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

Study Overview
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Brief Summary
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This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in pediatric participants who require regular red blood cell transfusions due to β-thalassemia. The study will be conducted in 2 parts: Part A will be in adolescent participants aged 12 to <18 years with two dose escalation cohorts of 6 participants each, followed by a dose expansion cohort of 30 participants. Part B will begin after a review of the safety in participants completing at least one year of treatment in Part A and will be in participants aged 6 to <12 with two dose escalation cohorts of 6 participants each. 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 (Cycle 1 Day 1). 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 (Cycle 1 Day 1), 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
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This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in pediatric participants who require regular red blood cell (RBC) transfusions due to β-thalassemia and to determine the recommended dose (RD). The primary endpoints are the determination of the RD and PK parameters (including Cmax, AUC, t1/2, CL/F and Vd/F). The secondary endpoints include the safety of luspatercept in pediatric participants, the immunogenicity (frequency of antidrug antibodies) of luspatercept, mean change in RBC transfusion burden, mean change in hemoglobin levels, mean change from baseline in mean daily dose of iron chelation therapy (ICT), and mean change from baseline in serum ferritin. The study will consist of the following periods: Screening/Run-in Period Treatment Period Long-term Treatment Period Posttreatment Follow-up Period Participant screening procedures will occur during the Screening/Run-in Period, within 12 weeks prior to the start of study treatment. Participants who meet the study eligibility criteria will be enrolled into the Treatment Period. The study will be conducted in a staggered manner, in descending order of age, with 2 parts as described below. Part A Adolescent participants aged 12 to < 18 years: Luspatercept 0.75 will be enrolled as outlined below: Part A Dose Escalation Phase Part A Dose Escalation Phase will explore up to 2 dose levels of luspatercept, 0.75 mg/kg and 1.0 mg/kg, to evaluate the safety and tolerability of luspatercept in this age group and determine the RD to be used for Part A Expansion Phase: Cohort 1: 6 adolescent participants 12 to < 18 years of age receiving luspatercept 0.75 mg/kg, administered subcutaneously (SC) once every 21 days (for up to 4 cycles in the Treatment Period) Cohort 2: 6 adolescent participants 12 to < 18 years of age receiving luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles in the Treatment Period) Part A Expansion Phase • Cohort 3 - The Expansion Cohort: 30 adolescent participants (12 to < 18 years of age) receiving luspatercept at the RD for up to 12 months in the Treatment Period. Part B Children from 6 years to < 12 years of age will be enrolled into Part B as outlined below: Part B Dose Escalation Phase will explore 2 dose levels of luspatercept, 1.0 mg/kg and 1.2 mg/kg, to evaluate the safety and tolerability of luspatercept in this age group and determine the RD. Cohort 4: 6 participants (6 to < 12 years of age) receiving luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles in the Treatment Period) Cohort 5: 6 participants (6 to < 12 years of age) receiving luspatercept 1.2 mg/kg, administered SC once every 21 days (for up to 4 cycles in the Treatment Period) During the Treatment Period of both Part A Dose Escalation Phase and Part B Dose Escalation Phase, once all 6 participants in a dose escalation cohort have completed the first cycle (Study Day 22), the Dose Review Team (DRT), will review all available safety data, including dose-limiting toxicities (DLTs), adverse events (AEs), serious adverse events (SAEs), and laboratory results (including hematology and chemistry) reported during Cycle 1 of each dose level. A DLT, using the current active version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, is defined as any of the following toxicities at any dose level occurring within 21 days of the first administered dose: Treatment-related SAE of ≥ Grade 3 Treatment-related nonhematologic AE of ≥ Grade 3 Treatment-related hematologic AE of ≥ Grade 4 The DRT will make a recommendation as to whether or not to enroll the next cohort at the next planned dose level based in part upon the following criteria: If a DLT occurs in ≤ 1 participant (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level may proceed; If a DLT occurs in ≥ 2 participants (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level should not proceed; If a hemoglobin increase of ≥ 2.0 g/dL (confirmed by central lab after initial study treatment administration and not attributable to RBC transfusion) occurs in ≥ 2 participants (out of 6) in a cohort, the decision to proceed to the next planned dose level will need to be evaluated by the DRT. At least 6 participants eligible for the Dose Determining Set (DDS) are planned to be enrolled per dose escalation cohort with up to 2 cohorts per age group. With up to 2 age groups being considered, a total of up to 24 participants are to be included in the DDS. To minimize safety risk to participants, best supportive care will be available, including RBC transfusions, iron-chelating agents, use of antibiotic therapy, antiviral and antifungal therapy, and/or nutritional support as needed.

Official Title
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A Phase 2a Study to Evaluate the Safety and Pharmacokinetics of Luspatercept (ACE-536) in Pediatric Participants Who Require Regular Red Blood Cell Transfusions Due to Beta (β)-Thalassemia

Conditions
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Beta-Thalassemia

Intervention / Treatment
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* Drug: ACE-536
* Drug: ACE-536
* Drug: ACE-536
* Drug: ACE-536
* Drug: ACE-536


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must satisfy the following criteria to be enrolled into the study: Participant must be 6 years to < 18 years of age at the time of signing the informed consent form (ICF)/informed assent form (IAF). Participant (and when applicable, parent/legal representative) must understand and voluntarily sign an ICF/IAF prior to conducting any study-related assessments/procedures. Participant (and when applicable, parent/legal representative) is willing and able to adhere to the study visit schedule and other protocol requirements. Participant must have documented diagnosis of β-thalassemia or Hemoglobin/β-thalassemia. Participant is regularly transfused, defined as: ≥ 4 red blood cell 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. Participant must have a history of regular transfusions for at least 2 years. Participant has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 50 at screening. Female children of childbearing potential (FCCBP), females of childbearing potential (FCBP), and male participants 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. 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 (one of these tests should be performed by central laboratory). Female children of childbearing potential/ females of childbearing potential (FCBP)must agree to ongoing pregnancy testing during the course of the study at the End of Treatment (EOT) visit and at the 9-week Safety Follow-up visit. Female participants 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. Male participants, 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 participant. [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 participant from enrollment into the study: Participant has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study. Participant has any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study. Participant has any condition that confounds the ability to interpret data from the study. 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. Participant has severe infection ≤ 28 days prior to enrollment. Additionally, in the case of prior SARS-CoV-2 infection, symptoms must have completely resolved, and based on Investigator assessment in consultation with the Clinical Trial Physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment. Participant has received a live COVID-19 vaccine ≤ 28 days prior to screening. Participant has deep vein thrombosis (DVT), stroke, or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24 weeks prior to enrollment. Participant 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). Participant has platelet count > 1000 x 109/L. Participant 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). Participant has treatment with another investigational drug or device ≤ 28 days prior to enrollment. Participant has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536). Participant underwent or is scheduled for HSCT or gene therapy Participant has used an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to enrollment. Participant use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior to enrollment (allowed if initiated > 8 weeks before or during treatment). Participant use of hydroxyurea treatment ≤ 24 weeks prior to enrollment. Participant is pregnant or breastfeeding female. Participant has uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 5.0. 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 which are clinically significant 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 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. Participant 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. Participant has major surgery ≤ 12 weeks prior to enrollment (participants must have completely recovered from any previous surgery prior to enrollment). Participant has history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IP (refer to the IB). Participant use of cytotoxic agents, immunosuppressants ≤ 28 days prior to enrollment (ie, antithymocite globulin (ATG) or cyclosporine). Participant has history of malignancy with the exception of: Curatively resected nonmelanoma skin cancer. Curatively treated cervical carcinoma in situ. Other solid tumor with no known active disease in the opinion of the Investigator. Participant who has EMH complications or requires treatment to control the growth of EMH masse(s) during the screening period.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: 12 to < 18 years - Luspatercept 0.75 mg/kg<br>Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles) | Drug: ACE-536<br>* Up to 6 participants will start with luspatercept at 0.75mg/kg and the Dose Review Team (DRT) will evaluate all toxicities of each participant after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level<br>* Other names: BMS-986346;|
| Experimental: Cohort 2: 12 to < 18 years: Luspatercept 1.0 mg/kg,<br>Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles) | Drug: ACE-536<br>* Up to 6 participants will start with luspatercept at 1.0mg/kg and the Dose review team (DRT) will evaluate all toxicities of each participant after Cycle 1 and determine whether or not to enroll the next cohort (Expansion Cohort)<br>* Other names: BMS-986346;|
| Experimental: Cohort 3 (Expansion Cohort): 12 to <18 years<br>Luspatercept administered SC once every 21 days (for up to 12 months) | Drug: ACE-536<br>* Up to 30 participants will start with luspatercept (at the Recommended Dose (RD) determined by the Dose Review Team (DRT)). Overall safety data from all cohorts in part A (Cohorts 1, 2 & 3) will be assessed before Part B (Cohorts 4 & 5) can be initiated<br>* Other names: BMS-986346;|
| Experimental: Cohort 4: 6 to < 12 years: Luspatercept 1.0 mg/kg<br>Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles) | Drug: ACE-536<br>* Up to 6 participants will start with luspatercept at 1.0mg/kg and the Dose Review Team (DRT) will evaluate all toxicities of each participant after Cycle 1 and determine whether or not to enroll the next cohort at the next planned dose level<br>* Other names: BMS-986346;|
| Experimental: Cohort 5: 6 to <12 years: Luspatercept 1.2 mg/kg<br>Luspatercept 1.2 mg/kg, administered SC once every 21 days (for up to 4 cycles) | Drug: ACE-536<br>* Up to 6 participants will start with luspatercept at 1.2 mg/kg and the Dose Review Team (DRT) will evaluate all toxicities of each participant after Cycle 1.<br>* Other names: BMS-986346;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the Recommended Dose (RD | Determine the recommended dose of luspatercept that is safe and tolerable in pediatric participants with transfusion-dependent B-thalassemia | Cycle 1 Day 1 through Cycle 1 Day 22 (each Cycle is 21 days) | 
| Pharmacokinetics - Cmax | Maximum serum concentration of drug | Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year | 
| Pharmacokinetics - AUC | Area under the curve | Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year | 
| Pharmacokinetics (PK) - t1/2 | Half-life | Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year | 
| Pharmacokinetics (PK) - CL/F | Apparent oral clearance | Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year | 
| Pharmacokinetics (PK) - Vd/F | Apparent volume of distribution | Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in Red Blood Cell (RBC) Transfusion Burden | Change from baseline as continuous variable | 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years | 
| Mean change in hemoglobin levels | Change from baseline as continuous variable | 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years | 
| Immunogenicity | Frequency of antidrug antibodies (ADA) | Time from Cycle 1 Day 1 of Treatment Period up to a maximum of 1 year | 
| Mean change from baseline in mean daily dose of iron chelation therapy (ICT) | Change from baseline as continuous variable | 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years | 
| Mean change from baseline in serum ferritin | Change from baseline as continuous variable | 12 weeks prior to enrollment; Treatment Period and up to End of Treatment including Long-term Treatment Period - Up to 5 years | 
| Safety - Incidence of Adverse Events (AEs) | 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 | From enrollment until at least 9 weeks after last dose of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACE-536, Luspatercept, Pharmacokinetics, Beta-Thalassemia, Red Blood Cell Transfusion