ACTR-20. A SMALL MOLECULE AXL INHIBITOR, BGB324 – FIRST-IN-HUMAN GBM SURGICAL PK TRIAL FOR RECURRENT TUMORS. (5th November 2018)

• Record Type: Journal Article
• Authors: Ghosh, Sadashib; Sadahiro, Hirokazu; Kang, Kyung-Don; Gibson, Justin T; Minata, Mutsuko; Yu, Hai; Shi, Junfeng; Chhipa, Rishi; Chen, Zhihong; Lu, Songjian; Simoni, Yannick; Furuta, Takuya; Sabit, Hemragul; Zhang, Suojun; Bastola, Soniya; Yamaguchi, Shinobu; Alsheikh, Heba Allah; Komarova, Svetlana; Wang, Jun; Kim, Sung-Hak; Hambardzumyan, Dolores; Lu, Xinghua; Newell, Evan W; Dasgupta, Biplab; Nakada, Mitsutoshi; Lee, L James; Nabors, L Burt; A. Norian, Lyse; Nakano, Ichiro
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi15
• Page End: vi15
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.054
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma (GBM) remains the deadliest of all primary brain tumors with very few effective treatment options. Recently, we reported that high AXL expression is correlated with poor prognosis in GBM patients and demonstrated the therapeutic benefits of targeting AXL, a member of TAM receptor tyrosine kinase family using a novel small molecule inhibitor, BGB324 in immunocompetent mouse GBM models and xenografts of patient-derived glioma stem cells(GSCs). The promise of BGB324 in tumor burden management prompted us to develop a clinical trial with BGB324 as a single agent therapeutic with the goal to extend it as a combinatorial therapy in the future. Our surgical PK/PD clinical trial with BGB324 in recurrent GBM has been approved by the Brain Malignancy Steering Committee at the National Cancer Institute. Study treatment will consist of 2 cohorts of adult GBM patients, one (Group A) receiving the treatment pre-operatively and the other (Group B) receiving no treatment at all prior to surgery. First 5 patients recruited to Group A will be checked for the desired intra-tumoral drug concentration achieved to continue the trial. Group A will be supplemented by an additional 5 patients bringing the number to n=10 in each arm of the trial. Following surgical resection, patients in both cohorts will receive BGB324 daily in 21-day cycles. Treatment will be continued unless patients exhibit significant toxicity or substantial tumor progression. Our preclinical findings show the upregulation of AXL and its role in apoptosis induction in mesenchymal GBM as well as its association with MLK4, a serine threonine kinase we previously characterized as a mesenchymal GSC molecular target. Inhibition of phosphorylation of AXL and concomitant NF-kB activation in mesenchymal GSCs was found to be the nodal target of the drug action. An up-to-date information of the trial will be presented in detail.