title: Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma.
abstract: Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 9E, Boston, MA, 02114, USA, Jennie.Taylor@ucsf.edu.
authors.forename: Jennie W
authors.initials: JW
authors.lastname: Taylor
authors.forename: Jorg
authors.initials: J
authors.lastname: Dietrich
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Norden
authors.forename: Mikael L
authors.initials: ML
authors.lastname: Rinne
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Diana H
authors.initials: DH
authors.lastname: Giorgio
authors.forename: Kellis
authors.initials: K
authors.lastname: Snodgrass
authors.forename: Alison E
authors.initials: AE
authors.lastname: Randall
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
mesh_terms: D000328:Adult; D000814:Aniline Compounds / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009570:Nitriles / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011804:Quinolines / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D011804:Quinolines; C471992:bosutinib; D019061:src-Family Kinases