Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma

Jennie W. Taylor, Jorg Dietrich, Elizabeth R. Gerstner, Andrew D. Norden, Mikael L. Rinne, Daniel P. Cahill, Anat Stemmer-Rachamimov, Patrick Y. Wen, Rebecca Betensky, Diana H. Giorgio, Kellis Snodgrass, Alison E. Randall, Tracy T. Batchelor, Andrew S. Chi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)557-563
Number of pages7
JournalJournal of Neuro-Oncology
Volume121
Issue number3
DOIs
StatePublished - Jan 1 2015

Fingerprint

Glioblastoma
Protein-Tyrosine Kinases
Neoplasms
bosutinib
Glioma
Vascular Endothelial Growth Factor A
Disease-Free Survival
Cell Movement
Up-Regulation
Therapeutics
Safety
Recurrence

Keywords

  • Bosutinib
  • Glioblastoma
  • Invasion
  • Src inhibitor

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Taylor, J. W., Dietrich, J., Gerstner, E. R., Norden, A. D., Rinne, M. L., Cahill, D. P., ... Chi, A. S. (2015). Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. Journal of Neuro-Oncology, 121(3), 557-563. https://doi.org/10.1007/s11060-014-1667-z

Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. / Taylor, Jennie W.; Dietrich, Jorg; Gerstner, Elizabeth R.; Norden, Andrew D.; Rinne, Mikael L.; Cahill, Daniel P.; Stemmer-Rachamimov, Anat; Wen, Patrick Y.; Betensky, Rebecca; Giorgio, Diana H.; Snodgrass, Kellis; Randall, Alison E.; Batchelor, Tracy T.; Chi, Andrew S.

In: Journal of Neuro-Oncology, Vol. 121, No. 3, 01.01.2015, p. 557-563.

Research output: Contribution to journalArticle

Taylor, JW, Dietrich, J, Gerstner, ER, Norden, AD, Rinne, ML, Cahill, DP, Stemmer-Rachamimov, A, Wen, PY, Betensky, R, Giorgio, DH, Snodgrass, K, Randall, AE, Batchelor, TT & Chi, AS 2015, 'Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma', Journal of Neuro-Oncology, vol. 121, no. 3, pp. 557-563. https://doi.org/10.1007/s11060-014-1667-z
Taylor JW, Dietrich J, Gerstner ER, Norden AD, Rinne ML, Cahill DP et al. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. Journal of Neuro-Oncology. 2015 Jan 1;121(3):557-563. https://doi.org/10.1007/s11060-014-1667-z
Taylor, Jennie W. ; Dietrich, Jorg ; Gerstner, Elizabeth R. ; Norden, Andrew D. ; Rinne, Mikael L. ; Cahill, Daniel P. ; Stemmer-Rachamimov, Anat ; Wen, Patrick Y. ; Betensky, Rebecca ; Giorgio, Diana H. ; Snodgrass, Kellis ; Randall, Alison E. ; Batchelor, Tracy T. ; Chi, Andrew S. / Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. In: Journal of Neuro-Oncology. 2015 ; Vol. 121, No. 3. pp. 557-563.
@article{5adebdfed1184b829397e588265f6029,
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.",
keywords = "Bosutinib, Glioblastoma, Invasion, Src inhibitor",
author = "Taylor, {Jennie W.} and Jorg Dietrich and Gerstner, {Elizabeth R.} and Norden, {Andrew D.} and Rinne, {Mikael L.} and Cahill, {Daniel P.} and Anat Stemmer-Rachamimov and Wen, {Patrick Y.} and Rebecca Betensky and Giorgio, {Diana H.} and Kellis Snodgrass and Randall, {Alison E.} and Batchelor, {Tracy T.} and Chi, {Andrew S.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1007/s11060-014-1667-z",
language = "English (US)",
volume = "121",
pages = "557--563",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",
number = "3",

}

TY - JOUR

T1 - Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma

AU - Taylor, Jennie W.

AU - Dietrich, Jorg

AU - Gerstner, Elizabeth R.

AU - Norden, Andrew D.

AU - Rinne, Mikael L.

AU - Cahill, Daniel P.

AU - Stemmer-Rachamimov, Anat

AU - Wen, Patrick Y.

AU - Betensky, Rebecca

AU - Giorgio, Diana H.

AU - Snodgrass, Kellis

AU - Randall, Alison E.

AU - Batchelor, Tracy T.

AU - Chi, Andrew S.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

KW - Bosutinib

KW - Glioblastoma

KW - Invasion

KW - Src inhibitor

UR - http://www.scopus.com/inward/record.url?scp=84925491476&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925491476&partnerID=8YFLogxK

U2 - 10.1007/s11060-014-1667-z

DO - 10.1007/s11060-014-1667-z

M3 - Article

C2 - 25411098

AN - SCOPUS:84925491476

VL - 121

SP - 557

EP - 563

JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

IS - 3

ER -