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 et al. Cancer. 2019.

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: Src family kinase inhibitors; bevacizumab; dasatinib; phase 2 trial; recurrent glioblastoma.

© 2019 American Cancer Society.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

The remaining authors declare no potential conflicts of interest.

Figures

Figure 1:

Figure 1:

CONSORT diagram

Figure 2:

Figure 2:

Kaplan-Meier curves of overall survival (A), progression-free survival (B), and time to progression (C), duration of response (D), and time to treatment failure (E) in Phase II patients.

Figure 2:

Figure 2:

Kaplan-Meier curves of overall survival (A), progression-free survival (B), and time to progression (C), duration of response (D), and time to treatment failure (E) in Phase II patients.

Figure 2:

Figure 2:

Kaplan-Meier curves of overall survival (A), progression-free survival (B), and time to progression (C), duration of response (D), and time to treatment failure (E) in Phase II patients.

Figure 2:

Figure 2:

Kaplan-Meier curves of overall survival (A), progression-free survival (B), and time to progression (C), duration of response (D), and time to treatment failure (E) in Phase II patients.

Figure 2:

Figure 2:

Kaplan-Meier curves of overall survival (A), progression-free survival (B), and time to progression (C), duration of response (D), and time to treatment failure (E) in Phase II patients.

Figure 3:

Figure 3:

Adverse events possibly related to treatment in the bevacizumab/dasatinib arm (A) and bevacizumab arm (B). AEs are included when 2 or more patients have grade 3 or 4 AEs, or 10 or more patients have grade 1 or 2 AEs which are deemed to be at least possibly related to treatment.

Figure 3:

Figure 3:

Adverse events possibly related to treatment in the bevacizumab/dasatinib arm (A) and bevacizumab arm (B). AEs are included when 2 or more patients have grade 3 or 4 AEs, or 10 or more patients have grade 1 or 2 AEs which are deemed to be at least possibly related to treatment.

References

    1. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol. 2015;17 Suppl 4: iv1-iv62. -PMC -PubMed
    1. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31: 4085–4091. -PMC -PubMed
    1. Stupp R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017;318: 2306–2316. -PMC -PubMed
    1. Seystahl K, Wick W, Weller M. Therapeutic options in recurrent glioblastoma--An update. Crit Rev Oncol Hematol. 2016;99: 389–408. -PubMed
    1. Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol. 2005;15: 297–310. -PMC -PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources