Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Participants With Beta (β)-Thalassemia
- Registration Number
- NCT04143724
- Lead Sponsor
- Celgene
- Brief Summary
This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in pediatric participants with β-thalassemia.
The study will be conducted in 2 parts for both transfusion-dependent (TD) and non-transfusion-dependent (NTD) β-thalassemia participants: TD Part A will be in adolescent participants aged 12 to \<18 years with two dose escalation cohorts, followed by a dose expansion cohorts. NTD Part A will be conducted in the same age group participants as TD Part A with dose confirmation and expansion cohorts. After Part A TD participants have completed at least one year of treatment, all available safety data from Part A adolescent participants will be evaluated before initiating TD and NTD Part B in the age group from 6 to \<12 years old. Part B will consist of two dose escalation cohorts for TD and two dose escalation cohorts for NTD.
Upon completion of the Treatment Period, participants of any cohort who are benefiting from the study treatment, will be offered the opportunity to continue luspatercept treatment in the Long-term Treatment Period for up to 5 years from their first dose.
Participants who discontinue study treatment at any time will continue in the Posttreatment Follow-up Period for at least 5 years from their first dose of luspatercept, or 3 years from their last dose, whichever occurs later, or until they withdraw consent/assent, are lost to follow-up, or the End of Trial, whichever occurs first.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 99
Not provided
- Participant has a diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); β-thalassemia combined with α-thalassemia is allowed.
- Participant has of active hepatitis C (HCV) infection, as demonstrated by a positive HCF-ribonucleic acid (RNS) test of sufficient sensitivity, or active infectious hepatitis B (as demonstrated by the presence of hepatitis B surface antigen (HBsAG) and/or hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) positive, or known positive human immunodeficiency virus (HIV).
Note: Participants receiving antiviral therapies should have 2 negative HCV-RNA tests 3 months apart before ICF/IAF signature, ie, one test at the end of the antiviral therapy and the second test 3 months following the first test.
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Participant has deep vein thrombosis (DVT), stroke, or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24 weeks prior to enrollment.
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Participant has platelet count > 1000 x 109/L.
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Participant has treatment with another investigational drug or device ≤ 28 days prior to enrollment.
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Participant has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
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Participant underwent or is scheduled for HSCT or gene therapy.
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Participant use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior to enrollment (allowed if initiated > 8 weeks before or during treatment).
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Participant received treatment with hydroxyurea immunomodulatory drugs IMiDs (such as thalidomide), other fetal Hb (HbF) inducers or erythropoiesis-stimulating agents (ESAs) ≤ 12 weeks prior to enrollment for NTD participants and ≤ 24 weeks for TD participants.
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Participant is pregnant or breastfeeding female or plan to get pregnant during the study.
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Participant has uncontrolled hypertension. Controlled hypertension for this protocol is considered: blood pressure value corresponding to ≤ Grade 1 according to NCI CTCAE version 5.0 with or without pharmacological treatment.
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Participant has major organ damage, including:
- Symptomatic splenomegaly
- Liver disease with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3X the upper limit of normal (ULN) for age
- 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
- Lung disease, including pulmonary fibrosis or pulmonary hypertension of Grade ≥ 3 according to NCI-CTCAE version 5.0.
- Renal insufficiency defined as:
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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.
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Participant has proteinuria ≥ Grade 3 according to NCI CTCAE version 5.0 (which is equivalent to a urine protein/creatinine ratio > 215 mg/mmol of creatinine), or a urine albumin/creatinine ratio > 129 mg/mmol of creatinine.
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Participant use of high dose long-term therapy with systemic glucocorticoids ≤ 12 weeks prior to enrollment (physiologic replacement therapy for adrenal insufficiency is allowed). Low-dose long-term (defined as ≤ 0.2 mg/kg/day or ≤ 10 mg/day of prednisone equivalent), short treatment (eg, for prevention or treatment of transfusion reactions) inhaled, intranasal and topical corticosteroids are allowed.
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Participant has history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IP (refer to the IB).
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Participant use of cytotoxic agents, immunosuppressants ≤ 28 days prior to enrollment (ie, antithymocite globulin (ATG) or cyclosporine).
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Participant has history of malignancy with the exception of:
- Curatively resected nonmelanoma skin cancer.
- Curatively treated carcinoma in situ.
- Other solid tumor with no known active disease in the opinion of the Investigator.
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Participant who has extramedullary hematopoiesis (EMH) complications or requires treatment to control the growth of EMH masse(s) during the screening period.
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Participants with any medical or psychiatric condition that in the opinion of the investigator would put the participant at unacceptable risk of participating in the study or may impact interpretation of the study results.
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Participants who use herbs or food supplements (eg: Chinese traditional medicine), if, per investigator's judgment, likely to impact the safety and efficacy assessment, for 24 weeks before initiating the study treatment for TD participants, and 12 weeks for NTD participants.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1: TD Dose Escalation Cohort: 12 to < 18 years Luspatercept 0.75 mg/kg ACE-536 - Cohort 2: TD Dose Escalation Cohort: 12 to < 18 years: Luspatercept 1.0 mg/kg ACE-536 - Cohort 3: TD Dose Expansion Cohort: 12 to <18 years Luspatercept 1.0 mg/kg ACE-536 - Cohort 4: TD Dose Escalation Cohort: 6 to < 12 years Luspatercept 1.0 mg/kg ACE-536 - Cohort 5: TD Dose Escalation Cohort: 6 to <12 years Luspatercept 1.2 mg/kg ACE-536 - Cohort 6: NTD Dose Confirmation Cohort: 12 to < 18 years Luspatercept 1.0 mg/kg ACE-536 - Cohort 7: NTD Dose Expansion Cohort: NTD 12 to < 18 years ACE-536 - Cohort 8: NTD Dose Escalation Cohort: 6 to < 12 years Luspatercept 1.0 mg/kg ACE-536 - Cohort 9: NTD Dose Escalation Cohort: 6 to < 12 years Luspatercept 1.2 mg/kg ACE-536 -
- Primary Outcome Measures
Name Time Method Pharmacokinetics (PK) - CL/F Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year Apparent oral clearance
Pharmacokinetics (PK) - t1/2 Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year Half-life
Pharmacokinetics (PK) - Vd/F Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year Apparent volume of distribution
Determination of the Recommended Dose (RD Cycle 1 up to the day before Cycle 2 Day 1 or Study Day 22 if not receiving the second treatment cycle Determine the recommended dose of luspatercept that is safe and tolerable in pediatric participants with transfusion-dependent B-thalassemia or non-transfusion-dependent β-thalassemia
Pharmacokinetics - Cmax Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year Maximum serum concentration of drug
Pharmacokinetics - AUC Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year Area under the curve
- Secondary Outcome Measures
Name Time Method Mean change in hemoglobin levels for non-transfusion-dependent β-thalassemia participants 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years Change from baseline as continuous variable
Immunogenicity Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year Frequency of antidrug antibodies (ADA)
Mean change from baseline in serum ferritin 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years Change from baseline as continuous variable
Safety - Incidence of Adverse Events (AEs) From enrollment until at least 9 weeks after last dose of study treatment An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant 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 participant'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
Mean change in Red Blood Cell (RBC) Transfusion Burden for transfusion-dependent β-thalassemia participants 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years Change from baseline as continuous variable
Mean change from baseline in mean daily dose of iron chelation therapy (ICT) 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years Change from baseline as continuous variable
Trial Locations
- Locations (25)
West China Hospital - Sichuan University
🇨🇳Chengdu, Sichuan, China
Local Institution - 601
🇺🇸Los Angeles, California, United States
New York Presbyterian Hospital
🇺🇸New York, New York, United States
Nanfang Hospital, Southern Medical University
🇨🇳Guangzhou, Guangdong, China
Shenzhen Second People's Hospital
🇨🇳Shenzhen, Guangdong, China
Local Institution - 904
🇨🇳Nanning Shi, Guangxi, China
Sun Yat-sen Memorial Hospital, Sun Yat-Sen University
🇨🇳Guangzhou, China
Universitätsklinikum Essen
🇩🇪Essen, Germany
Universitatsklinikum Ulm
🇩🇪Ulm, Germany
General Children's Hospital "Agia Sophia"
🇬🇷Athens, Greece
Kamala Hospital and Research Center
🇮🇳Hyderabad, Andhra Pradesh, India
MCGM - Comprehensive Thalassemia Care, Pediatric Hematology-Oncology & BMT Centre, Borivali (E)
🇮🇳Mumbai, Maharashtra, India
Kingsway Hospitals
🇮🇳Sakri, Maharashtra, India
Post Graduate Institute of Child Health
🇮🇳Noida, Uttar Pradesh, India
Local Institution - 803
🇮🇳Kolkata, India
Christian Medical College & Hospital
🇮🇳Vellore, India
Ospedale Pediatrico Bambino Gesù IRCCS
🇮🇹Rome, Roma, Italy
Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite
🇮🇹Genoa, Italy
AOU dell'Universita degli Studi della Campania Luigi Vanvitelli
🇮🇹Napoli, Italy
Azienda Ospedaliero Universitaria S. Luigi Gonzaga
🇮🇹Orbassano, Italy
Local Institution - 700
🇱🇧Beirut, Lebanon
Chulalongkorn University Faculty of Medicine - King Chulalongkorn Memorial Hospital
🇹🇭Bangkok, Thailand
Siriraj Hospital Mahidol University
🇹🇭Bangkok, Thailand
Ramathibodi Hospital, Mahidol University
🇹🇭Phyathai, Thailand
Local Institution - 401
🇹🇷Izmir, Turkey