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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 04/16/2021.
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Efficacy and Safety Study of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions

Clinicaltrials.gov identifier NCT03682536

Recruitment Status Recruiting

First Posted September 24, 2018

Last update posted December 2, 2020

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study description
Study Description

Brief summary:

The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This is an interventional active-controlled, open-label, randomized Phase 3 study to compare the efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of anemia due to IPSS-R very low, low or intermediate risk MDS in ESA naïve subjects who require RBC transfusions. The study is divided into the Screening Period, a Treatment Period and a Post-Treatment Follow-up Period.

  • Condition or Disease:Myelodysplastic Syndromes
  • Intervention/Treatment: Drug: Luspatercept
    Drug: Epoetin alfa
  • Phase: Phase 3
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 epoetin alfa in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), are ESA naïve, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or epoetin alfa arm, followed by an open-label treatment period. In both treatment arms, best supportive care (BSC) may be used in combination with study treatment when clinically indicated per investigator. Best supportive care includes, but is not limited to, treatment with transfusions, antibiotic, antiviral and/or antifungal therapy, and nutritional support as needed. Best supportive care for this study excludes the use of ESAs outside of the study treatment. Patients should receive treatment up to a minimum of 24 weeks after which an MDS Disease assessment visit is scheduled to assess the response to treatment. Patients who are determined to be experiencing clinical benefit may continue treatment. Continued clinical benefit will be re-assessed every 24 weeks. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 350 participants
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alpha for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Due to Myelodysplastic Syndrome (MDS) ESA in Native Subjects Who Require Red Blood Cell Transfusions
  • Actual Study Start Date: January 2019
  • Estimated Primary Completion Date: November 2022
  • Estimated Study Completion Date: November 2022
Arms and interventions
Arm Intervention/treatment
Experimental: Experimental Arm: luspatercept (ACE-536)
1.0 mg/kg subcutaneous (SC) every 3 weeks (Q3W)		 Drug: Luspatercept
Luspatercept
Active Comparator: Control Arm: epoetin alfa
450 IU/kg subcutaneous (SC) weekly		 Drug: Epoetin alfa
Epoetin alfa
Outcome Measures
  • Primary Outcome Measures: 1. Red Blood Cell Transfusion Independence (RBCTI) for 24 weeks [ Time Frame: Randomization through Week 24 ]
    Proportion of subjects who are RBC transfusion free over the first 24 weeks from randomization
  • Secondary Outcome Measures: 1. Hematologic improvement - erythroid response (HI-E) per International Working Group (IWG) within 24 weeks [ Time Frame: Randomization through Week 24 ]
    Proportion of subjects achieving HI-E over any consecutive 56-day period
  • 2. Mean hemoglobin increase ≥ 1.5 g/dL [ Time Frame: Randomization through Week 24 ]
    Proportion of subjects achieving ≥ 1.5 g/dL mean increase in hemoglobin over the first 24 weeks from randomization compared to baseline in the absence of RBC transfusions
  • 3. Time to Hematologic improvement - erythroid response (HI-E) [ Time Frame: Randomization through Week 48 ]
    Time from first dose to first onset of achieving ≥ 1.5 g/dL increase in hemoglobin over any consecutive 56-day period in the absence of RBC transfusions
  • 4. Duration of HI-E [ Time Frame: Randomization through Week 48 ]
    Maximum duration of achieving ≥ 1.5 g/dL increase in hemoglobin for subjects who achieve mean hemoglobin increase ≥ 56 days in the absence of RBC transfusions
  • 5. Duration of Red blood cell transfusion independence (RBC-TI) ≥ 24 weeks [ Time Frame: Randomization through Week 48 ]
    Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 24 weeks
  • 6. RBC-TI for ≥ 84 days [ Time Frame: Randomization through Week 24 ]
    Proportion of subjects who are RBC transfusion free over a consecutive 84-day period
  • 7. Duration of RBC-TI ≥ 84 days [ Time Frame: Randomization through Week 48 ]
    Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 84 days
  • 8. Time to RBC-TI ≥ 84 days [ Time Frame: Randomization through Week 24 ]
    Time from randomization to first onset of transfusion independence ≥ 84 days
  • 9. Time to first Red blood cell (RBC) transfusion [ Time Frame: Randomization through Week 48 ]
    Time from randomization to first transfusion on treatment
  • 10. RBC transfusion burden on treatment [ Time Frame: Randomization through Week 24 ]
    Total number of RBC units transfused on treatment
  • 11. For subjects with RBC transfusion burden of ≥4 units/8 weeks at baseline: [ Time Frame: Randomization through Week 48 ]
    Mean change in total Packed red blood cells (pRBC) units transfused over a rolling 8-week period
  • 12. RBC-TI during Weeks 4-24 [ Time Frame: Week 4 through Week 24 ]
    Proportion of subjects who are RBC transfusion independent during Weeks 4-24
  • 13. RBC-TI for a consecutive 24-week period [ Time Frame: Randomization through Week 48 ]
    Proportion of subjects who are RBC transfusion free for a consecutive 24-week period in the first 48 weeks from Randomization
  • 14. The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) [ Time Frame: Screening through Week 48 ]
    Is a validated HRQoL measure applicable to subjects with any cancer diagnosis. It is composed of 30 items that address general physical symptoms, physical functioning, fatigue and malaise, and social and emotional functioning.
  • 15. The Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) questionnaire [ Time Frame: Screening through Week 48 ]
    Is a validated instrument specific in measuring HRQoL related anemia. The 47-item FACT-An scale measures cancer-related symptoms with 13 items that measure fatigue (the FACIT-Fatigue subscale) and an additional 7 items that measure items pertinent to anemia.
  • 16. Adverse Event (AE) [ Time Frame: Randomization through Week 48 ]
    Type, frequency, severity of AEs and relationship of AEs to luspatercept/epoetin alfa
  • 17. Pharmacokinetic - AUC [ Time Frame: Randomization through 1-year post first dose. ]
    Area under the concentration-time curve
  • 18. Pharmacokinetic - Cmax [ Time Frame: Randomization through 1-year post first dose. ]
    Maximum plasma concentration of drug
  • 19. Antidrug antibodies (ADA) [ Time Frame: Randomization through 1-year post first dose. ]
    Frequency of antidrug antibodies and effects on efficacy, safety or PK
  • 20. Progression to AML [ Time Frame: Randomization through at least 5 years post last dose ]
    Number and percentage of subjects progressing to AML
  • 21. Time to AML [ Time Frame: Randomization through at least 5 years post last dose ]
    Time between randomization and first diagnosis of AML
  • 22. Overall survival [ Time Frame: Randomization through at least 5 years post last dose; ]
    Time from date of randomization to death due to any cause
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
Criteria

Inclusion Criteria:

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

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

2. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.

3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.

4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that
meets IPSS-R classification of very low, low, or intermediate risk disease, and:

• < 5% blasts in bone marrow. 5. Subject has an endogenous serum erythropoietin (sEPO) level of 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC
transfusions administered for elective surgery, infections or bleeding events
will not qualify as a required transfusion for the purpose of meeting eligibility
criteria or stratification.

- The hemoglobin level after the last RBC transfusion prior to randomization must
be < 11.0 g/dL (centrally or locally analyzed). 7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. 8. Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must: - Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. - If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy. 9. Male subjects must: - Practice true abstinence (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) 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 following investigational product discontinuation, even if he has undergone a successful vasectomy. Exclusion Criteria: The presence of any of the following will exclude a subject from randomization (with the randomization date defined as the date in which the subject is randomized in IRT): 1. Subject with the any of the following prior treatments: - Erythropoiesis-stimulating agents (ESAs) - Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for treatment of febrile neutropenia - Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide] - Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from randomization, at the investigator's discretion. - Hypomethylating agents - Subjects may be randomized at the investigator's discretion contingent that the subject received no more than 2 doses of HMA. The last dose must be ≥ 8 weeks from the date of randomization. - Luspatercept (ACE-536) or sotatercept (ACE-011) - Immunosuppressive therapy for MDS - Hematopoietic cell transplant 2. Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification. 3. Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia (JMML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), MDS/MPN unclassifiable. 4. Subject with 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. Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate). • Iron deficiency to be determined by serum ferritin < 100 μg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron). 6. Subject with known history of diagnosis of AML. 7. Subject receiving any of the following treatment within 8 weeks prior to randomization: - Anticancer cytotoxic chemotherapeutic agent or treatment - Systemic 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) - Androgens, unless to treat hypogonadism - Hydroxyurea - Oral retinoids (except for topical retinoids) - Arsenic trioxide - Interferon and interleukins - Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug) 8. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment. 9. Subject with any of the following laboratory abnormalities: - Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L) - Platelet count < 50,000/μL (50 x 109/L) - Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [MDRD] formula) - Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) - Total bilirubin ≥ 2.0 x ULN. - Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome. 10. Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease 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) 11. Subject with major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization. 12. Subject with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis within 6 months prior to randomization Note: prior superficial thrombophlebitis is not an exclusion criterion. 13. New-onset seizures or poorly controlled seizures within 12 weeks prior to randomization. 14. Subject with the following cardiac conditions within 6 months prior to randomization: myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New York Heart Association (NYHA) Class III-IV heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator. Subjects with a known ejection fraction ˂ 35%, confirmed by a local echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan performed within 6 months prior to randomization. 15. 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). 16. Subject with known human immunodeficiency virus (HIV), known evidence of active infectious Hepatitis B, and/or known evidence of active Hepatitis C. 17. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in luspatercept (see Investigator's Brochure). 18. Subject with known hypersensitivity to the active substance or to any of the excipients in epoetin alfa. 19. Subjects with history of pure red cell aplasia (PRCA) and/or antibody against erythropoietin. 20. Pregnant or breastfeeding females. 21. Subject has 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. 22. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 23. Subject has any condition or receives concomitant medication that confounds the ability to interpret data from the study.

Contacts and Locations
Contacts

Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations
Show 205 Study Locations
Sponsors and Collaborators

Celgene

Acceleron Pharma, Inc.

Investigators

Study Director: Rodrigo Ito, MD Celgene

More Information
  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT03682536 History of Changes
  • Other Study ID Numbers: ACE-536-MDS-002, U1111-1218-1810, 2017-003190-34
  • First Posted: September 24, 2018 Key Record Dates
  • Last Update Posted: December 2, 2020
  • Last Verified: November 2020
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: Luspatercept
    ACE-536
    Anemia
    Myelodysplastic Syndromes     Blood Transfusion
    RBC Transfusion
    MDS
  • Additional relevant MeSH terms: Preleukemia
    Anemia     Syndrome
    Myelodysplastic Syndromes
= Our trial