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Selumetinib

Selumetinib (AZD6244)  is an orally bioavailable small molecule with potential antineoplastic activity. Selumetinib inhibits mitogen-activated protein kinase kinases (MEK or MAPK/ERK kinases) 1 and 2, which may prevent the activation of MEK1/2-dependent effector proteins and transcription factors, and so may inhibit cellular proliferation in MEK-overexpressing tumor cells. MEK 1 and 2 are dual-specificity kinases that are essential mediators in the activation of the RAS/RAF/MEK/ERK pathway, are often upregulated in various tumor cell types, and are drivers of diverse cellular activities, including cellular proliferation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:  Array BioPharma and AstraZeneca.

Phase I trials using Selumetinib: In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C(max) and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t(max)) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated. The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population. (source: Cancer Chemother Pharmacol. 2011 Dec;68(6):1619-28).

Phase II trials using Selumetinib: In this randomized, multicenter phase II study (NCT00372944), patients received either 100 mg oral selumetinib twice daily or 1,250 mg/m(2) oral capecitabine twice daily for 2 weeks followed by a 1-week break, given in 3-weekly cycles. The primary endpoint was overall survival. In all 70 patients were randomized. The median survival was 5.4 months in the selumetinib group and 5.0 months in the capecitabine group (hazard ratio 1.03; two-sided 80% confidence interval = 0.68,1.57; P = 0.92). Disease progression events occurred in 84% and 88% of patients in the selumetinib and capecitabine treatment groups, respectively. Gastrointestinal adverse events (nausea, vomiting and diarrhea) were commonly observed in both treatment groups. Other frequently reported adverse events were acneiform dermatitis and peripheral edema with selumetinib, and palmar-plantar erythrodysaesthesia with capecitabine. There was no statistically significant difference in overall survival between selumetinib and capecitabine as second-line treatment in patients with advanced pancreatic cancer. Selumetinib was well tolerated with a manageable safety profile. (Invest New Drugs. 2011 May 19. [Epub ahead of print])

1: Morelli MP, Tentler JJ, Kulikowski GN, Tan AC, Bradshaw-Pierce EL, Pitts TM, Brown AM, Nallapareddy S, Arcaroli JJ, Serkova NJ, Hidalgo M, Ciardiello F, Eckhardt SG. Preclinical Activity of the Rational Combination of Selumetinib (AZD6244) in Combination with Vorinostat in KRAS Mutant Colorectal Cancer Models. Clin Cancer Res. 2011 Dec 15. [Epub ahead of print] PubMed PMID: 22173548.

2: Bartholomeusz C, Oishi T, Saso H, Akar U, Liu P, Kondo K, Kazansky A, Krishnamurthy S, Lee J, Esteva FJ, Kigawa J, Ueno NT. MEK 1/2 Inhibitor selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15-dependent Manner in a Mouse Xenograft Model. Mol Cancer Ther. 2011 Dec 14. [Epub ahead of print] PubMed PMID: 22144664.

3: Liu R, Liu D, Xing M. The Akt Inhibitor MK2206 Synergizes, but Perifosine Antagonizes, the BRAFV600E Inhibitor PLX4032 and the MEK1/2 Inhibitor AZD6244 in the Inhibition of Thyroid Cancer Cells. J Clin Endocrinol Metab. 2011 Nov 16. [Epub ahead of print] PubMed PMID: 22090271.

4: Leijen S, Soetekouw PM, Jeffry Evans TR, Nicolson M, Schellens JH, Learoyd M, Grinsted L, Zazulina V, Pwint T, Middleton M. A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011 Dec;68(6):1619-28. Epub 2011 Sep 28. PubMed PMID: 21953275; PubMed Central PMCID: PMC3220813.

5: Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, Tebbutt NC. Erratum to: A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2011 Jul 26. [Epub ahead of print] PubMed PMID: 21789511.

6: Bhalla S, Evens AM, Dai B, Prachand S, Gordon LI, Gartenhaus RB. The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma. Blood. 2011 Jul 28;118(4):1052-61. Epub 2011 May 31. PubMed PMID: 21628402; PubMed Central PMCID: PMC3148157.

7: Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, Tebbutt NC. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2011 May 19. [Epub ahead of print] PubMed PMID: 21594619.

8: Querfeld C, Duffy K, Magel G, Oble D, Cohen EE, Shea CR. Disseminated follicular eruption during therapy with the MEK inhibitor AZD6244. J Am Acad Dermatol. 2011 Feb;64(2):e17-9. PubMed PMID: 21238821.

9: Yoon J, Koo KH, Choi KY. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res. 2011 Jan 15;71(2):445-53. Epub 2010 Nov 30. PubMed PMID: 21118963.

10: Balagula Y, Barth Huston K, Busam KJ, Lacouture ME, Chapman PB, Myskowski PL. Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs. 2011 Oct;29(5):1114-21. Epub 2010 Oct 27. PubMed PMID: 20978926.

11: Gopal YN, Deng W, Woodman SE, Komurov K, Ram P, Smith PD, Davies MA. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res. 2010 Nov 1;70(21):8736-47. Epub 2010 Oct 19. PubMed PMID: 20959481.

12: Tentler JJ, Nallapareddy S, Tan AC, Spreafico A, Pitts TM, Morelli MP, Selby HM, Kachaeva MI, Flanigan SA, Kulikowski GN, Leong S, Arcaroli JJ, Messersmith WA, Eckhardt SG. Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. Mol Cancer Ther. 2010 Dec;9(12):3351-62. Epub 2010 Oct 5. PubMed PMID: 20923857.

13: Kolb EA, Gorlick R, Houghton PJ, Morton CL, Neale G, Keir ST, Carol H, Lock R, Phelps D, Kang MH, Reynolds CP, Maris JM, Billups C, Smith MA. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010 Oct;55(4):668-77. PubMed PMID: 20806365; PubMed Central PMCID: PMC3004092.

14: Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE, Damyanov D, Stella P, Ganchev H, Pover G, Morris C, Tzekova V. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010 Oct;5(10):1630-6. PubMed PMID: 20802351.

15: Garon EB, Finn RS, Hosmer W, Dering J, Ginther C, Adhami S, Kamranpour N, Pitts S, Desai A, Elashoff D, French T, Smith P, Slamon DJ. Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. Mol Cancer Ther. 2010 Jul;9(7):1985-94. Epub 2010 Jun 29. PubMed PMID: 20587667; PubMed Central PMCID: PMC2939826.

16: Denton CL, Gustafson DL. Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemother Pharmacol. 2011 Feb;67(2):349-60. Epub 2010 Apr 21. PubMed PMID: 20407895.

17: Dry JR, Pavey S, Pratilas CA, Harbron C, Runswick S, Hodgson D, Chresta C, McCormack R, Byrne N, Cockerill M, Graham A, Beran G, Cassidy A, Haggerty C, Brown H, Ellison G, Dering J, Taylor BS, Stark M, Bonazzi V, Ravishankar S, Packer L, Xing F, Solit DB, Finn RS, Rosen N, Hayward NK, French T, Smith PD. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Res. 2010 Mar 15;70(6):2264-73. Epub 2010 Mar 9. PubMed PMID: 20215513; PubMed Central PMCID: PMC3166660.

18: Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, Desar IM, Timmer-Bonte JN, Eckhardt SG, Lewis KD, Brown KH, Cantarini MV, Morris C, George SM, Smith PD, van Herpen CM. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010 Mar 1;16(5):1613-23. Epub 2010 Feb 23. PubMed PMID: 20179232.

19: Bennouna J, Lang I, Valladares-Ayerbes M, Boer K, Adenis A, Escudero P, Kim TY, Pover GM, Morris CD, Douillard JY. A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs. 2011 Oct;29(5):1021-8. Epub 2010 Feb 2. PubMed PMID: 20127139.

20: Huynh H. AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of human hepatocellular carcinoma. Cancer. 2010 Mar 1;116(5):1315-25. PubMed PMID: 20101735.

21: Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, Thng CH, Chow P, Ong HS, Chung A, Goh BC, Smith PD, Soo KC. AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol. 2010 Jan;52(1):79-87. Epub 2009 Oct 28. PubMed PMID: 19910069.

22: Board RE, Ellison G, Orr MC, Kemsley KR, McWalter G, Blockley LY, Dearden SP, Morris C, Ranson M, Cantarini MV, Dive C, Hughes A. Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study. Br J Cancer. 2009 Nov 17;101(10):1724-30. Epub 2009 Oct 27. PubMed PMID: 19861964; PubMed Central PMCID: PMC2778539.

23: Shannon AM, Telfer BA, Smith PD, Babur M, Logie A, Wilkinson RW, Debray C, Stratford IJ, Williams KJ, Wedge SR. The mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts. Clin Cancer Res. 2009 Nov 1;15(21):6619-29. Epub 2009 Oct 20. PubMed PMID: 19843666.

24: Ammoun S, Ristic N, Matthies C, Hilton DA, Hanemann CO. Targeting ERK1/2 activation and proliferation in human primary schwannoma cells with MEK1/2 inhibitor AZD6244. Neurobiol Dis. 2010 Jan;37(1):141-6. Epub 2009 Oct 3. PubMed PMID: 19804833.

25: Meng J, Peng H, Dai B, Guo W, Wang L, Ji L, Minna JD, Chresta CM, Smith PD, Fang B, Roth JA. High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886). Cancer Biol Ther. 2009 Nov;8(21):2073-80. Epub 2009 Nov 18. PubMed PMID: 19783898; PubMed Central PMCID: PMC2835993.

26: Yang S, Ngo VC, Lew GB, Chong LW, Lee SS, Ong WJ, Lam WL, Thng CH, Koong HN, Ong HS, Chung A, Chow P, Lee J, Soo KC, Huynh H. AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer. Mol Cancer Ther. 2009 Sep;8(9):2537-45. Epub 2009 Sep 1. PubMed PMID: 19723882.

27: Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ. Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer. 2009 Nov 15;125(10):2332-41. PubMed PMID: 19637312.

28: Desar IM, Bovenschen HJ, Timmer-Bonte AJ, Cantarini MV, Van Der Graaf WT, Van Rossum MM, Van Herpen CM. Case studies showing clinical signs and management of cutaneous toxicity of the MEK1/2 inhibitor AZD6244 (ARRY-142886) in patients with solid tumours. Acta Oncol. 2010;49(1):110-3. PubMed PMID: 19634052.

29: Chung EJ, Brown AP, Asano H, Mandler M, Burgan WE, Carter D, Camphausen K, Citrin D. In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 kinase. Clin Cancer Res. 2009 May 1;15(9):3050-7. Epub 2009 Apr 14. PubMed PMID: 19366835; PubMed Central PMCID: PMC2798161.

30: Friday BB, Yu C, Dy GK, Smith PD, Wang L, Thibodeau SN, Adjei AA. BRAF V600E disrupts AZD6244-induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and Raf proteins. Cancer Res. 2008 Aug 1;68(15):6145-53. PubMed PMID: 18676837.

31: Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008 May 1;26(13):2139-46. Epub 2008 Apr 7. PubMed PMID: 18390968; PubMed Central PMCID: PMC2718422.

32: Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, Herlyn M, Smalley KS. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res. 2008 Jan 1;14(1):230-9. PubMed PMID: 18172275.

33: Ball DW, Jin N, Rosen DM, Dackiw A, Sidransky D, Xing M, Nelkin BD. Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. J Clin Endocrinol Metab. 2007 Dec;92(12):4712-8. Epub 2007 Sep 18. PubMed PMID: 17878251.

34: Huynh H, Chow PK, Soo KC. AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma. Mol Cancer Ther. 2007 Sep;6(9):2468-76. PubMed PMID: 17876044.

35: Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007 Aug;6(8):2209-19. PubMed PMID: 17699718.

36: Nishioka C, Ikezoe T, Takeshita A, Yang J, Tasaka T, Yang Y, Kuwayama Y, Komatsu N, Togitani K, Koeffler HP, Taguchi H. ZD6474 induces growth arrest and apoptosis of human leukemia cells, which is enhanced by concomitant use of a novel MEK inhibitor, AZD6244. Leukemia. 2007 Jun;21(6):1308-10. Epub 2007 Mar 15. PubMed PMID: 17361222.

37: Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, Lyssikatos J, Lee PA, Winkler JD, Koch K, Wallace E. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007 Mar 1;13(5):1576-83. PubMed PMID: 17332304.

38: Huynh H, Soo KC, Chow PK, Tran E. Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther. 2007 Jan;6(1):138-46. PubMed PMID: 17237274.