A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

NCT ID: NCT02631070

Last Updated: 2021-12-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 229 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-09
• Study Completion Date: 2020-11-26

Brief Summary

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.

Detailed Description

Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

Conditions

Myelodysplastic Syndromes

Keywords

Luspatercept; Transfusion dependent; Lower risk; Low risk; Myelodysplastic Syndromes; ESA refractory; ESA intolerant; ESA ineligible; ACE-536; Anemia; Ring Sideroblasts; Require Red Blood Cell Transfusions; MEDALIST; MDS; IPSS-R very low/IPSS-R low/IPSS-R intermediate

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Experimental Arm - Luspatercept (ACE-536)

Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks

Group Type: EXPERIMENTAL

Luspatercept

Intervention Type: DRUG

Control Arm: Placebo

Subcutaneous injection every 3 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Interventions

Luspatercept

Intervention Type: DRUG

Placebo

Intervention Type: OTHER

Other Intervention Names

ACE-536

Eligibility Criteria

Inclusion Criteria

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

1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).

2. Documented diagnosis of MDS according to World Health Organization (WHO)/French American British (FAB) classification that meets IPSS R classification of very low, low, or intermediate risk disease, and:

Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but < 15%) if SF3B1 mutation is present.

• < 5% blasts in bone marrow
• Peripheral blood white blood cell (WBC) count < 13,000/µL 3. Requires red blood cell RBC transfusions 4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 5. Subjects who are refractory/intolerant/ineligible to prior erythropoietin-stimulating agents (ESA) treatment, defined as:
• Refractory to prior - erythropoietin stimulating agents treatment: documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with granulocyte colony stimulating factor (G-CSF); ESA regimen must have been either recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent OR darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent
• Intolerant to prior ESA treatment: documentation of discontinuation of prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event
• ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs

Exclusion Criteria

The presence of any of the following will exclude a subject from enrollment:

1. Prior therapy with disease modifying agents for underlying MDS disease.

2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)

3. MDS associated with del 5q cytogenetic abnormality

4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.

5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding

• iron deficiency to be determined by serum ferritin less than or equal to 15 ug/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity less than or equal to 20%] or bone marrow aspirate stain for iron).

6. Prior allogeneic or autologous stem cell transplant

7. Known history of diagnosis of acute myeloid leukemia (AML)

8. Use of any of the following within 5 weeks prior to randomization:

• anticancer cytotoxic chemotherapeutic agent or treatment
• corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS
• iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization
• other RBC hematopoietic growth factors (eg, Interleukin-3)
• investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the half-life prior to randomization or within 5 weeks, whichever is longer is excluded.

9. Prior history of malignancies, other than MDS, unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:

• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)

10. Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

INDUSTRY

Sponsor Role: collaborator

Celgene

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rodrigo Ito, MD

Role: STUDY_DIRECTOR

Celgene

Locations

Stanford Cancer Center

Stanford, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Emory University Hospital

Atlanta, Georgia, United States

Ochsner Medical Institutions

New Orleans, Louisiana, United States

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

Columbia-Presbyterian Medical Center

New York, New York, United States

Montefiore Medical Center Albert Einstein Cancer Center

The Bronx, New York, United States

Gabrail Cancer Center

Canton, Ohio, United States

Cleveland Clinic Taussig Cancer Institute

Cleveland, Ohio, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Algemeen Ziekenhuis Klina

Brasschaat, , Belgium

AZ Sint-Jan AV Brugge

Bruges, , Belgium

UZ Brussels

Brussels, , Belgium

Grand Hopital de Charleroi

Charleroi, , Belgium

UZ Gent

Ghent, , Belgium

UZ Leuven

Leuven, , Belgium

Cliniques Universitaires UCL de Mont-Godine

Yvoir, , Belgium

Tom Baker Cancer Center

Calgary, Alberta, Canada

Juravinski Cancer Centre

Hamilton, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Princess Margaret Hospital

Toronto, Ontario, Canada

CHU d'Angers

Angers, , France

CHU Hotel

Grenoble, , France

CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang

Lille, , France

Institut Paoli Calmettes

Marseille, , France

CHU de Nice Archet I

Nice, , France

Hopital Saint Louis

Paris, , France

Hopital Haut Leveque

Pessac, , France

Centre hospitalier Lyon Sud Hematologie

Pierre-Bénite, , France

Hopital civil

Strasbourg, , France

Institut Universitaire du Cancer de Toulouse - Oncopole

Toulouse, , France

Hopital Bretonneau

Tours, , France

Universitatsklinikum Bonn

Bonn, , Germany

Universitatsklinikum Carl Gustav Carus an der TU Dresden

Dresden, , Germany

Universitätsklinikum Düsseldorf

Düsseldorf, , Germany

Marien Hospital

Düsseldorf, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Klinikum rechts der Isar der Technischen Universität München

München, , Germany

Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo

Allessandria, , Italy

Azienda Ospedaliero Universitaria Di Bologna Policlinico Sorsola Malpighi

Bologna, , Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

Azienda Sanitaria Locale Lecce

Lecce, , Italy

Fondazione IRCCS Policlinico San Matteo

Pavia, , Italy

Azienda Ospedaliera Bianchi Melacrino Morelli

Reggio Calabria, , Italy

Fondazione Policlinico Universitario A Gemelli

Roma, , Italy

Fondazione PTV Policlinico Tor Vergata

Roma, , Italy

VU Medisch Centrum

Amsterdam, , Netherlands

Universitair Medisch Centrum Groningen

Groningen, , Netherlands

Spaarne Ziekenhuis

Hoofddorp, , Netherlands

Hospital Universitario Cruces

Barakaldo, , Spain

Hospital Universitario Vall D hebron

Barcelona, , Spain

Instituto Catalan de Oncologia-Hospital Duran i Reynals

Barcelona, , Spain

Hospital General Universitario Gregorio Marañon

Madrid, , Spain

Hospital Universitario Central de Asturias

Oviedo, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Hospital Universitario La Fe

Valencia, , Spain

Sahlgrenska Universitetssjukhus

Gothenburg, , Sweden

Skanes Universitetssjukhus Lund

Lund, , Sweden

Karolinska University Hospital

Stockholm, , Sweden

Akademiska Sjukhuset

Uppsala, , Sweden

Cukurova University Medical Faculty Balcali Hospital

Adana, , Turkey (Türkiye)

Ankara University Medical Faculty Cebeci Hospital

Ankara, , Turkey (Türkiye)

Istanbul University Cerrahpasa Medical Faculty Hospital

Istanbul, , Turkey (Türkiye)

Ege Universitesi Tip Fakultesi Hastanesi

Izmir, , Turkey (Türkiye)

Aberdeen Royal Infirmary

Aberdeen, , United Kingdom

John Radcliffe Hospital

Headington, , United Kingdom

St James University Hospital

Leeds, , United Kingdom

Guys Hospital

London, , United Kingdom

Kings College Hospital

London, , United Kingdom

Kings Mill Hospital

Sutton in Ashfield, , United Kingdom

Countries

Russia; United States; Belgium; Canada; France; Germany; Italy; Netherlands; Spain; Sweden; Turkey (Türkiye); United Kingdom

References

Porter J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):361-370. doi: 10.1182/asheducation-2018.1.361.

Reference Type: BACKGROUND

PMID: 30504333 (View on PubMed)

Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.

Reference Type: BACKGROUND

PMID: 30617198 (View on PubMed)

Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Diez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Gotze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellstrom-Lindberg E, Zeidan AM, Ades L, Verma A, Savona MR, Laadem A, Benzohra A, Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020 Jan 9;382(2):140-151. doi: 10.1056/NEJMoa1908892.

Reference Type: RESULT

PMID: 31914241 (View on PubMed)

Komrokji RS. Luspatercept in Myelodysplastic Syndromes: Who and When? Hematol Oncol Clin North Am. 2020 Apr;34(2):393-400. doi: 10.1016/j.hoc.2019.10.004. Epub 2020 Jan 21.

Reference Type: RESULT

PMID: 32089218 (View on PubMed)

Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019 Feb 21;133(8):790-794. doi: 10.1182/blood-2018-11-876888. Epub 2019 Jan 2.

Reference Type: RESULT

PMID: 30602619 (View on PubMed)

Germing U, Fenaux P, Platzbecker U, Buckstein R, Santini V, Diez-Campelo M, Yucel A, Tang D, Fabre S, Zhang G, Zoffoli R, Ha X, Miteva D, Hughes C, Komrokji RS, Zeidan AM, Garcia-Manero G. Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study. Ann Hematol. 2023 Feb;102(2):311-321. doi: 10.1007/s00277-022-05071-8. Epub 2023 Jan 13.

Reference Type: DERIVED

PMID: 36635381 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-003454-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ACE-536-MDS-001

Identifier Type: -

Identifier Source: org_study_id