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Low accrual
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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.
This is a two-tiered multi arm Phase 2 trial of vactosertib (TEW-7197) for the treatment of anemia in Ph-neg MPNs. Both tiers use a rule-based, accelerated dose escalation scheme to efficiently assess the potential of vactosertib to safely and effectively treat anemic patients with Ph-neg MPNs. The first tier of this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a low starting dose of vactosertib for all patients. Treatment dose is escalated according to prospectively-defined rules, and a toxicity and treatment effect algorithm during the period of 16 weeks (4 treatment cycles). If pre-established efficacy and safety endpoints are met, then Tier 1 of the study will be followed by a Tier 2 expansion study with an additional 25 patients for a period of 24 weeks (6 treatment cycles).
Vactosertib will be administered concurrently with the patient's current treatment (if any). Prior to enrollment, patients must be on a stable dose of their current therapy for 3 months prior to entering the study. Supportive care measures including packed red blood cell (PRBC) transfusions for HGB <7g/dL, or symptomatic anemia, will be permitted. Administration of erythropoiesis stimulating agents (ESAs), however, will not be permitted on the trial (patients recruited would have serum EPO >125 U/L above which the benefit of ESAs is not supported).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tier 1: Vactosertib 50 mg BID | Experimental | Vactosertib intra-patient dose finding cohort. |
|
| Tier 1: Vactosertib 100 mg BID | Experimental |
| |
| Tier 1: Vactosertib 150 mg BID | Experimental |
| |
| Tier 1: Vactosertib 200mg BID | Experimental |
| |
| Tier 2: Vactosertib | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Vactosertib | Drug | 50 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| Measure | Description | Time Frame |
|---|---|---|
| Identify the Safest, Minimally Effective Starting Dose Level for Patients on Tier 1 | The safest minimally effective dose is defined as the lowest dose level for which no dose limiting toxicity (DLT) was observed in Tier 1 AND the lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 meet Criteria for Clinical Benefit | Baseline to week 16 |
| Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 1 | Identify the incidence of dose limiting toxicity (DLT) within the first 12 weeks which are defined as:
| Baseline to week 12 |
| Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 1 | Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 1 stopping rule. The tier 1 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study. | Baseline to week 12 |
| Number of Tier 2 Patients Who Have Achieved Erythropoietic Response as Defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria | Number of patients who achieve an erythropoietic response defined by:
| baseline to week 16 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients in Which a Histological Response is Seen | Histological response is defined by reduction of any amount in grade of bone marrow fibrosis by histopathologic assessment at 16 weeks. | 16 weeks |
| Number of Patients in Which a Molecular Response is Seen |
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Inclusion Criteria:
Patients who meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, MPN-U).
Patients with MF must have DIPSS+ Intermediate or High-risk MF (primary of post-PV/ET).
For patients receiving cytoreductive therapy, they should be on a stable dose of current cytoreductive therapy for at least 3 months prior to C1D1.
Anemia as defined by HGB < 10 g/dL, or transfusion of ≥ 2 packed red blood cell (PRBC) unit within the past 4 weeks with HGB ≤8.5g/dL.
Ineligible, unsuitable or refractoriness to ESA therapy defined as any of the following:
Acceptable Cardiovascular status
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Joseph M Scandura, MD, PhD | Weill Medical College of Cornell University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Weill Medical College of Cornell University | New York | New York | 10021 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28009442 | 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. | |
| 23838352 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Vacosertib 50 mg BID | Vactosertib intra-patient dose finding cohort. Vactosertib: 50 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Vactosertib 50 mg BID (Tier 1) |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 9, 2024 |
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This is an intra-patient dose finding study which starts with low dose of vactosertib.
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|
|
| Vactosertib | Drug | 100 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
|
|
| Vactosertib | Drug | 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
|
|
| Vactosertib | Drug | 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
|
|
| Vactosertib | Drug | The lowest dose level of vactosertib for which no DLT was observed in Tier 1 AND The lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 met Criteria for Clinical Benefit. Or, if a single dose level does not fulfil both Criterion 1 and Criterion 2, the starting dose level for Tier 2 will lowest dose from Tier 1 for which no DLT was identified. |
|
|
| Number of Tier 2 Patients Who Have Achieved Clinical Response in Symptoms as Defined by International Working Group (IWG) Criteria | Number of patients who have achieved clinical response defined by a reduction in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score by ≥ 50% compared to pretreatment score | baseline to week 16 |
| Number of Tier 2 Patients Who Have Achieved Splenic Response in Symptoms as Defined by International Working Group (IWG) Criteria | Number of patients who have achieved splenic response defined by:
| baseline to week 16 |
| Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 2 | Identify the number of dose limiting toxicities (DLT) within the first 12 weeks which are defined as:
| baseline to week 12 |
| Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 2 | Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 2 stopping rule. The tier 2 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study. | baseline to week 12 |
Number of patients in which a molecular response is seen. Molecular response is defined by a decrease in VAF of MPN-driver mutations (eg. JAK2, CALR, and MPL allelic ratio) in blood and/or bone marrow cells |
| 16 weeks |
| Number of Patients in Which a Pharmacodynamic Response is Seen | A pharmacodynamic response is defined as any of the following:
| 16 weeks |
| Number of Patients Who Have Experienced Any of the Following: Hematologic Toxicities, Infections, Disease Progression, and Thrombosis Events | baseline to 16 weeks |
| Overall Survival Defined as the Amount of Time a Patient is Alive After Starting Study Treatment | The overall survival range describes the average length of time subjects were followed for survival | Week 1 Day 1 to 6 months post treatment discontinuation. This collection period for both subjects on study was over an average duration of 54 weeks. |
| Progression Free Survival Defined as the Duration of Time From Start of Treatment to Time of Progression | Week 1 Day 1 to 6 months post treatment discontinuation |
| 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. |
| 23591792 | 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. |
| 25037629 | 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. |
| 25616577 | 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. |
| 28674026 | 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. |
| 28860323 | 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. |
| 19366369 | 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. |
| 12968110 | 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. |
| 19796233 | 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. |
| 15477587 | 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. |
| 23440043 | 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. |
| 18757300 | 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. |
| 10989189 | 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. |
| 18474728 | 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. |
| 29331635 | 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. |
| 28870615 | 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. |
| 27053300 | 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. |
| 26309397 | 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. |
| 23403314 | 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. |
| 17473062 | 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. |
| 17198875 | 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. |
| 7803262 | 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. |
| 23462118 | 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. |
| 22200991 | 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. |
| 15726648 | 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. |
| 14991065 | 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. |
| 27592389 | 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. |
| 27810993 | 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. |
| 21562050 | 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. |
| 27069254 | 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. |
| 21536863 | 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. |
| 29522138 | 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. |
| 22375970 | 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. |
| FG001 | Vacosertib 100 mg BID | Vactosertib: 100 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| FG002 | Vacosertib 150 mg BID | Vactosertib: 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| FG003 | Vacosertib 200mg BID | Vactosertib: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| FG004 | Tier 2: Vactosertib | This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| COMPLETED |
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| NOT COMPLETED |
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| Vactosertib 100 mg BID (Tier 1) |
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| Vactosertib 150 mg BID (Tier 1) |
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| Vactosertib 200 mg BID (Tier 1) |
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| Vactosertib (Tier 2) |
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Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Vactosertib intra-patient dose finding cohort. Vactosertib This drug is a TG-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Identify the Safest, Minimally Effective Starting Dose Level for Patients on Tier 1 | The safest minimally effective dose is defined as the lowest dose level for which no dose limiting toxicity (DLT) was observed in Tier 1 AND the lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 meet Criteria for Clinical Benefit | Posted | Number | mg | Baseline to week 16 |
|
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| |||||||||||||||||||||||||||
| Primary | Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 1 | Identify the incidence of dose limiting toxicity (DLT) within the first 12 weeks which are defined as:
| Posted | Number | Count of DLTs | Baseline to week 12 |
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| Primary | Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 1 | Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 1 stopping rule. The tier 1 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study. | Posted | Number | mg | Baseline to week 12 |
|
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| Primary | Number of Tier 2 Patients Who Have Achieved Erythropoietic Response as Defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria | Number of patients who achieve an erythropoietic response defined by:
| No subjects went on to the Tier 2 portion of the study | Posted | baseline to week 16 |
|
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| Primary | Number of Tier 2 Patients Who Have Achieved Clinical Response in Symptoms as Defined by International Working Group (IWG) Criteria | Number of patients who have achieved clinical response defined by a reduction in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score by ≥ 50% compared to pretreatment score | No subjects went on to the Tier 2 portion of the study | Posted | baseline to week 16 |
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| Primary | Number of Tier 2 Patients Who Have Achieved Splenic Response in Symptoms as Defined by International Working Group (IWG) Criteria | Number of patients who have achieved splenic response defined by:
| No subjects went on to the Tier 2 portion of the study | Posted | baseline to week 16 |
|
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| Primary | Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 2 | Identify the number of dose limiting toxicities (DLT) within the first 12 weeks which are defined as:
| No subjects went on to the Tier 2 portion of the study | Posted | baseline to week 12 |
|
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| Primary | Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 2 | Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 2 stopping rule. The tier 2 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study. | No subjects went on to the Tier 2 portion of the study | Posted | baseline to week 12 |
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| Secondary | Number of Patients in Which a Histological Response is Seen | Histological response is defined by reduction of any amount in grade of bone marrow fibrosis by histopathologic assessment at 16 weeks. | 0 subjects were analyzed for Tier 1 subjects taking 50mg, 100mg, and 150mg of Vactosertib because no participants were taking those doses at 16 weeks. 0 subjects were analyzed in Tier 2 because no subjects were in Tier 2 at 16 weeks. | Posted | Count of Participants | Participants | 16 weeks |
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| Secondary | Number of Patients in Which a Molecular Response is Seen | Number of patients in which a molecular response is seen. Molecular response is defined by a decrease in VAF of MPN-driver mutations (eg. JAK2, CALR, and MPL allelic ratio) in blood and/or bone marrow cells | 0 subjects were analyzed for Tier 1 subjects taking 50mg, 100mg, and 150mg of Vactosertib because no participants were taking those doses at 16 weeks. 0 subjects were analyzed in Tier 2 because no subjects were in Tier 2 at 16 weeks. | Posted | Count of Participants | Participants | 16 weeks |
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| Secondary | Number of Patients in Which a Pharmacodynamic Response is Seen | A pharmacodynamic response is defined as any of the following:
| 0 subjects were analyzed for Tier 1 subjects taking 50mg, 100mg, and 150mg of Vactosertib because no participants were taking those doses at 16 weeks. 0 subjects were analyzed in Tier 2 because no subjects were in Tier 2 at 16 weeks. | Posted | Count of Participants | Participants | 16 weeks |
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| Secondary | Number of Patients Who Have Experienced Any of the Following: Hematologic Toxicities, Infections, Disease Progression, and Thrombosis Events | No subjects enrolled on Tier 2 | Posted | Count of Participants | Participants | baseline to 16 weeks |
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| Secondary | Overall Survival Defined as the Amount of Time a Patient is Alive After Starting Study Treatment | The overall survival range describes the average length of time subjects were followed for survival | Posted | Mean | Full Range | Weeks | Week 1 Day 1 to 6 months post treatment discontinuation. This collection period for both subjects on study was over an average duration of 54 weeks. |
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| Secondary | Progression Free Survival Defined as the Duration of Time From Start of Treatment to Time of Progression | Posted | Mean | Full Range | Weeks | Week 1 Day 1 to 6 months post treatment discontinuation |
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Deaths were collected from Week 1 Day 1 through 6 months post treatment discontinuation. This collection period for both subjects on study was over an average duration of 54 weeks. Serious and Other (Not Including Serious) Adverse Events were collected while subjects were on treatment. This collection period for both subjects on study was over an average duration of 28 weeks.
All subjects treated with Vactosertib
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tier 1: Vactosertib 50 mg BID | Vactosertib intra-patient dose finding cohort. Vactosertib: 50 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. | 0 | 2 | 0 | 2 | 2 | 2 |
| EG001 | Tier 1: Vactosertib 100 mg BID | Vactosertib: 100 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. | 0 | 2 | 0 | 2 | 2 | 2 |
| EG002 | Tier 1: Vactosertib 150 mg BID | Vactosertib: 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. | 0 | 2 | 0 | 2 | 2 | 2 |
| EG003 | Tier 1: Vactosertib 200mg BID | Vactosertib: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. | 0 | 2 | 0 | 2 | 2 | 2 |
| EG004 | Tier 2: Vactosertib | This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG005 | All Participants | Vactosertib intra-patient dose finding cohort. Vactosertib This drug is a TG-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. | 0 | 2 | 0 | 2 | 2 | 2 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Decreased Appetite | Metabolism and nutrition disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Depression | Psychiatric disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Diarrhea | Gastrointestinal disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Abdominal distension | Gastrointestinal disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Fatigue | General disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Vertigo | Ear and labyrinth disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Paresthesia | Nervous system disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Pain extremity (left lower leg) | Musculoskeletal and connective tissue disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | CTCAE (5.0) | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | CTCAE (5.0) | Systematic Assessment |
| |
| Alkaline phosphatase increased | Investigations | CTCAE (5.0) | Systematic Assessment |
| |
| Drowsiness | General disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Hyperuricemia | Metabolism and nutrition disorders | CTCAE (5.0) | Systematic Assessment |
| |
| Muscle cramp | Musculoskeletal and connective tissue disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Herpes simplex reactivation | Infections and infestations | CTCAE (5.0) | Systematic Assessment |
| |
| Gastrointestinal pain | Gastrointestinal disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Dizziness | Nervous system disorders | CTCAE (5.0) | Non-systematic Assessment |
| |
| Skin Infection | Infections and infestations | CTCAE (5.0) | Non-systematic Assessment |
|
Only a small number of subjects was analyzed due to low accrual and early termination. Additionally, only Tier 1 outcome measures could be analyzed due to 0 subjects enrolling onto Tier 2.
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Joseph Scandura, MD | Weill Cornell Medicine | (212) 746-2072 | jms2003@med.cornell.edu |
| Apr 9, 2025 |
| Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D009196 | Myeloproliferative Disorders |
| D000740 | Anemia |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C000590371 | vactosertib |
Not provided
Not provided
Not provided
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Tier 1: Vactosertib 150 mg BID |
Vactosertib: 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG003 | Tier 1: Vactosertib 200mg BID | Vactosertib: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
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Vactosertib: 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG003 | Tier 1: Vactosertib 200mg BID | Vactosertib: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG004 | Tier 2: Vactosertib | This drug is a TG-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
|
|
| Tier 1: Vactosertib 150 mg BID |
Vactosertib: 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG003 | Tier 1: Vactosertib 200mg BID | Vactosertib: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG004 | Tier 2: Vactosertib | Vactosertib This drug is a TG-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
|
|
| OG002 | Tier 1: Vactosertib 150 mg BID | Vactosertib: 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG003 | Tier 1: Vactosertib 200mg BID | Vactosertib: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG004 | Tier 2: Vactosertib | This drug is a TG-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
|
|
| OG003 | Tier 1: Vactosertib 200 mg BID | Vactosertib: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
| OG004 | Tier 2: Vactosertib | This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. |
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