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Clinical Trial
. 2019 Oct:120:132-139.
doi: 10.1016/j.ejca.2019.07.024. Epub 2019 Sep 12.

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Robin L Jones  1 , Mark J Ratain  2 , Peter J O'Dwyer  3 , Lillian L Siu  4 , Jacek Jassem  5 , Jacques Medioni  6 , Maja DeJonge  7 , Charles Rudin  8 , Michael Sawyer  9 , David Khayat  10 , Ahmad Awada  11 , Judith M P G M de Vos-Geelen  12 , T R Jeffry Evans  13 , Jennifer Obel  14 , Bruce Brockstein  14 , Jacques DeGreve  15 , Jean-Francois Baurain  16 , Robert Maki  17 , David D'Adamo  18 , Mark Dickson  19 , Samir Undevia  2 , David Geary  2 , Linda Janisch  2 , Philippe L Bedard  4 , Albiruni R Abdul Razak  4 , Rebecca Kristeleit  20 , Joanna Vitfell-Rasmussen  20 , Ian Walters  21 , Stan B Kaye  20 , Gary Schwartz  22
Affiliations
Clinical Trial

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Robin L Jones et al. Eur J Cancer. 2019 Oct.

Abstract

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.

Keywords: Brivanib; FGF2 status; Ovarian cancer; Randomised discontinuation trial; Sarcomas; Solid tumours.

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Conflict of interest statement

Conflict of interest statement

Robin L Jones has been a consultant for Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, Tracon, Upto Date.

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.

Jacek Jassem serves as a speaker for AstraZeneca, Roche and Pfizer and reports advisory roles for AstraZeneca, BMS, Pfizer, MSD and Takeda and travel support from Roche.

Jacques Medioni reports honoraria and advisory roles from Pierre Fabre, AstraZeneca, Invectys and Astellas.

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.

Ian Walters is an employee/stock owner of BMS at the time of the study and is currently, a CEO/board member of several small companies, including one public company (Portage Biotech).

Joanna Vitfell-Rasmussen, Stan Kaye, Samir Undevia, Ahmad Awada and other authors report no conflict of interest/disclosure.

Figures

Fig. 1.
Fig. 1.
Clinical responses to brivanib in patients with angiosarcoma.
Fig. 2.
Fig. 2.
Kaplane–Meier curves of progression-free survival in all randomised patients with soft tissue sarcomas (A), patients with FGF2-positive tumours (B) and randomised patients with progression on placebo and treated with brivanib (C). FGF, fibroblast growth factor.
See this image and copyright information in PMC

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