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Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Subjects Who Require Regular RBC Transfusions Due to Beta (β)-Thalassemia.

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ClinicalTrials.gov Identifier: NCT04143724
Recruitment Status : Not yet recruiting
First Posted : October 29, 2019
Last Update Posted : October 29, 2019
Sponsor:
Collaborator:
Acceleron Pharma, Inc.
Information provided by (Responsible Party):
Celgene

Brief Summary:
This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in pediatric subjects who require regular RBC transfusions due to β-thalassemia. At least 12 subjects are planned to be enrolled per each of the 4 age-group strata at 2 different dose levels. Any subject benefiting from the study treatment (at the Investigator's discretion), at the completion of the Treatment Period, will be offered the opportunity to continue luspatercept and long-term follow-up in the Long-term Treatment and Follow-up Period. Subjects entering the Long-term Treatment and Follow-up Period will continue to receive luspatercept at the same dose level as during the Treatment Period for up to 5 years from their first dose (Cycle 1 Day 1) or when the drug is approved for pediatric patients (whichever comes first). Subjects who receive treatment for the full 5 years will then have an End of Treatment visit and then a Post End of Treatment visit (12 weeks from last dose). Any subject that discontinues treatment prior to 5 years from Cycle 1 Day 1 will be have an End of Treatment visit, a Post End of Treatment visit (12 weeks from last dose), and then will continue in Long-Term Posttreatment Follow-up until 5 years from Cycle 1 Day 1 or until they withdraw consent/assent, are lost to follow-up, or the End of Trial, whichever occurs first.

Condition or disease Intervention/treatment Phase
Beta-Thalassemia Drug: ACE-536 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2A Open-label Multicenter Study to Evaluate the Safety and Pharmacokinetics of Luspatercept in Pediatric Subjects Who Require Regular Red Blood Cell Transfusions Due to B-Thalassemia
Estimated Study Start Date : November 1, 2019
Estimated Primary Completion Date : December 4, 2021
Estimated Study Completion Date : September 2, 2026


Arm Intervention/treatment
Experimental: Cohort 1: 12 to < 18 years - Luspatercept 0.75 mg/kg
Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 0.75mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept

Experimental: Cohort 2: 12 to < 18 years: Luspatercept 1.0 mg/kg,
Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 1.0mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept

Experimental: Cohort 3: 6 to < 12 years: Luspatercept 0.75 mg/kg
Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 0.75mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept

Experimental: Cohort 4: 6 to < 12 years: Luspatercept 1.0 mg/kg
Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 1.0mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept

Experimental: Cohort 5: 2 to < 6 years: Luspatercept 0.75 mg/kg
Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 0.75mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept

Experimental: Cohort 6: 2 to < 6 years: Luspatercept 1.0 mg/kg
Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 1.0mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept

Experimental: Cohort 7: 6 months to < 2 years: Luspatercept 0.75 mg/kg
Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 0.75mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept

Experimental: Cohort 8: 6 months to < 2 years: Luspatercept 1.0 mg/kg
Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)
Drug: ACE-536
Subjects will start with luspatercept at 1.0mg/kg and the Dose review team (DRT) will evaluate all toxicities of each subject after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level and/or next lower age group
Other Name: Luspatercept




Primary Outcome Measures :
  1. Determination of the Recommended Dose [ Time Frame: At the end of Cycle 1 (each Cycle is 21 days) ]
    Determine the recommended dose of luspatercept that is safe and tolerable in pediatric subjects with transfusion-dependent B-thalassemia.

  2. Pharmacokinetics - Cmax [ Time Frame: Up to Day 148 (+/-) 7 days ]
    Maximum plasma concentration of drug

  3. Pharmacokinetics - AUC [ Time Frame: Up to Day 148 (+/-) 7 days ]
    Area under the plasma concentration-time curve from time zero extrapolated to infinity


Secondary Outcome Measures :
  1. To evaluate the change in RBC transfusion burden [ Time Frame: Up to 15 weeks (Up to 12 weeks for the Treatment Period plus 3 weeks post last dose (End of Treatment), thus a total of 15 weeks) ]
    Change from baseline as continuous variable

  2. To evaluate the change in hemoglobin levels over the course of the study [ Time Frame: Up to 15 weeks (Up to 12 weeks for the Treatment Period plus 3 weeks post last dose (End of Treatment), thus a total of 15 weeks) ]
    Change from baseline as continuous variable

  3. Safety Adverse Events (AEs) [ Time Frame: up to 5 years ]
    Frequency/severity and seriousness of AEs, defined as any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.

  4. Frequency of antidrug antibodies and its effect on safety [ Time Frame: up to 2 years ]
    ADA measurements; key AEs and safety endpoints by ADA results (positive versus negative)

  5. Exposure-response relationships for measures of activities and toxicity [ Time Frame: Up to 15 weeks (Up to 12 weeks for the Treatment Period plus 3 weeks post last dose (End of Treatment), thus a total of 15 weeks) ]
    Exposure-response assessed by the time the subject is exposed to treatment to the change in response (e.g. either transfusion, Hb or AE).



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

  1. Subject must be 6 months to < 18 years of age at the time of signing the informed consent form (ICF)/informed assent form (IAF).
  2. Subject (and when applicable, parent/legal representative) must understand and voluntarily sign an ICF/IAF prior to conducting any study-related assessments/procedures.
  3. Subject (and when applicable, parent/legal representative) is willing and able to adhere to the study visit schedule and other protocol requirements.
  4. Subject must have documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia.
  5. Subject is regularly transfused, defined as: ≥ 4 RBC transfusions in the 24 weeks prior to enrollment with no transfusion-free period ≥ 42 days during that period.

    Note: For the purpose of the study, transfusions administered over 2 or 3 consecutive days are considered as part of a single transfusion event.

  6. Subject has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 50 at screening.
  7. Female children of childbearing potential (FCCBP), females of childbearing potential (FCBP), and male subjects that have reached puberty (and when applicable, parent/legal representative) must agree to undergo physician-approved reproductive education and discuss the side effects of the study therapy on reproduction.
  8. Female children of childbearing potential, defined as females who have achieved menarche and/or breast development in Tanner Stage 2 or greater and have not undergone a hysterectomy or bilateral oophorectomy and females of childbearing potential (FCBP)defined as a sexually mature woman who has achieved menarche at some point, has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) must meet the following conditions below (Note: Secondary amenorrhea from any cause does not rule out childbearing potential):

    • Medically supervised serum pregnancy tests with a sensitivity of at least 25 mIU/mL must be conducted in Female children of childbearing potential (FCCBP)/ females of childbearing potential (FCBP), including those who commit to complete abstinence. Female children of childbearing potential/ females of childbearing potential (FCBP)must have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. Female children of childbearing potential/ females of childbearing potential (FCBP)must agree to ongoing pregnancy testing during the course of the study, after the end of study treatment, and end of the study.
    • Female subjects must, as appropriate to age and at the discretion of the site Investigator, either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis) 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 t1/2 of luspatercept based on multiple-dose PK data) after discontinuation of study therapy.
  9. Male subjects, as appropriate to age and the discretion of the study physician:

    • Must practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a synthetic or latex condom during sexual contact with a pregnant female or a Female children of childbearing potential (FCCBP)/FCBP while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy

      • True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 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 progesterone/progestin containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen/progestin 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.

Exclusion Criteria:

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

  1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
  2. 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.
  3. Subject has any condition that confounds the ability to interpret data from the study.
  4. Subject has a diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); β-thalassemia combined with α-thalassemia is allowed.
  5. Subject has evidence of active hepatitis C (HCV) infection, or active infectious hepatitis B (HBV), or known positive human immunodeficiency virus (HIV).
  6. Subject has deep vein thrombosis (DVT), stroke, or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24 weeks prior to enrollment.
  7. Subject has chronic anticoagulant therapy ≤ 28 days prior to enrollment (Anticoagulant therapies used for prophylaxis for surgery or high risk procedures as well as low molecular weight [LMW] heparin for superficial vein thrombosis [SVT] and chronic aspirin are allowed).
  8. Subject has platelet count > 1000 x 109/L.
  9. Subject has poorly controlled diabetes mellitus within 24 weeks prior to enrollment as defined by short term (eg, hyperosmolar or ketoacidotic crisis) and/or history of diabetic cardiovascular complications (eg, stroke or myocardial infarction).
  10. Subject has treatment with another investigational drug or device ≤ 28 days prior to enrollment.
  11. Subject has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
  12. Subject has used an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to enrollment.
  13. Subject use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior to enrollment (allowed if initiated > 8 weeks before or during treatment).
  14. Subject use of hydroxyurea treatment ≤ 24 weeks prior to enrollment.
  15. Subject is pregnant or breastfeeding female.
  16. Subject has uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 5.0.
  17. Subject has major organ damage, including:

    1. Symptomatic splenomegaly
    2. Liver disease with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3X the upper limit of normal (ULN) for age
    3. Heart disease, heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of enrollment
    4. Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant
    5. Renal insufficiency defined as:

      • A serum creatinine based on age/gender based on threshold derived from Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control
  18. Subject has proteinuria ≥ Grade 3 according to NCI CTCAE version 5.0.
  19. Subject use of chronic systemic glucocorticoids ≤ 12 weeks prior to enrollment (physiologic replacement therapy for adrenal insufficiency is allowed). Single day glucocorticoid treatment (eg, for prevention or treatment of transfusion reactions) is allowed.
  20. Subject has major surgery ≤ 12 weeks prior to enrollment (subjects must have completely recovered from any previous surgery prior to enrollment).
  21. Subject has history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IP (see IB).
  22. Subject use of cytotoxic agents, immunosuppressants ≤ 28 days prior to enrollment (ie, antithymocite globulin (ATG) or cyclosporine).
  23. Subject has history of malignancy with the exception of:

    1. Curatively resected nonmelanoma skin cancer.
    2. Curatively treated cervical carcinoma in situ.
    3. Other solid tumor with no known active disease in the opinion of the Investigator.

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): NCT04143724


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

Locations
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United States, California
Children's Hospital of Los Angeles Not yet recruiting
Los Angeles, California, United States, 90027
Germany
Universitatsklinikum Ulm Not yet recruiting
Ulm, Germany, 89081
Greece
General Children's Hospital "Agia Sophia" Not yet recruiting
Athens, Greece, 115 27
Italy
Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite Not yet recruiting
Genoa, Italy, 16128
Azienda Ospedaliera Universitaria "Federico II" Not yet recruiting
Napoli, Italy, 80131
Azienda Ospedaliero Universitaria S. Luigi Gonzaga Not yet recruiting
Orbassano, Italy, 10043
Thailand
Siriraj Hospital Mahidol University Not yet recruiting
Bangkok, Thailand, 10700
Turkey
Ege Universitesi Tip Fakultesi Hastanesi Not yet recruiting
Izmir, Turkey, 35100
Sponsors and Collaborators
Celgene
Acceleron Pharma, Inc.
Investigators
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Study Director: Bouchra Benettaib, MD Celgene Corporation

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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT04143724     History of Changes
Other Study ID Numbers: ACE-536-B-THAL-004
U1111-1241-4168 ( Other Identifier: WHO )
2019-000208-13 ( EudraCT Number )
First Posted: October 29, 2019    Key Record Dates
Last Update Posted: October 29, 2019
Last Verified: October 2019
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:
ACE-536
Luspatercept
Pharmacokinetics
Beta-Thalassemia
Red Blood Cell Transfusion
Additional relevant MeSH terms:
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Thalassemia
beta-Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Immunoglobulin Fc Fragments
Immunologic Factors
Physiological Effects of Drugs