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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)

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ClinicalTrials.gov Identifier: NCT04717414
Recruitment Status : Recruiting
First Posted : January 22, 2021
Last Update Posted : September 22, 2021
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Myeloproliferative Disorders Myelofibrosis Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Anemia Drug: ACE-536 Other: Placebo Phase 3

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 the study:

  • 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 309 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 25, 2021
Estimated Primary Completion Date : January 9, 2025
Estimated Study Completion Date : February 11, 2025


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 Name: Luspatercept

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




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


Secondary Outcome Measures :
  1. Red blood cell-transfusion independence ≥ 16 weeks (RBC-TI 16) [ Time Frame: Up to 24 weeks ]
    Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period

  2. Duration of Red blood cell-transfusion independence (RBC-TI 12) [ Time Frame: Up to end of treatment, approximately 3 years ]
    Maximum duration of RBC-TI response

  3. Reduction of transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period [ Time Frame: Up to 24 weeks ]
    Proportion of subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period

  4. Duration of reduction in transfusion burden [ Time Frame: Up to end of treatment, approximately 3 years ]
    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

  5. Red blood cell-transfusion independence ≥ 12 weeks in the treatment period (RBC-TI 12/TP) [ Time Frame: Up to end of treatment, approximately 3 years ]
    Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period

  6. Red blood cell-transfusion independence ≥ 16 weeks in the treatment period (RBC-TI 16/TP) [ Time Frame: Up to end of treatment, approximately 3 years ]
    Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period

  7. Change in RBC transfusion burden [ Time Frame: Up to 24 weeks ]
    Mean change in transfusion burden (RBC units) from baseline

  8. Cumulative duration of RBC-transfusion independence [ Time Frame: Up to end of treatment, approximately 3 years ]
    Cumulative response duration for subjects achieving multiple episodes of RBC-TI 12

  9. Mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions [ Time Frame: Up to end of treatment, approximately 3 years ]
    Proportion of subjects achieving a mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions

  10. Change in serum ferritin from baseline [ Time Frame: Up to end of treatment, approximately 3 years ]
    Change in serum ferritin

  11. Incidence of Adverse Events (AEs) [ Time Frame: From screening up to 42 days post last dose ]
    Number of participants with adverse events

  12. Transformation to blast phase: Number of subjects who transform into AML [ Time Frame: Up to approximately 5 years ]
    AML = acute myeloid leukemia

  13. Frequency of Antidrug antibodies (ADA) [ Time Frame: From randomization and up to including 48 weeks post first dose ]
    Will be collected for assessment of anti-drug antibodies (ADA) against Luspatercept in serum in all subjects

  14. Pharmacokinetics - Area Under the Concentration-Time Curve (AUC) [ Time Frame: From randomization and up to including 48 weeks post first dose ]
    Measures of luspatercept exposure area under the curve

  15. Pharmacokinetics - Maximum plasma concentration of drug (Cmax) [ Time Frame: From randomization and up to including 48 weeks post first dose ]
    Maximum plasma concentration of drug



Information from the National Library of Medicine

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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 at the time of signing the ICF.
  2. 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.
  3. Subject is requiring RBC transfusions as defined as:

    a. 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.

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

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

    • Asymptomatic anemia with a pretransfusion Hgb ≤ 7 g/dL c. RBC transfusions given for worsening of anemia due to bleeding or infections are not scored in determining eligibility.
  4. 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.
  5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
  6. 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:

    a. 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.

    b. 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.

  7. 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.

    * 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.]

    ** 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.

  8. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
  9. 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:

  1. 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).
  2. 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.

    1. 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.
    2. Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable dose for the 8 weeks immediately up to randomization.
  3. Subject with any of the following laboratory abnormalities at screening:

    1. Neutrophils: < 1 x 109/L
    2. White blood count (WBC): > 100 x 109/L
    3. Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not < 25 x 109/L or > 1000 x 109/L
    4. Peripheral blood myeloblasts:> 5%
    5. Estimated glomerular filtration rate:< 40 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)
    6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT):> 3.0 x upper limit of normal (ULN)
    7. Direct bilirubin: ≥ 2 x ULN

      • Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis)
  4. 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.
  5. 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:

    1. Basal or squamous cell carcinoma of the skin
    2. Carcinoma in situ of the cervix
    3. Carcinoma in situ of the breast
    4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
  6. 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.

8. 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.

9. 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.

10.Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction < 35%.

11.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).

12.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.

13.Subject with prior therapy of luspatercept or sotatercept. 14.Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product.

15.Pregnant or breastfeeding females. 16.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.

17.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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04717414


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

Locations
Show Show 154 study locations
Sponsors and Collaborators
Celgene
Investigators
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Study Director: Torsten Gerike, MD Bristol-Myers Squibb
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT04717414    
Other Study ID Numbers: ACE-536-MF-002
2020-000607-36 ( EudraCT Number )
U1111-1260-9595 ( Registry Identifier: WHO )
First Posted: January 22, 2021    Key Record Dates
Last Update Posted: September 22, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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/

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: See Plan Description
Access Criteria: See Plan Description
URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

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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
Myeloproliferative Neoplasm
Myelofibrosis
JAK2
Red blood cell transfusion
Post-ET MF
Post-PV MF
Reblozyl
Anemia
Additional relevant MeSH terms:
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Neoplasms
Polycythemia Vera
Primary Myelofibrosis
Myeloproliferative Disorders
Polycythemia
Hematologic Diseases
Bone Marrow Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Luspatercept
Hematinics