Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Subjects Who Require Regular RBC Transfusions Due to Beta (β)-Thalassemia.
Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Subjects Who Require Regular RBC Transfusions Due to Beta (β)-Thalassemia.
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.
This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in
 pediatric subjects who require regular red blood cell (RBC) transfusions due to β-thalassemia
 and to determine the recommended dose (RD) to be used in the planned confirmatory pediatric
 study.

 The primary endpoints are the determination of the RD and the development of a PK model that
 describes the PK exposure data of luspatercept and associated variability.

 The secondary endpoints include change in RBC transfusion burden, change in hemoglobin
 levels, safety, frequency of antidrug antibodies and its effect on safety and
 Exposure-response relationships for measures of activities and toxicity.

 The study will consist of the following periods:

 -  Screening/Run-in Period

 -  Treatment Period

 -  Posttreatment Follow-up Period

 -  Long-term Treatment and Follow-up Period

 Subject screening procedures will occur during the Screening/Run-in Period, within 12 weeks
 prior to the start of study treatment. Subjects who meet the study eligibility criteria will
 be enrolled into the Treatment Period.

 Patients enrolled into the study should have β-thalassaemia (including Hemoglobin
 E/β-thalassaemia) with ≥ 4 RBC transfusions in the 24 weeks prior to enrollment with no
 transfusion-free period ≥ 42 days during that period.

 Subjects in all planned dose escalation cohorts will receive luspatercept, administered as a
 subcutaneous (SC) injection, every 3 weeks (21 days) for up to 4 cycles (84 days) in the
 Treatment Period. Dose delay(s) and dose reduction(s) may be required for individual
 subjects.

 Each dose escalation cohort will consist of up to 6 subjects. Subjects will be treated at one
 of 2 dose levels, 0.75 mg/kg or 1.0 mg/kg, and enrollment will be sequential in descending
 order of age:

 -  Cohort 1: 12 to < 18 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 2: 12 to < 18 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 3: 6 to < 12 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 4: 6 to < 12 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 5: 2 to < 6 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 6: 2 to < 6 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 7: 6 months to < 2 years: Luspatercept 0.75 mg/kg, administered SC once every 21
 days (for up to 4 cycles)

 -  Cohort 8: 6 months to < 2 years: Luspatercept 1.0 mg/kg, administered SC once every 21
 days (for up to 4 cycles).

 The first dose of luspatercept should be administered at least 14 days after the last
 transfusion prior to enrollment. Subject enrollment via the Integrated Response Technology
 (IRT) system and study treatment administration should be on the same day (Cycle 1 Day 1),
 provided that the eligibility criteria are met. Otherwise, the subject will need to be
 rescreened.

 Once all 6 subjects in a cohort have completed the first cycle (Study Day 22), a Dose Review
 Team (DRT), consisting of the Celgene Medical Monitor, Celgene lead safety physician, Celgene
 biostatistician, other Celgene functional area representatives or designees, as appropriate,
 and all active site Investigators and/or designees (at sites with a subject who has received
 study drug), will review all 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 Common Toxicity
 Criteria for Adverse Events, version 5.0 (NCI-CTCAE v.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 recommendations to enroll the next cohort at the next planned dose level and/or
 proceed to the next lower age group will be based in part upon the following criteria:

 -  If a DLT occurs in ≤ 1 subject (out of 6) in a cohort within 21 days following the
 initial dose of luspatercept, the next planned dose level and/or next lower age group
 dose may proceed;

 -  If a DLT occurs in ≥ 2 subjects (out of 6) in a cohort within 21 days following the
 initial dose of luspatercept, the next planned dose level and/or the next lower age
 group should not proceed;

 -  If a hemoglobin increase of ≥ 2.0 g/dL (confirmed within 14 days after initial study
 treatment administration and not attributable to RBC transfusion) occurs in ≥ 2 subjects
 (out of 6) in a cohort, the decision to proceed to the next planned dose level and/or
 the next lower age group will need to be evaluated by the DRT.

 At least 12 subjects are planned to be enrolled with up to 12 subjects per age-group strata
 eligible for the Dose Determining Sets (DDS). With up to 4 age groups, a total of up to 48
 subjects are to be included in the DDS.

 This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in
 pediatric subjects who require regular red blood cell (RBC) transfusions due to β-thalassemia
 and to determine the recommended dose (RD) to be used in the planned confirmatory pediatric
 study.

 The primary endpoints are the determination of the RD and the development of a
 pharmacokinetic (PK) model that describes the PK exposure data of luspatercept and associated
 variability.

 The secondary endpoints include change in RBC transfusion burden, change in hemoglobin
 levels, safety, frequency of antidrug antibodies and its effect on safety and
 Exposure-response relationships for measures of activities and toxicity.

 The study will consist of the following periods:

 -  Screening/Run-in Period

 -  Treatment Period

 -  Posttreatment Follow-up Period

 -  Long-term Treatment and Follow-up Period

 Subject screening procedures will occur during the Screening/Run-in Period, within 12 weeks
 prior to the start of study treatment. Subjects who meet the study eligibility criteria will
 be enrolled into the Treatment Period.

 Patients enrolled into the study should have β-thalassaemia (including Hemoglobin
 E/β-thalassaemia) with ≥ 4 RBC transfusions in the 24 weeks prior to enrollment with no
 transfusion-free period ≥ 42 days during that period.

 Subjects in all planned dose escalation cohorts will receive luspatercept, administered as a
 subcutaneous (SC) injection, every 3 weeks (21 days) for up to 4 cycles (84 days) in the
 Treatment Period. Dose delay(s) and dose reduction(s) may be required for individual
 subjects.

 Each dose escalation cohort will consist of up to 6 subjects. Subjects will be treated at one
 of 2 dose levels, 0.75 mg/kg or 1.0 mg/kg, and enrollment will be sequential in descending
 order of age:

 -  Cohort 1: 12 to < 18 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 2: 12 to < 18 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 3: 6 to < 12 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 4: 6 to < 12 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 5: 2 to < 6 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 6: 2 to < 6 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days
 (for up to 4 cycles)

 -  Cohort 7: 6 months to < 2 years: Luspatercept 0.75 mg/kg, administered SC once every 21
 days (for up to 4 cycles)

 -  Cohort 8: 6 months to < 2 years: Luspatercept 1.0 mg/kg, administered SC once every 21
 days (for up to 4 cycles)

 The first dose of luspatercept should be administered at least 14 days after the last
 transfusion prior to enrollment. Subject enrollment via the Integrated Response Technology
 (IRT) system and study treatment administration should be on the same day (Cycle 1 Day 1),
 provided that the eligibility criteria are met. Otherwise, the subject will need to be
 rescreened.

 Once all 6 subjects in a cohort have completed the first cycle (Study Day 22), a Dose Review
 Team (DRT), consisting of the Celgene Medical Monitor, Celgene lead safety physician, Celgene
 biostatistician, other Celgene functional area representatives or designees, as appropriate,
 and all active site Investigators and/or designees (at sites with a subject who has received
 study drug), will review all 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 Common Toxicity
 Criteria for Adverse Events, version 5.0 (NCI-CTCAE v.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 recommendations to enroll the next cohort at the next planned dose level and/or
 proceed to the next lower age group will be based in part upon the following criteria:

 -  If a DLT occurs in ≤ 1 subject (out of 6) in a cohort within 21 days following the
 initial dose of luspatercept, the next planned dose level and/or next lower age group
 dose may proceed;

 -  If a DLT occurs in ≥ 2 subjects (out of 6) in a cohort within 21 days following the
 initial dose of luspatercept, the next planned dose level and/or the next lower age
 group should not proceed;

 -  If a hemoglobin increase of ≥ 2.0 g/dL (confirmed within 14 days after initial study
 treatment administration and not attributable to RBC transfusion) occurs in ≥ 2 subjects
 (out of 6) in a cohort, the decision to proceed to the next planned dose level and/or
 the next lower age group will need to be evaluated by the DRT.

 At least 12 subjects are planned to be enrolled with up to 12 subjects per age-group strata
 eligible for the Dose Determining Sets (DDS). With up to 4 age groups, a total of up to 48
 subjects are to be included in the DDS.

 To minimize safety risk to subjects, 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.

 Dose interruptions/delays and dose reductions may be used to manage toxicities. Subjects can
 receive study treatment for up to 4 cycles during the Treatment Period, until study treatment
 becomes intolerable, or the subject wishes to discontinue study treatment for any reason. The
 decision to discontinue a subject from study treatment, is the responsibility of the treating
 physician; however, prior to discontinuing a subject, it is recommended that the Investigator
 contact the Medical Monitor and forward appropriate supporting documents for review and
 discussion. Subjects are to undergo end-of-treatment evaluations when study treatment is
 discontinued. The reason for treatment discontinuation will be recorded in the electronic
 case report form (eCRF) pages and in the source document.

 During the Treatment Period, any subjects discontinued from study treatment will continue to
 be assessed in the Posttreatment Follow-up Period for AEs, concomitant medications,
 concomitant procedures, transfusions, hematologic improvement, and subsequent therapies.

 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 (EOT)
 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.
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.