TY - JOUR
T1 - Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours
AU - Jones, Robin L.
AU - Ratain, Mark J.
AU - O'Dwyer, Peter J.
AU - Siu, Lillian L.
AU - Jassem, Jacek
AU - Medioni, Jacques
AU - DeJonge, Maja
AU - Rudin, Charles
AU - Sawyer, Michael
AU - Khayat, David
AU - Awada, Ahmad
AU - de Vos-Geelen, Judith M. P. G. M.
AU - Evans, T. R. Jeffry
AU - Obel, Jennifer
AU - Brockstein, Bruce
AU - DeGreve, Jacques
AU - Baurain, Jean-Francois
AU - Maki, Robert
AU - D'Adamo, David
AU - Dickson, Mark
AU - Undevia, Samir
AU - Geary, David
AU - Janisch, Linda
AU - Bedard, Philippe L.
AU - Razak, Albiruni R. Abdul
AU - Kristeleit, Rebecca
AU - Vitfell-Rasmussen, Joanna
AU - Walters, Ian
AU - Kaye, Stan B.
AU - Schwartz, Gary
N1 - Funding Information:
This trial was funded by the Bristol-Myers Squibb company.
Funding Information:
Mark Ratain reports receiving grants from AbbVie, Dicerna and Genentech, reports receiving personal fees from AbbVie, Amgen, Ascentage, Cyclacel, Elion Oncology, multiple generic pharmaceutical companies, Shionogi and Portola Pharmaceuticals, outside the submitted work, is a coinventor on patent US6395481B1 with royalties paid from Mayo Clinic, patent US20160239636A1 pending, patent US8877723B2 issued and patent EP1629111B1 with royalties paid from Mayo Clinic, and serves as a director and treasurer of the Value in Cancer Care Consortium.Peter J. O'Dwyer reports research support from Pfizer, Genentech, BMS, GSK, Five Prime, Forty Seven, BBI, Novartis, Celgene, Incyte, Lilly / Imclone, Array, H3 Biomedicine and Taiho Pharma, has been consulting in the past 2 years for Genentech, Celgene and Array, provides expert testimony for Bayer and Lilly and is not a stock owner of any companies.Lillian Siu serves as a consultant for Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/MedImmune (compensated), MorphoSys (compensated), Roche (compensated), Geneseeq (compensated), Loxo (compensated), Oncorus (compensated), Symphogen (compensated), Seattle Genetics (compensated) and GSK (compensated), is not a member of the speaker's bureau for any companies, reports grant/research support (clinical trials for institution) from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm Therapeutics, Inc., AstraZeneca/MedImmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati and Shattucksm Avid, is a stockholder of Agios (spouse) and is not an employee of any companies.Robert Maki reports consulting fees from Arcus, Bayer, Deciphera, Eisai, Immune Design, Janssen R&D, Karyopharm Therapeutics, Lilly, Novartis, Pfizer, Presage, Sarcoma Alliance for Research Through Collaboration (SARC), SpringWorks, American Board of Internal Medicine and UpToDate and reports institutional receipts for clinical trials from Bayer, Karyopharm, Lilly, Pfizer, Regeneron, Presage, Sarcoma Alliance for Research Through Collaboration (SARC), SpringWorks and Tracon.This trial was funded by the Bristol-Myers Squibb company.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/10
Y1 - 2019/10
N2 - Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours.Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11).Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib. (C) 2019 The Author(s). Published by Elsevier Ltd.
AB - Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours.Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11).Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib. (C) 2019 The Author(s). Published by Elsevier Ltd.
KW - Brivanib
KW - Solid tumours
KW - Randomised discontinuation trial
KW - FGF2 status
KW - Sarcomas
KW - Ovarian cancer
KW - GROWTH-FACTOR RECEPTOR-2
KW - SOFT-TISSUE SARCOMA
KW - INHIBITOR
KW - PAZOPANIB
U2 - 10.1016/j.ejca.2019.07.024
DO - 10.1016/j.ejca.2019.07.024
M3 - Article
C2 - 31522033
SN - 0959-8049
VL - 120
SP - 132
EP - 139
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -