A Trial of a Novel XPO1 Inhibitor in Participants With Advanced Solid Tumors

Summary

Study SL-801-0115 is a dose-escalation study evaluating multiple doses and schedules of orally administered SL-801 in participants with advanced solid tumors.

Timeline

Start

2016-02-23

Primary completion

2021-10-06

Completion

2021-10-13

Publications

• Background Ahn C. An evaluation of phase I cancer clinical trial designs. Stat Med. 1998 Jul 30;17(14):1537-49. doi: 10.1002/(sici)1097-0258(19980730)17:143.0.co;2-f.
• Background Arnaoutov A, Azuma Y, Ribbeck K, Joseph J, Boyarchuk Y, Karpova T, McNally J, Dasso M. Crm1 is a mitotic effector of Ran-GTP in somatic cells. Nat Cell Biol. 2005 Jun;7(6):626-32. doi: 10.1038/ncb1263.
• Background Dillman RO, Koziol JA. Phase I cancer trials: limitations and implications. Mol Biother. 1992 Sep;4(3):117-21.
• Background Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
• Background Gatsonis C, Greenhouse JB. Bayesian methods for phase I clinical trials. Stat Med. 1992 Jul;11(10):1377-89. doi: 10.1002/sim.4780111011.
• Background Gerecitano J. SINE (selective inhibitor of nuclear export)--translational science in a new class of anti-cancer agents. J Hematol Oncol. 2014 Oct 4;7:67. doi: 10.1186/s13045-014-0067-3.
• Background Huang WY, Yue L, Qiu WS, Wang LW, Zhou XH, Sun YJ. Prognostic value of CRM1 in pancreas cancer. Clin Invest Med. 2009 Dec 1;32(6):E315.
• Background International Conference on Harmonisation. E8: General Considerations for Clinical Trials, July 1997.
• Background Kojima K, Kornblau SM, Ruvolo V, Dilip A, Duvvuri S, Davis RE, Zhang M, Wang Z, Coombes KR, Zhang N, Qiu YH, Burks JK, Kantarjian H, Shacham S, Kauffman M, Andreeff M. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood. 2013 May 16;121(20):4166-74. doi: 10.1182/blood-2012-08-447581. Epub 2013 Apr 5.
• Background Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y, Goettl V, Mahoney E, Berglund C, Gupta S, Farmer A, Mani R, Johnson AJ, Lucas D, Mo X, Daelemans D, Sandanayaka V, Shechter S, McCauley D, Shacham S, Kauffman M, Chook YM, Byrd JC. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood. 2012 Nov 29;120(23):4621-34. doi: 10.1182/blood-2012-05-429506. Epub 2012 Oct 3.
• Background Lassen UN, Mau-Soerensen M, Kung AL, Wen PY, Lee EQ, Plotkin SR, et al. A phase 2 study on efficacy, safety and intratumoral pharmacokinetics of oral selinexor (KPT-330) in patients with recurrent glioblastoma (GBM). J Clin Oncol 33, 2015 (suppl; abstr 2044)
• Background Noske A, Weichert W, Niesporek S, Roske A, Buckendahl AC, Koch I, Sehouli J, Dietel M, Denkert C. Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer. Cancer. 2008 Apr 15;112(8):1733-43. doi: 10.1002/cncr.23354.
• Background Pathria G, Wagner C, Wagner SN. Inhibition of CRM1-mediated nucleocytoplasmic transport: triggering human melanoma cell apoptosis by perturbing multiple cellular pathways. J Invest Dermatol. 2012 Dec;132(12):2780-90. doi: 10.1038/jid.2012.233. Epub 2012 Jul 26.
• Background Saito N, Sakakibara K, Sato T, Friedman JM, Kufe DW, VonHoff DD, Kawabe T. CBS9106-induced CRM1 degradation is mediated by cullin ring ligase activity and the neddylation pathway. Mol Cancer Ther. 2014 Dec;13(12):3013-23. doi: 10.1158/1535-7163.MCT-14-0064. Epub 2014 Sep 24.
• Background Sakakibara K, Saito N, Sato T, Suzuki A, Hasegawa Y, Friedman JM, Kufe DW, Vonhoff DD, Iwami T, Kawabe T. CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity. Blood. 2011 Oct 6;118(14):3922-31. doi: 10.1182/blood-2011-01-333138. Epub 2011 Aug 12.
• Background Senapedis WT, Baloglu E, Landesman Y. Clinical translation of nuclear export inhibitors in cancer. Semin Cancer Biol. 2014 Aug;27:74-86. doi: 10.1016/j.semcancer.2014.04.005. Epub 2014 Apr 19.
• Background Siddiqui N, Borden KL. mRNA export and cancer. Wiley Interdiscip Rev RNA. 2012 Jan-Feb;3(1):13-25. doi: 10.1002/wrna.101. Epub 2011 Jul 27.
• Background Storer BE. Design and analysis of phase I clinical trials. Biometrics. 1989 Sep;45(3):925-37.
• Background Tan DS, Bedard PL, Kuruvilla J, Siu LL, Razak AR. Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy. Cancer Discov. 2014 May;4(5):527-37. doi: 10.1158/2159-8290.CD-13-1005. Epub 2014 Apr 17.
• Background Tan DSP, Pang M-Y, Yong WP, Soo RA, Chee CE, Thian YL et al. Phase I study of the safety and tolerability of the Exportin 1 (XPO1) inhibitor Selinexor (SXR) in Asian patients (pts) with advanced solid cancers. J Clin Oncol 33, 2015 (suppl; abstr 2542).
• Background Turner JG, Dawson J, Sullivan DM. Nuclear export of proteins and drug resistance in cancer. Biochem Pharmacol. 2012 Apr 15;83(8):1021-32. doi: 10.1016/j.bcp.2011.12.016. Epub 2011 Dec 20.
• Background van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, Birrer MJ, Leaner VD. The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer. 2009 Apr 15;124(8):1829-40. doi: 10.1002/ijc.24146.
• Background Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G, Ellis JJ, Landesman Y, Eisfeld AK, Gabrail NY, Smith CL, Caligiuri MA, Hokland P, Roy DC, Reid A, Milojkovic D, Goldman JM, Apperley J, Garzon R, Marcucci G, Shacham S, Kauffman MG, Perrotti D. Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood. 2013 Oct 24;122(17):3034-44. doi: 10.1182/blood-2013-04-495374. Epub 2013 Aug 22.
• Background Wang W, Budhu A, Forgues M, Wang XW. Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Nat Cell Biol. 2005 Aug;7(8):823-30. doi: 10.1038/ncb1282. Epub 2005 Jul 24.

Drugs

Indications