Leading in MPNs Beyond Ruxolitinib in Combo With T-Regs

Summary

To assess the safety and tolerability of CK0804 as add-on therapy in participants with myelofibrosis, with suboptimal response to ruxolitinib

Timeline

Start

2022-12-27

Primary completion

2026-04-30

Completion

2026-12-30

Publications

• Background Abdelouahab H, Zhang Y, Wittner M, Oishi S, Fujii N, Besancenot R, Plo I, Ribrag V, Solary E, Vainchenker W, Barosi G, Louache F. CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner. Oncotarget. 2016 Jul 22;8(33):54082-54095. doi: 10.18632/oncotarget.10789. eCollection 2017 Aug 15.
• Background Barbui T, Thiele J, Gisslinger H, Finazzi G, Vannucchi AM, Tefferi A. The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood Rev. 2016 Nov;30(6):453-459. doi: 10.1016/j.blre.2016.06.001. Epub 2016 Jun 11.
• Background Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, Orazi A, Tefferi A. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018 Feb 9;8(2):15. doi: 10.1038/s41408-018-0054-y.
• Background Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, Dupriez B, Levine RL, Passamonti F, Gotlib J, Reilly JT, Vannucchi AM, Hanson CA, Solberg LA, Orazi A, Tefferi A; International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008 Feb;22(2):437-8. doi: 10.1038/sj.leu.2404914. Epub 2007 Aug 30. No abstract available.
• Background Bogani C, Ponziani V, Guglielmelli P, Desterke C, Rosti V, Bosi A, Le Bousse-Kerdiles MC, Barosi G, Vannucchi AM; Myeloproliferative Disorders Research Consortium. Hypermethylation of CXCR4 promoter in CD34+ cells from patients with primary myelofibrosis. Stem Cells. 2008 Aug;26(8):1920-30. doi: 10.1634/stemcells.2008-0377. Epub 2008 May 29.
• Background Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15.
• Background Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D, Curtsinger J, Verneris MR, MacMillan ML, Levine BL, Riley JL, June CH, Le C, Weisdorf DJ, McGlave PB, Blazar BR, Wagner JE. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016 Feb 25;127(8):1044-51. doi: 10.1182/blood-2015-06-653667. Epub 2015 Nov 12.
• Background Cho SY, Xu M, Roboz J, Lu M, Mascarenhas J, Hoffman R. The effect of CXCL12 processing on CD34+ cell migration in myeloproliferative neoplasms. Cancer Res. 2010 Apr 15;70(8):3402-10. doi: 10.1158/0008-5472.CAN-09-3977. Epub 2010 Apr 13.
• Background Emanuel RM, Dueck AC, Geyer HL, Kiladjian JJ, Slot S, Zweegman S, te Boekhorst PA, Commandeur S, Schouten HC, Sackmann F, Kerguelen Fuentes A, Hernandez-Maraver D, Pahl HL, Griesshammer M, Stegelmann F, Doehner K, Lehmann T, Bonatz K, Reiter A, Boyer F, Etienne G, Ianotto JC, Ranta D, Roy L, Cahn JY, Harrison CN, Radia D, Muxi P, Maldonado N, Besses C, Cervantes F, Johansson PL, Barbui T, Barosi G, Vannucchi AM, Passamonti F, Andreasson B, Ferrari ML, Rambaldi A, Samuelsson J, Birgegard G, Tefferi A, Mesa RA. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012 Nov 20;30(33):4098-103. doi: 10.1200/JCO.2012.42.3863. Epub 2012 Oct 15.
• Background Gladstone DE, Kim BS, Mooney K, Karaba AH, D'Alessio FR. Regulatory T Cells for Treating Patients With COVID-19 and Acute Respiratory Distress Syndrome: Two Case Reports. Ann Intern Med. 2020 Nov 17;173(10):852-853. doi: 10.7326/L20-0681. Epub 2020 Jul 6. No abstract available.
• Background Gleitz HFE, Dugourd AJF, Leimkuhler NB, Snoeren IAM, Fuchs SNR, Menzel S, Ziegler S, Kroger N, Triviai I, Busche G, Kreipe H, Banjanin B, Pritchard JE, Hoogenboezem R, Bindels EM, Schumacher N, Rose-John S, Elf S, Saez-Rodriguez J, Kramann R, Schneider RK. Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN. Blood. 2020 Oct 29;136(18):2051-2064. doi: 10.1182/blood.2019004095.
• Background Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):787-98. doi: 10.1056/NEJMoa1110556.
• Background Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003 Feb 14;299(5609):1057-61. doi: 10.1126/science.1079490. Epub 2003 Jan 9.
• Background Kadia TM, Ma, H, Zeng K, Nishimoto M, Lyu Mi-Ae, Huang M, Yilmaz M, DiNardo DC, Issa GC, Parmar S, Iyer SP, Hari P, Daver NG, Jabbour E, Borthakur GM, and Verstovsek S. 2019. 'Phase I Clinical Trial of CK0801 (cord blood regulatory T cells) in Patients with Bone Marrow Failure Syndrome (BMF) Including Aplastic Anemia, Myelodysplasia and Myelofibrosis', Blood.
• Background Kadia TM, Pemmaraju N, Yilmaz M, Li L, Lyu M, Huang M, Zeng K, Parmar S, DiNardo CD, Daver N, Issa GC, Jabbour E, Borthakur G, Verstovsek S. 2020. 'Adoptive Therapy with Allogeneic Cord Blood T Regulatory Cells Show Safety and Early Clinical Signal in Primary Myelofibrosis', Blood, 136: 41-42.
• Background Kellner JN, Delemarre EM, Yvon E, Nierkens S, Boelens JJ, McNiece I, Olson A, Nieto Y, Ciurea S, Popat U, Ahmed S, Champlin R, Ramos J, Nishimoto M, Ma H, Ke Z, Thall P, Khoury JD, Negrin R, Andersson B, Parmar S. Third party, umbilical cord blood derived regulatory T-cells for prevention of graft versus host disease in allogeneic hematopoietic stem cell transplantation: feasibility, safety and immune reconstitution. Oncotarget. 2018 Nov 2;9(86):35611-35622. doi: 10.18632/oncotarget.26242. eCollection 2018 Nov 2.
• Background Kotsianidis I, Bouchliou I, Nakou E, Spanoudakis E, Margaritis D, Christophoridou AV, Anastasiades A, Tsigalou C, Bourikas G, Karadimitris A, Tsatalas C. Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS). Leukemia. 2009 Mar;23(3):510-8. doi: 10.1038/leu.2008.333. Epub 2008 Nov 20.
• Background Lucca LE, Dominguez-Villar M. Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat Rev Immunol. 2020 Nov;20(11):680-693. doi: 10.1038/s41577-020-0296-3. Epub 2020 Apr 8.
• Background Massa M, Campanelli R, Fois G, Villani L, Bonetti E, Catarsi P, Poletto V, Viarengo G, De Amici M, Rosti V, Gale RP, Barosi G. Reduced frequency of circulating CD4+CD25brightCD127lowFOXP3+ regulatory T cells in primary myelofibrosis. Blood. 2016 Sep 22;128(12):1660-2. doi: 10.1182/blood-2016-03-704577. Epub 2016 Aug 16. No abstract available.
• Background Migliaccio AR, Adamson JW, Stevens CE, Dobrila NL, Carrier CM, Rubinstein P. Cell dose and speed of engraftment in placental/umbilical cord blood transplantation: graft progenitor cell content is a better predictor than nucleated cell quantity. Blood. 2000 Oct 15;96(8):2717-22.
• Background Migliaccio AR, Martelli F, Verrucci M, Migliaccio G, Vannucchi AM, Ni H, Xu M, Jiang Y, Nakamoto B, Papayannopoulou T, Hoffman R. Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1 low mouse model of the disease. Exp Hematol. 2008 Feb;36(2):158-71. doi: 10.1016/j.exphem.2007.10.001.
• Background Miwa Y, Hayashi T, Suzuki S, Abe S, Onishi I, Kirimura S, Kitagawa M, Kurata M. Up-regulated expression of CXCL12 in human spleens with extramedullary haematopoiesis. Pathology. 2013 Jun;45(4):408-16. doi: 10.1097/PAT.0b013e3283613dbf.
• Background Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. No abstract available.
• Background Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, Masszi T, Mishchenko E, Jourdan E, Vannucchi AM, Drummond MW, Jurgutis M, Kuliczkowski K, Gheorghita E, Passamonti F, Neumann F, Patki A, Gao G, Tefferi A. Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2015 Aug;1(5):643-51. doi: 10.1001/jamaoncol.2015.1590.
• Background Rosti V, Massa M, Vannucchi AM, Bergamaschi G, Campanelli R, Pecci A, Viarengo G, Meli V, Marchetti M, Guglielmelli P, Bruno E, Xu M, Hoffman R, Barosi G; Italian Registry of Myelofibrosis with Myeloid Metaplasia; Myeloproliferative Disorders Research Consortium. The expression of CXCR4 is down-regulated on the CD34+ cells of patients with myelofibrosis with myeloid metaplasia. Blood Cells Mol Dis. 2007 May-Jun;38(3):280-6. doi: 10.1016/j.bcmd.2007.01.003. Epub 2007 Mar 9.
• Background Song MK, Park BB, Uhm JE. Understanding Splenomegaly in Myelofibrosis: Association with Molecular Pathogenesis. Int J Mol Sci. 2018 Mar 18;19(3):898. doi: 10.3390/ijms19030898.
• Background Storer BE. An evaluation of phase I clinical trial designs in the continuous dose-response setting. Stat Med. 2001 Aug 30;20(16):2399-408. doi: 10.1002/sim.903.
• Background Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, Gotlib J, Dupriez B, Pardanani A, Harrison C, Hoffman R, Gisslinger H, Kroger N, Thiele J, Barbui T, Barosi G. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013 Aug 22;122(8):1395-8. doi: 10.1182/blood-2013-03-488098. Epub 2013 Jul 9.
• Background Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007 Aug 15;110(4):1092-7. doi: 10.1182/blood-2007-04-083501. Epub 2007 May 8.
• Background Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011 Apr 1;29(10):1356-63. doi: 10.1200/JCO.2010.32.9490. Epub 2011 Feb 7.
• Background Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Koumenis IL, Sun W, Sandor V, Kantarjian HM. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799-807. doi: 10.1056/NEJMoa1110557.
• Background Wang JC, Sindhu H, Chen C, Kundra A, Kafeel MI, Wong C, Lichter S. Immune derangements in patients with myelofibrosis: the role of Treg, Th17, and sIL2Ralpha. PLoS One. 2015 Mar 20;10(3):e0116723. doi: 10.1371/journal.pone.0116723. eCollection 2015.
• Background Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016 Sep 1;22(17):4291-301. doi: 10.1158/1078-0432.CCR-16-0592. Epub 2016 Jul 12.
• Background Zeng K, Ma H, Popat U, Nieto Y, Ciurea SO, Olson AL, Lyu M, Huang M, Nishimoto M, Qazilbash MH, Ramos JD, Shpall EJ, Champlin RE, Parmar S, Andersson BS. . 2019. 'Allogeneic Cord Blood Regulatory T Cells Can Prevent Graft Vs. Host Disease and Preserve Graft Vs Leukemia Effect: Update on Phase I/II Clinical Tria', Blood, 134.

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Indications