@article{a12d24fcb94a4bb996e885c19aa612f5,
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 = "Src family kinase inhibitors, bevacizumab, dasatinib, phase 2 trial, recurrent glioblastoma",
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 C.} and Anastasiadis, {Panos Z.} and David Schiff",
note = "Funding Information: Supported by the National Cancer Institute of the National Institutes of Health under awards UG1CA189823 (Alliance for Clinical Trials in Oncology National Cancer Institute Community Oncology Research Program Grant) U10CA180821, U10CA180882, and U10CA180833. Correlative analysis was supported with funding from Bristol-Myers Squibb and Genentech. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The most common AEs in both treatment arms combined and considered to be at least possibly related to treatment (toxicities) are summarized in Table and Figure. The most frequent treatment-related AEs (all grades and at least possibly related to treatment) included fatigue (62.0%), anemia (52.9%), thrombocytopenia (44.6%), and diarrhea (41.3%). Adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). Overall, the incidence of grade ≥3 toxicities was slightly higher but not statistically significant in patients in arm A versus arm B (47.0% vs 36.8%, respectively; P =.33, Fisher exact test). This remained the case when considering grade ≥3 hematologic toxicities (15.7% in arm A and 7.9% in arm B; P =.39) and grade ≥3 nonhematologic toxicities (44.6% in arm A and 34.2% in arm B; P =.33) separately. Common grade ≥3 toxicities (occurring in ≥5% of patients in either treatment arm) are shown in Table. Lymphopenia was the most frequent grade ≥3 hematologic toxicity (9.6% in arm A and 2.6% in arm B), whereas the most common nonhematologic toxicities were hypophosphatemia (14.5% in arm A and 2.6% in arm B) and fatigue (12% in arm A and 0% in arm B). Four patients died during the study (2 patients in arm A and 2 patients in arm B). One death was considered possibly related to treatment. This patient, who was in the bevacizumab-only arm, experienced grade 5 pneumonia with an unknown absolute neutrophil count. Publisher Copyright: {\textcopyright} 2019 American Cancer Society",
year = "2019",
month = nov,
day = "1",
doi = "10.1002/cncr.32340",
language = "English (US)",
volume = "125",
pages = "3790--3800",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "21",
}