SL-401 in Combination With Pomalidomide and Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma

Summary

A Phase 1/2, Open Label Study of SL-401 in Combination with Pomalidomide and Dexamethasone In Relapsed and Refractory Multiple Myeloma

Timeline

Start

2016-01

Primary completion

2019-12

Completion

2019-12

Publications

• Background Agarwal A, Ghobrial IM. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratification, and management of myeloma precursor disease. Clin Cancer Res. 2013 Mar 1;19(5):985-94. doi: 10.1158/1078-0432.CCR-12-2922. Epub 2012 Dec 5.
• Background Aldinucci D, Olivo K, Lorenzon D, Poletto D, Gloghini A, Carbone A, Pinto A. The role of interleukin-3 in classical Hodgkin's disease. Leuk Lymphoma. 2005 Mar;46(3):303-11. doi: 10.1080/10428190400013712.
• Background Aldinucci D, Poletto D, Gloghini A, Nanni P, Degan M, Perin T, Ceolin P, Rossi FM, Gattei V, Carbone A, Pinto A. Expression of functional interleukin-3 receptors on Hodgkin and Reed-Sternberg cells. Am J Pathol. 2002 Feb;160(2):585-96. doi: 10.1016/S0002-9440(10)64878-X.
• Background Alexander RL, Kucera GL, Klein B, Frankel AE. In vitro interleukin-3 binding to leukemia cells predicts cytotoxicity of a diphtheria toxin/IL-3 fusion protein. Bioconjug Chem. 2000 Jul-Aug;11(4):564-8. doi: 10.1021/bc000009q.
• Background American Cancer Society. Cancer Facts and Figures 2013. Available from: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc- 036845.pdf.
• Background Angelot-Delettre F, Frankel AE, Liu SE et al. The IL-3Rα-Targeted Drug SL-401 Selectively kills Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Cells. ASH 2011, Poster #2588.
• Background Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006 Dec 7;444(7120):756-60. doi: 10.1038/nature05236. Epub 2006 Oct 18.
• Background Black JH, McCubrey JA, Willingham MC, Ramage J, Hogge DE, Frankel AE. Diphtheria toxin-interleukin-3 fusion protein (DT(388)IL3) prolongs disease-free survival of leukemic immunocompromised mice. Leukemia. 2003 Jan;17(1):155-9. doi: 10.1038/sj.leu.2402744.
• Background Chauhan D, Ray A, Brooks C et al. A Novel Agent SL-401 Targeting Interleukin-3 (IL-3)- Receptor Blocks Plasmacytoid Dendritic Cell (pDC)-induced Myeloma Cell Growth and Overcomes Drug Resistance. J Clin Oncol 2013; 31;(suppl; abstr 8582).
• Background Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, Bianchi G, Podar K, Tai YT, Mitsiades C, Raje N, Jaye DL, Kumar SK, Richardson P, Munshi N, Anderson KC. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell. 2009 Oct 6;16(4):309-23. doi: 10.1016/j.ccr.2009.08.019.
• Background Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA, Anderson KC. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood. 1996 Feb 1;87(3):1104-12.
• Background Deng Q, Barbieri JT. Molecular mechanisms of the cytotoxicity of ADP-ribosylating toxins. Annu Rev Microbiol. 2008;62:271-88. doi: 10.1146/annurev.micro.62.081307.162848.
• Background Feuring-Buske M, Frankel AE, Alexander RL, Gerhard B, Hogge DE. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors. Cancer Res. 2002 Mar 15;62(6):1730-6.
• Background FitzGerald D, Pastan I. Targeted toxin therapy for the treatment of cancer. J Natl Cancer Inst. 1989 Oct 4;81(19):1455-63. doi: 10.1093/jnci/81.19.1455.
• Background Florian S, Sonneck K, Hauswirth AW, Krauth MT, Schernthaner GH, Sperr WR, Valent P. Detection of molecular targets on the surface of CD34+/CD38-- stem cells in various myeloid malignancies. Leuk Lymphoma. 2006 Feb;47(2):207-22. doi: 10.1080/10428190500272507.
• Background Frankel AE, McCubrey JA, Miller MS, Delatte S, Ramage J, Kiser M, Kucera GL, Alexander RL, Beran M, Tagge EP, Kreitman RJ, Hogge DE. Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias. Leukemia. 2000 Apr;14(4):576-85. doi: 10.1038/sj.leu.2401743.
• Background Frolova O, Frankel AE, Korchin B et al. IL3R-Directed Agents, SL-401 and SL-501, Inhibit the Growth of Leukemia Stem cells in CML. Blood (ASH Meeting Abstracts) 2010 116: Abstract 3403.
• Background Giles F, O'Brien S, Cortes J, Verstovsek S, Bueso-Ramos C, Shan J, Pierce S, Garcia-Manero G, Keating M, Kantarjian H. Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer. 2005 Aug 1;104(3):547-54. doi: 10.1002/cncr.21187.
• Background Hermann PC, Huber SL, Heeschen C. Metastatic cancer stem cells: a new target for anti-cancer therapy? Cell Cycle. 2008 Jan 15;7(2):188-93. doi: 10.4161/cc.7.2.5326. Epub 2007 Nov 18.
• Background Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006 Sep 21;355(12):1253-61. doi: 10.1056/NEJMra061808. No abstract available.
• Background Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, Meyerrose T, Rossi R, Grimes B, Rizzieri DA, Luger SM, Phillips GL. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000 Oct;14(10):1777-84. doi: 10.1038/sj.leu.2401903.
• Background Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008 Mar 1;111(5):2516-20. doi: 10.1182/blood-2007-10-116129. Epub 2007 Nov 1.
• Background Lhermitte L, de Labarthe A, Dupret C, Lapillonne H, Millien C, Landman-Parker J, Hermine O, Baruchel A, Sigaux F, Macintyre E, Asnafi V. Most immature T-ALLs express Ra-IL3 (CD123): possible target for DT-IL3 therapy. Leukemia. 2006 Oct;20(10):1908-10. doi: 10.1038/sj.leu.2404349. Epub 2006 Aug 10. No abstract available.
• Background Louie GV, Yang W, Bowman ME, Choe S. Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor. Mol Cell. 1997 Dec;1(1):67-78. doi: 10.1016/s1097-2765(00)80008-8.
• Background McCann S, Akilov OE, Geskin L. Adverse effects of denileukin diftitox and their management in patients with cutaneous T-cell lymphoma. Clin J Oncol Nurs. 2012 Oct;16(5):E164-72. doi: 10.1188/12.CJON.E164-E172.
• Background Munoz L, Nomdedeu JF, Lopez O, Carnicer MJ, Bellido M, Aventin A, Brunet S, Sierra J. Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica. 2001 Dec;86(12):1261-9.
• Background National Cancer Institute-Common Terminology Criteria: Version 4.03 reference, accessible through the NCI website at http://ctep.info.nih.gov/reporting/ctc.html.
• Background Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, Jegasothy B, Wood G, Gordon M, Heald P, Oseroff A, Pinter-Brown L, Bowen G, Kuzel T, Fivenson D, Foss F, Glode M, Molina A, Knobler E, Stewart S, Cooper K, Stevens S, Craig F, Reuben J, Bacha P, Nichols J. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001 Jan 15;19(2):376-88. doi: 10.1200/JCO.2001.19.2.376.
• Background Perentesis JP, Miller SP, Bodley JW. Protein toxin inhibitors of protein synthesis. Biofactors. 1992 Jan;3(3):173-84.
• Background Pomalidomide Perscribing Information. POMPI.001/MG.001 02/13. Reference ID: 325852
• Background Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, Straus D, Acosta M, Negro-Vilar A. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2010 Apr 10;28(11):1870-7. doi: 10.1200/JCO.2009.26.2386. Epub 2010 Mar 8.
• Background Ratts R, Trujillo C, Bharti A, vanderSpek J, Harrison R, Murphy JR. A conserved motif in transmembrane helix 1 of diphtheria toxin mediates catalytic domain delivery to the cytosol. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15635-40. doi: 10.1073/pnas.0504937102. Epub 2005 Oct 17.
• Background Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson KC. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. doi: 10.1182/blood-2013-11-538835. Epub 2014 Jan 13.
• Background Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-1066. doi: 10.1016/S1470-2045(13)70380-2. Epub 2013 Sep 3.
• Background Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ, Astrand-Grundstrom I, Strombeck B, Horvat A, Ferry H, Dhanda RS, Hast R, Ryden T, Vyas P, Gohring G, Schlegelberger B, Johansson B, Hellstrom-Lindberg E, List A, Nilsson L, Jacobsen SE. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J Med. 2010 Sep 9;363(11):1025-37. doi: 10.1056/NEJMoa0912228.
• Background Thorburn A, Thorburn J, Frankel AE. Induction of apoptosis by tumor cell-targeted toxins. Apoptosis. 2004 Jan;9(1):19-25. doi: 10.1023/B:APPT.0000012118.95548.88.
• Background van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S, van der Pol MA, Waisfisz Q, Ossenkoppele GJ, Schuurhuis GJ. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res. 2005 Sep 15;11(18):6520-7. doi: 10.1158/1078-0432.CCR-05-0468.
• Background Vergez F, Green AS, Tamburini J, Sarry JE, Gaillard B, Cornillet-Lefebvre P, Pannetier M, Neyret A, Chapuis N, Ifrah N, Dreyfus F, Manenti S, Demur C, Delabesse E, Lacombe C, Mayeux P, Bouscary D, Recher C, Bardet V. High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study. Haematologica. 2011 Dec;96(12):1792-8. doi: 10.3324/haematol.2011.047894. Epub 2011 Sep 20.
• Background Yamaizumi M, Mekada E, Uchida T, Okada Y. One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell. 1978 Sep;15(1):245-50. doi: 10.1016/0092-8674(78)90099-5.
• Background Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC. Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res. 2008 Jan 1;14(1):123-9. doi: 10.1158/1078-0432.CCR-07-0932.

Drugs

Indications