MedKoo product information:

Brivanib alaninate

Brivanib alaninate is the alaninate ester of a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with potential antineoplastic activity. Brivanib strongly binds to and inhibits VEGFR2, a tyrosine kinase receptor expressed almost exclusively on vascular endothelial cells; inhibition of VEGFR2 may result in inhibition of tumor angiogenesis, inhibition of tumor cell growth, and tumor regression. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:  Bristol-Myers Squibb.

Brivanib alaninate has pharmacokinetic properties suitable for once- or twice-daily oral dosing and is completely hydrolyzed to the parent drug, brivanib, in vivo. Brivanib has a favorable cytochrome P450 profile and a low potential for drug-drug interactions. It inhibits growth of various solid carcinomas including hepatocellular carcinoma (HCC) xenografts in vivo. Brivanib-induced growth inhibition is associated with inhibition of angiogenesis and cell proliferation, and increased apoptosis. In phase I studies in patients with advanced or metastatic solid tumors, brivanib was well tolerated and had antitumor activity. In the phase II, open-label study, brivanib demonstrated promising efficacy and tolerability in patients with unresectable locally advanced or metastatic HCC as both first- and second-line treatment after exposure to prior therapy, including other antiangiogenics. As a result of these data, brivanib is in phase III development in HCC and in combination with other agents for treatment of various tumors, including colorectal cancer. [source: Huynh, H., Fargnoli, J. Brivanib alaninate, Drugs of the Future, 2009, 34(11): 881)

Brivanib alaninate - Phase I trial results:

According to Jonker et al's recent paper, in patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.  PATIENTS AND METHODS: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. [source: http://www.ncbi.nlm.nih.gov/pubmed/21131369].  

1: Finn RS, Kang YK, Mulcahy M, Polite BN, Lim HY, Walters I, Baudelet C, Manekas D, Park JW. Phase II, Open-label Study of Brivanib as Second-line Therapy in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res. 2012 Jan 11. [Epub ahead of print] PubMed PMID: 22238246.

2: Gong J, Gan J, Iyer RA. Identification of the oxidative and conjugative enzymes involved in the biotransformation of brivanib. Drug Metab Dispos. 2012 Jan;40(1):219-26. Epub 2011 Oct 11. PubMed PMID: 21989950.

3: Garcia JA, Roberts LR. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. J Hepatol. 2011 Sep 29. [Epub ahead of print] PubMed PMID: 21963517.

4: Kudo M. Future treatment option for hepatocellular carcinoma: a focus on brivanib. Dig Dis. 2011;29(3):316-20. Epub 2011 Aug 9. Review. PubMed PMID: 21829023.

5: Syed S, Clemens PL, Lathers D, Kollia G, Dhar A, Walters I, Masson E. Lack of Effect of Brivanib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, Administered Intravenously and Orally in Healthy Participants. J Clin Pharmacol. 2011 Jun 9. [Epub ahead of print] PubMed PMID: 21659627.

6: Garrett CR, Siu LL, El-Khoueiry A, Buter J, Rocha-Lima CM, Marshall J, LoRusso P, Major P, Chemidlin J, Mokliatchouk O, Velasquez L, Hayes W, Feltquate D, Syed S, Ford S, Kollia G, Galbraith S, Nuyten DS. Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br J Cancer. 2011 Jun 28;105(1):44-52. doi: 10.1038/bjc.2011.182. Epub 2011 May 31. PubMed PMID: 21629245; PubMed Central PMCID: PMC3137402.

7: Allen E, Walters IB, Hanahan D. Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res. 2011 Aug 15;17(16):5299-310. doi: 10.1158/1078-0432.CCR-10-2847. Epub 2011 May 27. PubMed PMID: 21622725; PubMed Central PMCID: PMC3156934.

8: LoRusso P, Shapiro GI, Hurwitz H, Pilat MJ, Chemidlin J, Kollia G, Syed S, Fischer B, Masson E. Lack of food effect on single-dose pharmacokinetics of brivanib, and safety and efficacy following multiple doses in subjects with advanced or metastatic solid tumors. Cancer Chemother Pharmacol. 2011 Dec;68(6):1377-85. Epub 2011 Apr 3. PubMed PMID: 21461891.

9: Diaz-Padilla I, Siu LL. Brivanib alaninate for cancer. Expert Opin Investig Drugs. 2011 Apr;20(4):577-86. Epub 2011 Mar 11. Review. PubMed PMID: 21391890.

10: Park JW, Finn RS, Kim JS, Karwal M, Li RK, Ismail F, Thomas M, Harris R, Baudelet C, Walters I, Raoul JL. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2011 Apr 1;17(7):1973-83. Epub 2011 Feb 24. PubMed PMID: 21349999.

11: Gong J, Gan J, Caceres-Cortes J, Christopher LJ, Arora V, Masson E, Williams D, Pursley J, Allentoff A, Lago M, Tran SB, Iyer RA. Metabolism and disposition of [14C]brivanib alaninate after oral administration to rats, monkeys, and humans. Drug Metab Dispos. 2011 May;39(5):891-903. Epub 2011 Feb 2. PubMed PMID: 21289073.

12: Jonker DJ, Rosen LS, Sawyer MB, de Braud F, Wilding G, Sweeney CJ, Jayson GC, McArthur GA, Rustin G, Goss G, Kantor J, Velasquez L, Syed S, Mokliatchouk O, Feltquate DM, Kollia G, Nuyten DS, Galbraith S. A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors. Ann Oncol. 2011 Jun;22(6):1413-9. Epub 2010 Dec 3. PubMed PMID: 21131369; PubMed Central PMCID: PMC3139984.

13: Dempke WC, Zippel R. Brivanib, a novel dual VEGF-R2/bFGF-R inhibitor. Anticancer Res. 2010 Nov;30(11):4477-83. Review. PubMed PMID: 21115896.

14: Mekhail T, Masson E, Fischer BS, Gong J, Iyer R, Gan J, Pursley J, Patricia D, Williams D, Ganapathi R. Metabolism, excretion, and pharmacokinetics of oral brivanib in patients with advanced or metastatic solid tumors. Drug Metab Dispos. 2010 Nov;38(11):1962-6. Epub 2010 Jul 29. PubMed PMID: 20671097; PubMed Central PMCID: PMC2967392.

15: Patel RR, Sengupta S, Kim HR, Klein-Szanto AJ, Pyle JR, Zhu F, Li T, Ross EA, Oseni S, Fargnoli J, Jordan VC. Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors. Eur J Cancer. 2010 Jun;46(9):1537-53. Epub 2010 Mar 18. PubMed PMID: 20303261; PubMed Central PMCID: PMC2927957.

16: Bhide RS, Lombardo LJ, Hunt JT, Cai ZW, Barrish JC, Galbraith S, Jeyaseelan R Sr, Mortillo S, Wautlet BS, Krishnan B, Kukral D, Malone H, Lewin AC, Henley BJ, Fargnoli J. The antiangiogenic activity in xenograft models of brivanib, a dual inhibitor of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinases. Mol Cancer Ther. 2010 Feb;9(2):369-78. Epub 2010 Jan 26. PubMed PMID: 20103604.

17: Shiang CY, Qi Y, Wang B, Lazar V, Wang J, Fraser Symmans W, Hortobagyi GN, Andre F, Pusztai L. Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate. Breast Cancer Res Treat. 2010 Oct;123(3):747-55. Epub 2009 Dec 19. PubMed PMID: 20024612.

18: Marathe PH, Kamath AV, Zhang Y, D'Arienzo C, Bhide R, Fargnoli J. Preclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate. Cancer Chemother Pharmacol. 2009 Dec;65(1):55-66. Epub 2009 Apr 26. PubMed PMID: 19396600.

19: Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung A, Chow P, Pollock P, Byron S, Tran E. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res. 2008 Oct 1;14(19):6146-53. PubMed PMID: 18829493.

20: He BL, Shi Y, Kleintop B, Raglione T. Direct and indirect separations of five isomers of Brivanib Alaninate using chiral high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Nov 1;875(1):122-35. PubMed PMID: 18815076.

21: Cai ZW, Zhang Y, Borzilleri RM, Qian L, Barbosa S, Wei D, Zheng X, Wu L, Fan J, Shi Z, Wautlet BS, Mortillo S, Jeyaseelan R Sr, Kukral DW, Kamath A, Marathe P, D'Arienzo C, Derbin G, Barrish JC, Robl JA, Hunt JT, Lombardo LJ, Fargnoli J, Bhide RS. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4] triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem. 2008 Mar 27;51(6):1976-80. Epub 2008 Feb 21. PubMed PMID: 18288793.

22: Ayers M, Fargnoli J, Lewin A, Wu Q, Platero JS. Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res. 2007 Jul 15;67(14):6899-906. PubMed PMID: 17638901.