An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK2 Inhibitor Therapy and Who Require Red Blood Cell Transfusions (INDEPENDENCE)

A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK Inhibitor Therapy and Who Require Red Blood Cell Transfusions

The purpose of this Phase 3 study is to evaluate the efficacy and safety of Luspatercept compared with placebo in subjects with myeloproliferative neoplasm (MPN)-associated Myelofibrosis (MF) and anemia on concomitant Janus kinase 2 (JAK2) inhibitor therapy and who require red blood cell count (RBC) transfusions.

The study is divided into Screening Period, a Treatment Phase (consisting of a Blinded Core Treatment Period, a Day 169 Response Assessment, a Blinded Extension Treatment Period, and an Open-label Extension Treatment Period), and a Posttreatment Follow-up Period.

Following the Day 169 Response Assessment, subjects who did not show clinical benefit will have the option to unblind. Subjects who were on placebo during the Blinded Core Treatment Period will have the opportunity to crossover into the Open-Label Extension Treatment Period and receive Luspatercept.

Study Overview

• Status: Active, not recruiting
• Conditions: Primary Myelofibrosis; Myeloproliferative Disorders; Anemia; Myelofibrosis; Post-Polycythemia Vera Myelofibrosis
• Intervention / Treatment: Drug: ACE-536; Other: Placebo

Detailed Description

Permitted Concomitant Medications and Procedures

• Subjects are receiving a JAK2 inhibitor for the treatment of MPN-associated MF that is approved in the country where the study is being conducted. JAK2 inhibitors are to be used according to their respective label and as prescribed as part of the subject's standard-of-care therapy as prescribed by their physician prior to study entry.
• Best supportive care (BSC) includes, but is not limited to, treatment with transfusions (eg, RBC, platelet, whole blood), ICTs, antibiotic, antiviral and/or antifungal therapy, and nutritional support as needed.
• Granulocyte colony-stimulating factors (ie, G-CSF, granulocyte macrophage colony-stimulating factor [GM-CSF]) are allowed only in cases of neutropenic fever or as clinically indicated per product label.
• Prophylactic antithrombotic therapy is permitted.
• Thrombopoietin and platelet transfusions are permitted.
• Treatment with systemic corticosteroids is permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to ≤ 10 mg prednisone during the study.
• Administration of attenuated vaccines (eg, influenza vaccine) is allowed if clinically indicated per Investigator discretion.
• Iron chelation therapy (ICT) is to be used according to the product label. If the label permits, the ICT dose should be stable during at least the first 24 weeks of IP. Initiation of ICT while within the first 24 weeks of IP should be clinically indicated to treat an AE.

Prohibited Concomitant Medications

The following concomitant medications are specifically excluded during the course of study treatment:

• Cytotoxic, chemotherapeutic, targeted, or investigational agents/therapies (excluding JAK2 inhibitor therapy)
• Azacitidine, decitabine, or other hypomethylating agents
• Lenalidomide, thalidomide, and pomalidomide
• Erythropoietin stimulating agents (ESAs) and other RBC hematopoietic growth factors (eg, IL-3)
• Hydroxyurea or other alkylating agents
• Androgens (unless given to treat hypogonadism)
• Oral retinoids (topical retinoids are permitted)
• Arsenic trioxide
• Interferon
• Anagrelide
• Systemic corticosteroids at a dose equivalent to > 10 mg prednisone
• Investigational products for the treatment of MPN-associated MF

• Study Type: Interventional
• Enrollment (Actual): 313
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aires, Argentina, C1199ABB
    • Hospital Italiano de Buenos Aires
  • Buenos Aires
    • Ciudad Autónoma de BuenosAires, Buenos Aires, Argentina, C1280AEB
      • Local Institution - 172
    • La Plata, Buenos Aires, Argentina, B1900AX
      • Hospital Italiano de La Plata
• Australia
  • Gosford, Australia, 2250
    • Gosford Hospital
  • Hobart, Australia, 7000
    • Royal Hobart Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Austria
  • Graz, Austria, 8036
    • Local Institution - 272
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen Linz, I Interne Abteilung
  • Vienna, Austria, 1090
    • Local Institution - 271
  • Vienna, Austria, 1140
    • Local Institution - 274
• Belgium
  • Brugge, Belgium, 8000
    • Local Institution - 318
  • Brussels, Belgium, 1200
    • Local Institution - 312
  • Hasselt, Belgium, 3500
    • Local Institution - 313
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Liège, Belgium, 4000
    • Local Institution - 319
  • Roeselare, Belgium, 8800
    • Local Institution - 316
  • Verviers, Belgium, 4800
    • Local Institution - 315
  • Yvoir, Belgium, 5530
    • Cliniques Universitaires UCL de Mont-Godine
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Local Institution - 181
    • Edmonton, Alberta, Canada, T6G 2S2
      • Local Institution - 179
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2A5
      • Local Institution - 183
  • Ontario
    • London, Ontario, Canada, N6C 6B5
      • University Hospital - London Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution - 180
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Sir Mortimer B. Davis - Jewish Genl
    • Montreal, Quebec, Canada, H1T 2M4
      • Local Institution - 177
    • Sherbrooke, Quebec, Canada, J1H5N4
      • Local Institution - 176
• Chile
  • Santiago, Chile, 7500587
    • Local Institution - 193
  • Coquimbo
    • La Serena, Coquimbo, Chile, 1720430
      • IC La Serena Research
  • Metropolitana De Santiago
    • Las Condes, Metropolitana De Santiago, Chile, 7560742
      • Local Institution - 192
• China
  • Beijing, China, 100730
    • Beijing Peking Union Medical College Hospital
  • Changchun, China, 130021
    • Local Institution - 802
  • Guangzhou, China, 510030
    • Guangdong General Hospital
  • Harbin, China, 150081
    • The First Affiliated Hospital of Harbin Medical University
  • Shanghai, China, 200025
    • Local Institution - 809
  • Shanghai, China, 200233
    • Local Institution - 801
  • Suzhou, China, 215006
    • Local Institution - 811
  • Tianjin, China, 300052
    • Tianjin Medical University General Hospital
  • Tianjin, China, 300041
    • Local Institution - 800
  • Zhengzhou, China
    • Local Institution - 810
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Nanfang Hospital of Southern Medical University
  • Henan
    • Nanyang, Henan, China
      • The First Affiliated Hospital of Nanyang Medical College
  • Hunan
    • Changsha, Hunan, China, 410008
      • Xiangya Hospital Central-South University
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Local Institution - 804
    • Nantong, Jiangsu, China, 226001
      • Local Institution - 818
  • Jiangxi
    • Nanchang, Jiangxi, China, 330008
      • Nanchang University - The Second Affiliated Hospital
    • Nanchang, Jiangxi, China, 330006
      • Local Institution - 820
  • Shandong
    • Qingdao, Shandong, China
      • Local Institution - 821
  • Shanxi
    • Taiyuan, Shanxi, China, 030001
      • Local Institution - 816
  • Yunnan
    • Kunming, Yunnan, China, 650101
      • The Second Affiliated Hospital of Kunming Medical University
• Colombia
  • Antioquia
    • Medellin, Antioquia, Colombia, 50034
      • Local Institution - 161
  • Distrito Capital De Bogotai
    • Bogota, Distrito Capital De Bogotai, Colombia, 111511
      • Local Institution - 163
  • Soto
    • Floridablanca, Soto, Colombia, 681002
      • Local Institution - 162
• Czechia
  • Prague 2, Czechia, 128 08
    • Local Institution - 341
• France
  • Angers, France, 49033
    • Local Institution - 331
  • Clermont Ferrand, France, 63000
    • Local Institution - 333
  • Creteil, France, 94010
    • Local Institution - 324
  • Grenoble, France, 38043
    • CHU de Grenoble
  • Lille, France, 59037
    • Local Institution - 327
  • Lyon, France, 69008
    • Local Institution - 332
  • Nice, France, 06202
    • CHU de Nice Archet I
  • Nimes Cedex 9, France, 30029
    • Centre Hospitalier Universitaire de Nimes (CHU) - Hopital Universitaire Caremeau
  • Paris Cedex 10, France, 75475
    • Hopital Saint Louis
  • Pessac, France, 33604
    • Groupe Hospitalier Sud Hopital Haut Leveque USN
  • Poitiers Cedex, France, 86021
    • CHU La Milétrie
  • Strasbourg, France, 67200
    • ICANS Institut de cancérologie Strasbourg Europe
  • Toulouse Cedex 9, France, 31059
    • Local Institution - 330
• Germany
  • Aachen, Germany, 52074
    • Unviversitatsklinikum Aachen
  • Baden-Warttemberg, Germany, 73557
    • Stauferklinikum Schwab. Gmund
  • Dusseldorf, Germany, 40225
    • Local Institution - 299
  • Halle, Germany, 06120
    • Universitatsklinikum Halle Saale
  • Hamburg, Germany, 22081
    • Local Institution - 300
  • Jena, Germany, 07740
    • Universitaetsklinikum Jena
  • Leipzig, Germany, 04103
    • Local Institution - 297
  • Mannheim, Germany, 68167
    • Local Institution - 301
  • Minden, Germany, 32429
    • Johannes Wiesling Klinikum Minden
• Greece
  • Alexandroupolis, Greece, 08100
    • Local Institution - 383
  • Athens, Greece, 10676
    • Evangelismos General Hospital of Athens
  • Athens, Greece, 12464
    • Attikon University General Hospital
  • Athens, Greece, 11 527
    • Local Institution - 386
  • Rio Patras, Greece, 26500
    • University General Hospital of Patras
  • Thessaloniki, Greece, 57010
    • Georgios Papanikolaou General Hospital of Thessaloniki
  • Achaia
    • Patra, Achaia, Greece, 264 43
      • Local Institution - 387
• Hong Kong
  • Hong Kong, Hong Kong
    • Local Institution - 661
  • Sha Tin, Hong Kong
    • Prince of Wales Hospital the Chinese University of Hong Kong
• Hungary
  • Budapest, Hungary, 1096
    • Local Institution - 462
  • Gyor, Hungary, 9023
    • Local Institution - 463
• Ireland
  • Cork, Ireland, T12 DFK4
    • Cork University Hospital
  • Dublin, Ireland, Dublin 8
    • St James Hospital
  • Dublin 7, Ireland, 7
    • Mater Misercordiae Hospital
• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Jerusalem, Israel, 91120
    • Hadassah Medical Organization
  • Kfar-Saba, Israel, 44281
    • Meir Medical Center
  • Zerifin, Israel, 70300
    • Shamir Medical Center - Assaf Harofeh
  • Tel Aviv
    • Tel-Aviv, Tel Aviv, Israel, 64239
      • Tel-Aviv Sourasky Medical Center
• Italy
  • Ancona, Italy, 60126
    • Local Institution - 250
  • Bologna, Italy, 40138
    • Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
  • Brescia, Italy, 25123
    • Asst Spedali Civili Di Brescia
  • Catania, Italy, 95123
    • Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele - Ospedale Gaspare Rodolico
  • Firenze, Italy, 50134
    • Azienda Ospedaliera Universitaria Careggi
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Napoli Campania, Italy, 80131
    • Local Institution - 246
  • Novara, Italy, 28100
    • A.O.U. Maggiore della Carit
  • Padova, Italy, 35128
    • Azienda Ospedaliera Di Padova
  • Pisa, Italy, 56100
    • Local Institution - 248
  • Reggio Di Calabria, Italy, 89124
    • Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli
  • Roma, Italy, 00100
    • Azienda Policlinico Universitario Umberto I
  • Roma, Italy, 144
    • Local Institution - 249
  • Roma, Italy, 00189
    • Local Institution - 251
  • Terni, Italy, 05100
    • Local Institution - 245
  • Torino, Italy, 10126
    • Local Institution - 259
  • Varese, Italy, 21100
    • Universita degli Studi dell'Insubria - Ospedale di Circolo e Fondazione Macchi - Varese
  • Verona, Italy, 37134
    • Centro Ricerche Cliniche di Verona s.r.l.
  • Fc
    • Meldola (fc), Fc, Italy, 47014
      • IRCCS - Istituto Romagnolo per lo Studio Dei Tumori "Dino Amadori" (IRST)
• Japan
  • Aomori, Japan, 030-8553
    • Aomori Prefectural Central Hospital
  • Bunkyo-ku, Japan, 113-8677
    • Local Institution - 713
  • Isehara City, Kanagawa, Japan, 259-1193
    • Tokai University Hospital
  • Kamakura, Japan, 247-8533
    • Local Institution - 717
  • Kamogawa, Japan, 296-8602
    • Kameda General Hospital
  • Maebashi, Japan, 371-8511
    • Local Institution - 706
  • Miyazaki, Japan, 889-1692
    • University of Miyazaki Hospital
  • Ogaki, Japan, 503-8502
    • Ogaki Municipal Hospital
  • Osaka, Japan, 545-8586
    • Osaka Metropolitan University Hospital
  • Sapporo, Japan, 003-0006
    • Local Institution - 708
  • Shinagawa-ku, Tokyo, Japan, 141-8625
    • NTT Medical Center Tokyo
  • Shinjuku City, Japan, 162-8666
    • Tokyo Women's Medical University Hospital
  • Shinjyuku-ku, Japan, 160-0023
    • Local Institution - 710
  • Toyohashi, Japan, 441-8570
    • Toyohashi Municipal Hospital
  • Nagasaki
    • Nagasaki-shi, Nagasaki, Japan, 8528511
      • The Japanese Red Cross Nagasaki Genbaku Hospital
  • Osaka
    • Osakasayama, Osaka, Japan, 5898511
      • Kindai University Hospital- Osakasayama Campus
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8431
      • Local Institution - 701
  • Yamanashi
    • Chuo, Yamanashi, Japan, 409-3898
      • Local Institution - 709
• Korea, Republic of
  • Daegu, Korea, Republic of, 700-721
    • Kyungpook National University Hospital
  • Hwasun-Gun, Korea, Republic of, 58128
    • Chonnam National University Hwasun Hospital
  • Seongnam-si, Korea, Republic of, 13620
    • Local Institution - 643
  • Seoul, Korea, Republic of, 3080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 5505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea Seoul - Saint Mary's Hospital
  • Seoul, Korea, Republic of, 06351
    • Local Institution - 647
• Lebanon
  • Badaro Beirut, Lebanon, 11072280
    • Local Institution - 550
  • Beirut, Lebanon, 11-3288
    • Local Institution - 552
  • South
    • Saida, South, Lebanon, 652
      • Local Institution - 551
• Poland
  • Gdansk, Poland, 80-952
    • Local Institution - 436
  • Krakow, Poland, 31-501
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Szpital Uniwersytecki w Krakowie
  • Lodz, Poland, 93-510
    • Wojewodzki Szpital Specjalistyczny im. M. Kopernika w Lodzi
  • Poznan, Poland, 61-696
    • Local Institution - 433
  • Walbrzych, Poland, 58-309
    • Specjalistyczny Szpital im. dra Alfreda Sokolowskiego
  • Wroclaw, Poland, 50367
    • Local Institution - 435
• Romania
  • Brasov, Romania, 500052
    • Onco Card Srl
  • Bucharest, Romania, 022328
    • Local Institution - 391
  • Cluj-Napoca, Romania, 400015
    • Prof. Dr. I. Chiricuta Institute of Oncology
  • Dolj
    • Craiova, Dolj, Romania, 200143
      • Local Institution - 395
• Russian Federation
  • Moscow, Russian Federation, 125284
    • Local Institution - 500
  • St Petersburg, Russian Federation, 197341
    • Local Institution - 502
  • St. Petersburg, Russian Federation, 197022
    • Local Institution - 503
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Barcelona, Spain, 08916
    • Hospital Universitari Germans Trias i Pujol ICO Badalona
  • Granada, Spain, 18014
    • Local Institution - 208
  • Las Palmas de Gran Canaria, Spain, 35012
    • Hospital Universitario de Gran Canaria Dr. Negrin
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Palma de Mallorca, Spain, 7120
    • Local Institution - 202
  • Salamanca, Spain, 37007
    • Universitario de Salamanca - Hospital Clinico
  • Santiago de Compostela, Spain, 15706
    • Complejo Hospitalario Universitario de Santiago
  • Seville, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Heart of England Nhs Foundation Trust
  • Boston, United Kingdom, PE21 9QS
    • United Lincolnshire Hospitals NHS Trust
  • Oxford, United Kingdom, OX3 7LI
    • Churchhill Hospital
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
      • Nottingham City Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Local Institution - 110
  • Florida
    • Orlando, Florida, United States, 32804
      • Local Institution - 135
    • Plantation, Florida, United States, 33322
      • Local Institution - 133
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Local Institution - 112
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0293
      • Local Institution - 124
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Local Institution - 114
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Local Institution - 108
  • New Jersey
    • Hackensack, New Jersey, United States, 07601-2191
      • John Theurer Cancer Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburg Medical Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • Allegheny Health Network
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Local Institution - 130
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas - MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Local Institution - 119

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Subjects must satisfy the following criteria to be randomized in the study:

Inclusion Criteria

- Subject is ≥18 years of age at the time of signing the ICF.

• Subject has a diagnosis of PMF according to the 2016 World Health Organization (WHO) criteria or diagnosis of post-ET or post-PV MF according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report.

• Subject is requiring RBC transfusions as defined as:.

  i) Average RBC-transfusion frequency: 4 to 12 RBC units/12 weeks immediately up to randomization. There must be no interval > 6 weeks (42 days) without ≥ 1 RBC transfusion.

ii) RBC transfusions are scored in determining eligibility when given for treatment of:.

A. Symptomatic (ie, fatigue or shortness of breath) anemia with a pretransfusion Hgb ≤ 9.5 g/dL or.

B. Asymptomatic anemia with a pretransfusion Hgb ≤ 7 g/dL.

iii) RBC transfusions given for worsening of anemia due to bleeding or infections are not scored in determining eligibility.

- Subjects on continuous (eg, absent of dose interruptions lasting ≥ 2 consecutive weeks) JAK2 inhibitor therapy as approved in the country of the study site for the treatment for MPN-associated MF as part of their standard-of-care therapy for at least 32 weeks, on stable daily dose for at least 16 weeks immediately up to the date of randomization and anticipated to be on a stable daily dose of that JAK2 inhibitor for at least 24 weeks after randomization.

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

• A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (eg, has had menses at any time in the preceding 24 consecutive months). Females of childbearing potential (FCBP)participating in the study must:.

  i) Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the study, and after end of IP. This applies even if the subject practices true abstinence* from heterosexual contact.

ii) Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception** without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) after discontinuation of study therapy.

- Male subjects must: Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential** while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy.

i) True abstinence is acceptable when it is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.].

ii) Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception: Oral, Intravaginal, Transdermal; Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, Injectable hormonal contraception, Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.

• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements including the use of the electronic patient reported outcomes device.

Exclusion Criteria

• The presence of any of the following will exclude a subject from randomization:.
• Subject with anemia from cause other than MPN-associated MForJAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration).

• Subject use of hydroxyurea, immunomodulatory compounds such as pomalidomide, thalidomide, ESAs, androgenic steroids or other drugs with potential effects on hematopoiesis ≤ 8 weeks immediately up to the date of randomization.

  i) Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 4 weeks immediately up to randomization.

ii) Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable dose for the 8 weeks immediately up to randomization.

- Subject with any of the following laboratory abnormalities at screening:.

i) Neutrophils: < 1 x 10^9/L.

ii) White blood count (WBC): > 100 x 10^9/L.

iii) Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not < 25 x 10^9/L or > 1000 x 10^9/L.

iv) Peripheral blood myeloblasts:> 5%.

v) Estimated glomerular filtration rate:< 30 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [MDRD] formula) or nephrotic subjects (eg, urine albumin-to-creatinine ratio > 3500 mg/g).

vi) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT):> 3.0 x upper limit of normal (ULN).

vii) Direct bilirubin: ≥ 2 x ULN.

A. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis).

• Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, that is not resolved at the time of randomization.

• Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for ≥ 3 years. However, subject with the following history/concurrent conditions is allowed:.

  i) Basal or squamous cell carcinoma of the skin.

ii) Carcinoma in situ of the cervix.

iii) Carcinoma in situ of the breast.

iv) Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system).

• Subject with prior hematopoietic cell transplant or subject anticipated to receive a hematopoietic cell transplant during the 24 weeks from the date of randomization. 7. Subject with stroke, myocardial infarction, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the date of randomization.
• Subject with major surgery within 2 months up to the date of randomization. Subject must have completely recovered from any previous surgery immediately up to the date of randomization.
• Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 6 months prior to the date of randomization.
• Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction < 35%.
• Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
• Subject with known human immunodeficiency virus (HIV), evidence of active Hepatitis B (HepB) as demonstrated by the presence of Hepatitis B surface antigen (HBsAg) and/or positive for Hepatitis B virus DNA (HBVDNA-positive), and/or evidence of active Hepatitis C (HepC) as demonstrated by a positive Hepatitis C virus RNA (HCV-RNA) test of sufficient sensitivity.
• Subject with prior therapy of luspatercept or sotatercept.
• Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product.
• Pregnant or breastfeeding females.
• Subject participation in any other clinical protocol or investigational trial that involves use of experimental therapy (including investigational agents) and/or therapeutic devices within 30 days or for investigational agents within five half-lives, whichever comes later, immediately up to the date of randomization.
• Subject with any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study or places the subject at unacceptable risk if he/she were to participate in the study. 18.Subject with any condition or concomitant medication that confounds the ability to interpret data from the study.
• Other protocol-defined Inclusion/Exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm: Luspatercept (ACE-536); Luspatercept will be given to participants via subcutaneous injection (administered on Day 1 of each 21-day treatment cycle)	Drug: ACE-536; Subcutaneous Injection; Other Names: Luspatercept; BMS-986346
Placebo Comparator: Control Arm: Placebo; Placebo starting dose with volume equivalent to experimental arm subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle)	Other: Placebo; Subcutaneous Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Red blood cell-transfusion independence (RBC-TI) ≥ 12 weeks (RBC-TI 12)	Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period starting within the first 24 weeks.	Up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Red blood cell-transfusion independence ≥ 16 weeks (RBC-TI 16)	Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period	Up to 24 weeks
Duration of Red blood cell-transfusion independence (RBC-TI 12)	Maximum duration of RBC-TI response	Up to end of treatment, approximately 3 years
Reduction of transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period	Proportion of subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period	Up to 24 weeks
Duration of reduction in transfusion burden	Maximum duration of when RBC-transfusion dependent subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12 week period	Up to end of treatment, approximately 3 years
Red blood cell-transfusion independence ≥ 12 weeks in the treatment period (RBC-TI 12/TP)	Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period	Up to end of treatment, approximately 3 years
Red blood cell-transfusion independence ≥ 16 weeks in the treatment period (RBC-TI 16/TP)	Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period	Up to end of treatment, approximately 3 years
Change in RBC transfusion burden	Mean change in transfusion burden (RBC units) from baseline	Up to 24 weeks
Cumulative duration of RBC-transfusion independence	Cumulative response duration for subjects achieving multiple episodes of RBC-TI 12	Up to end of treatment, approximately 3 years
Mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions	Proportion of subjects achieving a mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions	Up to end of treatment, approximately 3 years
Change in serum ferritin from baseline	Change in serum ferritin	Up to end of treatment, approximately 3 years
Incidence of Adverse Events (AEs)	Number of participants with adverse events	From screening up to 42 days post last dose
Transformation to blast phase: Number of subjects who transform into AML	AML = acute myeloid leukemia	Up to approximately 5 years
Frequency of Antidrug antibodies (ADA)	Will be collected for assessment of anti-drug antibodies (ADA) against Luspatercept in serum in all subjects	From randomization and up to including 48 weeks post first dose
Pharmacokinetics - Area Under the Concentration-Time Curve (AUC)	Measures of luspatercept exposure area under the curve	From randomization and up to including 48 weeks post first dose
Pharmacokinetics - Maximum plasma concentration of drug (Cmax)	Maximum plasma concentration of drug	From randomization and up to including 48 weeks post first dose

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2021
• Primary Completion (Actual): May 26, 2025
• Study Completion (Estimated): August 18, 2032

Study Registration Dates

• First Submitted: December 29, 2020
• First Submitted That Met QC Criteria: January 15, 2021
• First Posted (Actual): January 22, 2021

Study Record Updates

• Last Update Posted (Actual): July 10, 2025
• Last Update Submitted That Met QC Criteria: July 7, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Anemia; Myelofibrosis; Luspatercept; ACE-536; Myeloproliferative Neoplasm; JAK2; Red blood cell transfusion; Post-ET MF; Post-PV MF; Reblozyl
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Bone Marrow Diseases; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms; Myeloproliferative Disorders; Polycythemia Vera; Polycythemia; Primary Myelofibrosis; Hematinics; Luspatercept
• Other Study ID Numbers: ACE-536-MF-002; 2020-000607-36 (EudraCT Number); U1111-1260-9595 (Registry Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

• IPD Sharing Time Frame: See Plan Description
• IPD Sharing Access Criteria: See Plan Description
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No