A Study of Selumetinib in Patients With Kaposi's Sarcoma

Summary

Cancer is a leading cause of death in individuals living with human immunodeficiency virus (HIV), and Kaposi's sarcoma (KS) remains the commonest HIV-associated cancer. KS is caused when individuals become infected with both HIV and another virus, Human herpesvirus-8 (HHV-8). Laboratory studies have shown that HHV-8 can stimulate biological pathways within KS lesions which promotes their growth. Selumetinib targets these pathways and may therefore be a useful new therapy for KS. Phase I of this trial aims to identify the best dose for the use of selumetinib and investigate the effects of selumetinib treatment on the anti-viral treatment HIV patients receive to control HIV infection. Phase II of this trial will investigate how well selumetinib works as a treatment for KS at the best dose determined in phase I.

Timeline

Start

2012-06-15

Primary completion

2015-09-30

Completion

2017-12-20

Publications

• Background 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. doi: 10.1200/JCO.2007.14.4956. Epub 2008 Apr 7.
• Background 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. doi: 10.1158/1078-0432.CCR-09-2483. Epub 2010 Feb 23.
• Background 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. 2012 Jun;30(3):1216-23. doi: 10.1007/s10637-011-9687-4. Epub 2011 May 19.
• Background Bower M, Collins S, Cottrill C, Cwynarski K, Montoto S, Nelson M, Nwokolo N, Powles T, Stebbing J, Wales N, Webb A; AIDS Malignancy Subcommittee. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Med. 2008 Jul;9(6):336-88. doi: 10.1111/j.1468-1293.2008.00608.x. No abstract available.
• Background Cooley T, Henry D, Tonda M, Sun S, O'Connell M, Rackoff W. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma. Oncologist. 2007 Jan;12(1):114-23. doi: 10.1634/theoncologist.12-1-114.
• Background Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, Di Trolio R, De Placido S, Dezube BJ. Management of AIDS-related Kaposi's sarcoma. Lancet Oncol. 2007 Feb;8(2):167-76. doi: 10.1016/S1470-2045(07)70036-0.
• Background Krown SE, Metroka C, Wernz JC. Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol. 1989 Sep;7(9):1201-7. doi: 10.1200/JCO.1989.7.9.1201.
• Background Sharma-Walia N, Krishnan HH, Naranatt PP, Zeng L, Smith MS, Chandran B. ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. J Virol. 2005 Aug;79(16):10308-29. doi: 10.1128/JVI.79.16.10308-10329.2005.
• Background Stebbing J, Sanitt A, Nelson M, Powles T, Gazzard B, Bower M. A prognostic index for AIDS-associated Kaposi's sarcoma in the era of highly active antiretroviral therapy. Lancet. 2006 May 6;367(9521):1495-502. doi: 10.1016/S0140-6736(06)68649-2.
• Background Tulpule A, Groopman J, Saville MW, Harrington W Jr, Friedman-Kien A, Espina BM, Garces C, Mantelle L, Mettinger K, Scadden DT, Gill PS. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer. 2002 Jul 1;95(1):147-54. doi: 10.1002/cncr.10634.
• Background Vart RJ, Nikitenko LL, Lagos D, Trotter MW, Cannon M, Bourboulia D, Gratrix F, Takeuchi Y, Boshoff C. Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res. 2007 May 1;67(9):4042-51. doi: 10.1158/0008-5472.CAN-06-3321.
• Background Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Makinen T, Elliman S, Flanagan AM, Alitalo K, Boshoff C. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet. 2004 Jul;36(7):687-93. doi: 10.1038/ng1384. Epub 2004 Jun 27.
• Background Xie J, Ajibade AO, Ye F, Kuhne K, Gao SJ. Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways. Virology. 2008 Feb 5;371(1):139-54. doi: 10.1016/j.virol.2007.09.040. Epub 2007 Oct 26.
• Background Yang X, Gabuzda D. Regulation of human immunodeficiency virus type 1 infectivity by the ERK mitogen-activated protein kinase signaling pathway. J Virol. 1999 Apr;73(4):3460-6. doi: 10.1128/JVI.73.4.3460-3466.1999.

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