A phase 2a study to evaluate the safety and pharmacokinetics of Luspatercept (ACE-536) in paediatric Participants who required regular red blood cell transfusions due to beta (ß) thalassemia

Phase 1

Conditions: Beta-Thalassemia
MedDRA version: 20.1Level: LLTClassification code 10054660Term: Thalassemia betaSystem Organ Class: 100000004850
Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Registration Number: EUCTR2019-000208-13-GR

Lead Sponsor: Celgene Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 54

Inclusion Criteria

1. Participants must be 6 years to < 18 years of age at the time of signing
the informed consent form (ICF)/informed assent form (IAF).
2. Participants (and when applicable, parent/legal representative) must
understand and voluntarily sign an ICF/IAF prior to conducting any
study-related assessments/procedures.
3. Participant (and when applicable, parent/legal representative) is willing
and able to adhere to the study visit schedule and other protocol
requirements.
4. Participants must have documented diagnosis of ß-thalassemia or HbE/ß-
thalassemia.
5. Participant is regularly transfused, defined as: = 4 RBC transfusion
events in the 24 weeks prior to enrollment with no transfusion-free
period = 42 days during that period.
6 Note: For the purpose of the study, transfusions administered over 2 or
3 consecutive days are considered as part of a single transfusion event.
Participants must have a history of regular transfusions for at least 2 years.
7. Participant has Karnofsky (age =16 years) or Lansky (age < 16 years)
performance status score = 50 at screening.
8. 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.
9. 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 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 FCCBP/FCBP, including those
who commit to complete abstinence*. Female children 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/FCBP must agree to ongoing pregnancy testing
during the course of the study, at the EOT visit and at 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.
10. 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 FCCBP/FCBP while participating in
the study, during dose interruptions and for at least 12 weeks
(approximately 5 tim

Exclusion Criteria

1.Participant has any significant medical condition, laboratory abnormality,
or psychiatric illness that would prevent the participant from participating in
the study.
2. 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.
3.Participant has any condition that confounds the ability to interpret data
from the study.
4. Participant has a diagnosis of Hemoglobin S/ß-thalassemia or alpha (a)-
thalassemia (eg, Hemoglobin H); ß-thalassemia combined with a-
thalassemia is allowed.
5.Participant has active hepatitis C (HCV) infection as demonstrated by a
positive HCV-ribonucleic acid (RNA) 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).
6.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.
7.Participant has received a live COVID-19 vaccine = 28 days prior to
screening.
8.Participant has deep vein thrombosis (DVT), stroke, or other
thromboembolic event(s) (except clogged indwelling catheter) requiring
medical intervention = 24 weeks prior to enrollment.
9. 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).
10. Participant has platelet count > 1000 x 109/L.
11. 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).
12.Participant has treatment with another investigational drug or device =
28 days prior to enrollment.
13. Participant has prior exposure to sotatercept (ACE-011) or luspatercept
(ACE-536).
14.Participant underwent or is scheduled for HSCT or gene therapy.
15.Participant has used an erythropoiesis-stimulating agent (ESA) = 24
weeks prior to enrollment.
16.Participant use of iron chelation therapy (ICT), if initiated = 8 weeks
prior to enrollment (allowed if initiated > 8 weeks before or during
treatment).
17. Participant use of hydroxyurea treatment = 24 weeks prior to
enrollment.
18.Participant is pregnant or breastfeeding female.
19.Participant has uncontrolled hypertension. Controlled hypertension for
this protocol is considered = Grade 1 according to NCI CTCAE version
5.0.
20.Participant has major organ damage, including:
a.Symptomatic splenomegaly
b.Liver disease with alanine aminotransferase (ALT)/aspartate
aminotransferase (AST) > 3X the upper limit of normal (ULN) for age
c.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
d.Lung disease, including pulmonary fibrosis or pulmonary hypertension
which are clinically

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objectives of the study are:<br>- To determine the recommended dose (RD) of luspatercept that is safe and tolerable in pediatric participants with transfusion-dependent (TD) ß-thalassemia<br>- To evaluate the pharmacokinetic (PK) profile of luspatercept in pediatric participants with TD ß-thalassemia;Secondary Objective: The secondary objectives are to evaluate:<br>• The Safety of luspatercept in pediatric participants<br>• The immunogenicity of luspatercept<br>• The mean change in RBC transfusion burden<br>• The mean change in hemoglobin levels<br>• The mean change in mean daily dose of iron chelation therapy (ICT)<br>• The mean change in serum ferritin;Primary end point(s): - Determination of the Recommended Dose<br>- PK parameters;Timepoint(s) of evaluation of this end point: - Cycle 1 Day 1 through Cycle 1 Day 22<br>- Cycle 1 Day 1 up to maximum 1 year post Cycle 1 Day 1 of Treatment<br>Period

Secondary Outcome Measures

Name	Time	Method

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