Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients

Summary

This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferative neoplasms. TGFβ signaling is known to be abnormally high in patients with myeloproliferative neoplasms and it is thought that abnormal TGFβ signals cause many of the problems with blood cell formation in these diseases. The study design allows all patients to receive the study drug, vactosertib. The dose of vactosertib is individualized within a pre-set range based upon its effectiveness and tolerability. A total of up to 37 patients will be treated.

Timeline

Start

2019-11-22

Primary completion

2024-07-10

Completion

2024-07-10

Publications

• Background Hernandez-Boluda JC, Correa JG, Garcia-Delgado R, Martinez-Lopez J, Alvarez-Larran A, Fox ML, Garcia-Gutierrez V, Perez-Encinas M, Ferrer-Marin F, Mata-Vazquez MI, Raya JM, Estrada N, Garcia S, Kerguelen A, Duran MA, Albors M, Cervantes F. Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis. Eur J Haematol. 2017 Apr;98(4):407-414. doi: 10.1111/ejh.12846. Epub 2017 Jan 19.
• 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 Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Vannucchi AM, Besses C, Gisslinger H, Samuelsson J, Verstovsek S, Hoffman R, Pardanani A, Cervantes F, Tefferi A, Barbui T. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013 Jun 6;121(23):4778-81. doi: 10.1182/blood-2013-01-478891. Epub 2013 Apr 16.
• Background Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, Gangat N, Fjerza R, Belachew AA, Lasho TL, Ketterling RP, Hanson CA, Rambaldi A, Finazzi G, Thiele J, Barbui T, Pardanani A, Vannucchi AM. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014 Oct 16;124(16):2507-13; quiz 2615. doi: 10.1182/blood-2014-05-579136. Epub 2014 Jul 18.
• Background Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Raza A, Vaddi K, Sun W, Peng W, Sandor V, Kantarjian H; COMFORT-I investigators. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015 Apr;100(4):479-88. doi: 10.3324/haematol.2014.115840. Epub 2015 Jan 23.
• Background Newberry KJ, Patel K, Masarova L, Luthra R, Manshouri T, Jabbour E, Bose P, Daver N, Cortes J, Kantarjian H, Verstovsek S. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017 Aug 31;130(9):1125-1131. doi: 10.1182/blood-2017-05-783225. Epub 2017 Jul 3.
• Background Vannucchi AM, Guglielmelli P. Traffic lights for ruxolitinib. Blood. 2017 Aug 31;130(9):1075-1077. doi: 10.1182/blood-2017-07-795880. No abstract available.
• Background Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol. 2009 Aug;83(2):154-5. doi: 10.1111/j.1600-0609.2009.01266.x. Epub 2009 Apr 10. No abstract available.
• Background Akel S, Petrow-Sadowski C, Laughlin MJ, Ruscetti FW. Neutralization of autocrine transforming growth factor-beta in human cord blood CD34(+)CD38(-)Lin(-) cells promotes stem-cell-factor-mediated erythropoietin-independent early erythroid progenitor development and reduces terminal differentiation. Stem Cells. 2003;21(5):557-67. doi: 10.1634/stemcells.21-5-557.
• Background Soderberg SS, Karlsson G, Karlsson S. Complex and context dependent regulation of hematopoiesis by TGF-beta superfamily signaling. Ann N Y Acad Sci. 2009 Sep;1176:55-69. doi: 10.1111/j.1749-6632.2009.04569.x.
• Background Scandura JM, Boccuni P, Massague J, Nimer SD. Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15231-6. doi: 10.1073/pnas.0406771101. Epub 2004 Oct 11.
• Background Brenet F, Kermani P, Spektor R, Rafii S, Scandura JM. TGFbeta restores hematopoietic homeostasis after myelosuppressive chemotherapy. J Exp Med. 2013 Mar 11;210(3):623-39. doi: 10.1084/jem.20121610. Epub 2013 Feb 25.
• Background Chabanon A, Desterke C, Rodenburger E, Clay D, Guerton B, Boutin L, Bennaceur-Griscelli A, Pierre-Louis O, Uzan G, Abecassis L, Bourgeade MF, Lataillade JJ, Le Bousse-Kerdiles MC. A cross-talk between stromal cell-derived factor-1 and transforming growth factor-beta controls the quiescence/cycling switch of CD34(+) progenitors through FoxO3 and mammalian target of rapamycin. Stem Cells. 2008 Dec;26(12):3150-61. doi: 10.1634/stemcells.2008-0219. Epub 2008 Aug 28.
• Background Zermati Y, Fichelson S, Valensi F, Freyssinier JM, Rouyer-Fessard P, Cramer E, Guichard J, Varet B, Hermine O. Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors. Exp Hematol. 2000 Aug;28(8):885-94. doi: 10.1016/s0301-472x(00)00488-4.
• Background Zhou L, Nguyen AN, Sohal D, Ying Ma J, Pahanish P, Gundabolu K, Hayman J, Chubak A, Mo Y, Bhagat TD, Das B, Kapoun AM, Navas TA, Parmar S, Kambhampati S, Pellagatti A, Braunchweig I, Zhang Y, Wickrema A, Medicherla S, Boultwood J, Platanias LC, Higgins LS, List AF, Bitzer M, Verma A. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood. 2008 Oct 15;112(8):3434-43. doi: 10.1182/blood-2008-02-139824. Epub 2008 May 12.
• Background Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, Sekeres MA, Berdeja J, Savona MR, Beyne-Rauzy O, Stamatoullas A, DeZern AE, Delaunay J, Borthakur G, Rifkin R, Boyd TE, Laadem A, Vo B, Zhang J, Puccio-Pick M, Attie KM, Fenaux P, List AF. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018 Feb;5(2):e63-e72. doi: 10.1016/S2352-3026(18)30002-4. Epub 2018 Jan 10.
• Background Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, Radsak M, Wolff T, Zhang X, Laadem A, Sherman ML, Attie KM, Giagounidis A. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017 Oct;18(10):1338-1347. doi: 10.1016/S1470-2045(17)30615-0. Epub 2017 Sep 1.
• Background Zhang H, Kozono DE, O'Connor KW, Vidal-Cardenas S, Rousseau A, Hamilton A, Moreau L, Gaudiano EF, Greenberger J, Bagby G, Soulier J, Grompe M, Parmar K, D'Andrea AD. TGF-beta Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia. Cell Stem Cell. 2016 May 5;18(5):668-81. doi: 10.1016/j.stem.2016.03.002. Epub 2016 Mar 24.
• Background Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, Slapak CA, Lahn MM. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther. 2015 Aug 10;9:4479-99. doi: 10.2147/DDDT.S86621. eCollection 2015.
• Background Badalucco S, Di Buduo CA, Campanelli R, Pallotta I, Catarsi P, Rosti V, Kaplan DL, Barosi G, Massa M, Balduini A. Involvement of TGFbeta1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis. Haematologica. 2013 Apr;98(4):514-7. doi: 10.3324/haematol.2012.076752. Epub 2013 Feb 12.
• Background Ciurea SO, Merchant D, Mahmud N, Ishii T, Zhao Y, Hu W, Bruno E, Barosi G, Xu M, Hoffman R. Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood. 2007 Aug 1;110(3):986-93. doi: 10.1182/blood-2006-12-064626. Epub 2007 May 1.
• Background Gastinne T, Vigant F, Lavenu-Bombled C, Wagner-Ballon O, Tulliez M, Chagraoui H, Villeval JL, Lacout C, Perricaudet M, Vainchenker W, Benihoud K, Giraudier S. Adenoviral-mediated TGF-beta1 inhibition in a mouse model of myelofibrosis inhibit bone marrow fibrosis development. Exp Hematol. 2007 Jan;35(1):64-74. doi: 10.1016/j.exphem.2006.08.016.
• Background Martyre MC, Romquin N, Le Bousse-Kerdiles MC, Chevillard S, Benyahia B, Dupriez B, Demory JL, Bauters F. Transforming growth factor-beta and megakaryocytes in the pathogenesis of idiopathic myelofibrosis. Br J Haematol. 1994 Sep;88(1):9-16. doi: 10.1111/j.1365-2141.1994.tb04970.x.
• Background Zingariello M, Martelli F, Ciaffoni F, Masiello F, Ghinassi B, D'Amore E, Massa M, Barosi G, Sancillo L, Li X, Goldberg JD, Rana RA, Migliaccio AR. Characterization of the TGF-beta1 signaling abnormalities in the Gata1low mouse model of myelofibrosis. Blood. 2013 Apr 25;121(17):3345-63. doi: 10.1182/blood-2012-06-439661. Epub 2013 Mar 5.
• Background Ponce CC, de Lourdes F Chauffaille M, Ihara SS, Silva MR. The relationship of the active and latent forms of TGF-beta1 with marrow fibrosis in essential thrombocythemia and primary myelofibrosis. Med Oncol. 2012 Dec;29(4):2337-44. doi: 10.1007/s12032-011-0144-1. Epub 2011 Dec 27.
• Background Bock O, Loch G, Schade U, von Wasielewski R, Schlue J, Kreipe H. Aberrant expression of transforming growth factor beta-1 (TGF beta-1) per se does not discriminate fibrotic from non-fibrotic chronic myeloproliferative disorders. J Pathol. 2005 Apr;205(5):548-57. doi: 10.1002/path.1744.
• Background Shehata M, Schwarzmeier JD, Hilgarth M, Hubmann R, Duechler M, Gisslinger H. TGF-beta1 induces bone marrow reticulin fibrosis in hairy cell leukemia. J Clin Invest. 2004 Mar;113(5):676-85. doi: 10.1172/JCI19540.
• Background Ceglia I, Dueck AC, Masiello F, Martelli F, He W, Federici G, Petricoin EF 3rd, Zeuner A, Iancu-Rubin C, Weinberg R, Hoffman R, Mascarenhas J, Migliaccio AR. Preclinical rationale for TGF-beta inhibition as a therapeutic target for the treatment of myelofibrosis. Exp Hematol. 2016 Dec;44(12):1138-1155.e4. doi: 10.1016/j.exphem.2016.08.007. Epub 2016 Aug 31.
• Background Margolskee E, Krichevsky S, Orazi A, Silver RT. Evaluation of bone marrow morphology is essential for assessing disease status in recombinant interferon alpha-treated polycythemia vera patients. Haematologica. 2017 Mar;102(3):e97-e99. doi: 10.3324/haematol.2016.153973. Epub 2016 Nov 3. No abstract available.
• Background Anand S, Stedham F, Beer P, Gudgin E, Ortmann CA, Bench A, Erber W, Green AR, Huntly BJ. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood. 2011 Jul 7;118(1):177-81. doi: 10.1182/blood-2010-12-327593. Epub 2011 May 11.
• Background Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11.
• Background Scherber R, Dueck AC, Johansson P, Barbui T, Barosi G, Vannucchi AM, Passamonti F, Andreasson B, Ferarri ML, Rambaldi A, Samuelsson J, Birgegard G, Tefferi A, Harrison CN, Radia D, Mesa RA. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011 Jul 14;118(2):401-8. doi: 10.1182/blood-2011-01-328955. Epub 2011 May 2.
• Background Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, Szoke A, Drummond M, Pristupa A, Granston T, Daly R, Al-Fayoumi S, Callahan JA, Singer JW, Gotlib J, Jamieson C, Harrison C, Mesa R, Verstovsek S. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2018 May 1;4(5):652-659. doi: 10.1001/jamaoncol.2017.5818.
• 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.

Drugs

Indications