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Motesanib

Description of Motesanib: Motesanib diphosphate  is the orally bioavailable diphosphate salt of a multiple-receptor tyrosine kinase inhibitor with potential antineoplastic activity. Motesanib selectively targets and inhibits vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR), kit, and Ret receptors, thereby inhibiting angiogenesis and cellular proliferation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

 Current developer:   Amgen

Motesanib is an orally-administered small molecule antagonist of vascular endothelial growth factor receptors 1, 2 and 3 (“VEGFR1-3”), platelet-derived growth factor receptor (“PDGFR”) and stem cell factor receptor (“c-kit”). It is being investigated as a cancer treatment. We are developing this product in collaboration with Takeda.  

 1: Kruser TJ, Wheeler DL, Armstrong EA, Iida M, Kozak KR, van der Kogel AJ, Bussink J, Coxon A, Polverino A, Harari P. Augmentation of Radiation Response by Motesanib, A Multikinase Inhibitor That Targets Vascular Endothelial Growth Factor Receptors. Clin Cancer Res. 2010 May 27. [Epub ahead of print] PubMed PMID: 20507929.

2: Rosen PJ, Sweeney CJ, Park DJ, Beaupre DM, Deng H, Leitch IM, Shubhakar P, Zhu M, Oliner KS, Anderson A, Yee LK. A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors. Clin Cancer Res. 2010 May 1;16(9):2677-87. Epub 2010 Apr 20. PubMed PMID: 20406832.

3: Fujisaka Y, Yamada Y, Yamamoto N, Shimizu T, Fujiwara Y, Yamada K, Tamura T, Watanabe H, Sun YN, Bass MB, Seki M. Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2010 Jan 28. [Epub ahead of print] PubMed PMID: 20107802.

4: Keefe SM, Cohen MA, Brose MS. Targeting vascular endothelial growth factor receptor in thyroid cancer: the intracellular and extracellular implications. Clin Cancer Res. 2010 Feb 1;16(3):778-83. Epub 2010 Jan 26. Review. PubMed PMID: 20103668.

5: Blumenschein GR Jr, Reckamp K, Stephenson GJ, O'Rourke T, Gladish G, McGreivy J, Sun YN, Ye Y, Parson M, Sandler A. Phase 1b study of motesanib, an oral angiogenesis inhibitor, in combination with carboplatin/paclitaxel and/or panitumumab for the treatment of advanced non-small cell lung cancer. Clin Cancer Res. 2010 Jan 1;16(1):279-90. Epub 2009 Dec 22. PubMed PMID: 20028752.

6: Sherman SI. Tyrosine kinase inhibitors and the thyroid. Best Pract Res Clin Endocrinol Metab. 2009 Dec;23(6):713-22. Review. PubMed PMID: 19942148.

7: Sawaki A, Yamada Y, Komatsu Y, Kanda T, Doi T, Koseki M, Baba H, Sun YN, Murakami K, Nishida T. Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate. Cancer Chemother Pharmacol. 2010 Apr;65(5):961-7. Epub 2009 Aug 19. PubMed PMID: 19690858; PubMed Central PMCID: PMC2824121.

8: Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):367-72. Review. PubMed PMID: 19633548.

9: Schlumberger MJ, Elisei R, Bastholt L, Wirth LJ, Martins RG, Locati LD, Jarzab B, Pacini F, Daumerie C, Droz JP, Eschenberg MJ, Sun YN, Juan T, Stepan DE, Sherman SI. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009 Aug 10;27(23):3794-801. Epub 2009 Jun 29. PubMed PMID: 19564535.

10: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Mar;31(2):107-46. PubMed PMID: 19455266.

11: Li C, Kuchimanchi M, Hickman D, Poppe L, Hayashi M, Zhou Y, Subramanian R, Kumar G, Surapaneni S. In vitro metabolism of the novel, highly selective oral angiogenesis inhibitor motesanib diphosphate in preclinical species and in humans. Drug Metab Dispos. 2009 Jul;37(7):1378-94. Epub 2009 Apr 16. PubMed PMID: 19372226.

12: Malouf G, Baudin E, Soria JC, Schlumberger M. [Advances in the treatment of thyroid cancer in the era of molecularly targeted therapies]. Bull Cancer. 2009 Jan;96(1):95-101. Review. French. PubMed PMID: 19211364.

13: Kiselyov AS, Semenova M, Semenov VV. 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2. Bioorg Med Chem Lett. 2009 Feb 15;19(4):1195-8. Epub 2008 Dec 24. PubMed PMID: 19124243.

14: Coxon A, Bush T, Saffran D, Kaufman S, Belmontes B, Rex K, Hughes P, Caenepeel S, Rottman JB, Tasker A, Patel V, Kendall R, Radinsky R, Polverino A. Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors. Clin Cancer Res. 2009 Jan 1;15(1):110-8. PubMed PMID: 19118038.

15: Diaz-Cano SJ. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008 Dec 18;359(25):2727; author reply 2727. PubMed PMID: 19092161.

16: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Oct;30(8):643-72. PubMed PMID: 19088949.

17: Lanzi C, Cassinelli G, Nicolini V, Zunino F. Targeting RET for thyroid cancer therapy. Biochem Pharmacol. 2009 Feb 1;77(3):297-309. Epub 2008 Nov 6. PubMed PMID: 19028457.

18: Azad A, Herbertson RA, Pook D, White S, Mitchell PL, Tebbutt NC. Motesanib diphosphate (AMG 706), an oral angiogenesis inhibitor, demonstrates clinical efficacy in advanced thymoma. Acta Oncol. 2009;48(4):619-21. PubMed PMID: 18979266.

19: Price TJ, Lipton L, McGreivy J, McCoy S, Sun YN, Rosenthal MA. Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours. Br J Cancer. 2008 Nov 4;99(9):1387-94. PubMed PMID: 18971935; PubMed Central PMCID: PMC2579691.

20: Döme B, Magyar M. [Tumor vasculature as a therapeutic target in non-small cell lung cancer]. Magy Onkol. 2008 Sep;52(3):247-59. Review. Hungarian. PubMed PMID: 18845495.

21: Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, Licitra L, Eschenberg MJ, Sun YN, Juan T, Stepan DE, Schlumberger MJ; Motesanib Thyroid Cancer Study Group. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008 Jul 3;359(1):31-42. PubMed PMID: 18596272.

22: Lorusso P, Heath EI, McGreivy J, Sun YN, Melara R, Yan L, Malburg L, Ingram M, Wiezorek J, Chen L, Pilat MJ. Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors. Invest New Drugs. 2008 Oct;26(5):455-62. Epub 2008 Jun 24. PubMed PMID: 18574557.

23: Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am. 2008 Jun;37(2):511-24, xi. Review. PubMed PMID: 18502340.

24: Lee CB, Socinski MA. Vascular endothelial growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: a review of recent clinical trials. Rev Recent Clin Trials. 2007 May;2(2):117-20. Review. PubMed PMID: 18473996.

25: Apice G, Milano A, Bruni GS, Iaffaioli RV, Caponigro F. Medical treatment of gastrointestinal stromal tumors: state of the art and future perspectives. Rev Recent Clin Trials. 2006 Jan;1(1):35-42. Review. PubMed PMID: 18393778.

26: Italiano A, Bui B. [Gastrointestinal stromal tumors: molecular aspects and therapeutic implications]. Bull Cancer. 2008 Jan;95(1):107-16. Review. French. PubMed PMID: 18230576.

27: Grabellus F, Ebeling P, Worm K, Sheu SY, Antoch G, Frilling A, Schmid KW. Double resistance to imatinib and AMG 706 caused by multiple acquired KIT exon 17 mutations in a gastrointestinal stromal tumour. Gut. 2007 Jul;56(7):1025-6. PubMed PMID: 17566038.

28: Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, Xu RY, Polverino A, Wiezorek JS, Chang DD, Benjamin R, Herbst RS. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007 Jun 10;25(17):2369-76. PubMed PMID: 17557949.

29: Verweij J, de Jonge M. Multitarget tyrosine kinase inhibition: [and the winner is...]. J Clin Oncol. 2007 Jun 10;25(17):2340-2. Review. PubMed PMID: 17557945.

30: von Mehren M. Beyond imatinib: second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors. Clin Colorectal Cancer. 2006 Nov;6 Suppl 1:S30-4. Review. PubMed PMID: 17419150.

31: Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, Bready J, Estrada J, Cattley R, Kaufman S, Chen D, Gan Y, Kumar G, Meyer J, Neervannan S, Alva G, Talvenheimo J, Montestruque S, Tasker A, Patel V, Radinsky R, Kendall R. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006 Sep 1;66(17):8715-21. PubMed PMID: 16951187.