Phase 2a Study of Luspatercept in Pediatric Participants With Beta (β)-Thalassemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celgene Corp.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

15 Oct 2019 → ongoing

Decision date (initial)

2023-07-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Celgene Corporation

External identifiers

EU CT number

2022-502499-22-00

EudraCT number

2019-000208-13

WHO UTN

U1111-1241-4168

ClinicalTrials.gov

NCT04143724

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

To determine the recommended dose (RD) of luspatercept that is safe and tolerable in pediatric participants with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia.
To evaluate the pharmacokinetics (PK) of luspatercept in pediatric participants with TD or NTD β-thalassemia.

Secondary objectives 2

1. To evaluate For TD and NTD β-thalassemia Participants: Safety of luspatercept in pediatric participants. The immunogenicity of luspatercept. The mean change in mean daily dose of iron chelation therapy (ICT). The mean change in serum ferritin.
2. For TD β-thalassemia Participants: •The mean change in red blood cell (RBC) transfusion burden For NTD β-thalassemia Participants: •The mean change in hemoglobin levels

Conditions and MedDRA coding

Beta (β) Thalassemia

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-343642-PIP02-10

Plan to share IPD

Yes

IPD plan description

BMS will provide access to individual anonymized participant data upon request from qualified researchers, and subject to certain criteria. Additional information regarding Bristol Myer Squibb's data sharing policy and process can be found at: https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Participants must satisfy the following criteria to be enrolled into the study: 1) Participant must be 6 years to < 18 years of age the time of signing the informed consent form (ICF)/informed assent form (IAF).
2. 2. Participant (and when applicable, parent/legal representative) must understand and voluntarily sign an ICF/IAF prior to conducting any study-related assessments/procedures.
3. 3. Participant (and when applicable, parent/legal representative) is willing and able to adhere to the study visit schedule and other protocol requirements.
4. 4. Participant must have documented diagnosis of β-thalassemia or HbE/β-thalassemia.
5. 5. Transfusion dependence: a) TD participant i) 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. 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. b) NTD participant (ex-US sites only) i) Participant must have received < 4 RBC transfusion events in the 24 weeks prior to enrollment. ii) Participant must not be on a regular transfusion program and must be RBC transfusion-free for at least 8 weeks prior to enrollment. iii) Participant must have mean baseline hemoglobin ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to enrollment; hemoglobin values within 21 days post-transfusion will be excluded.
6. 6. Participant has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 50 at screening
7. 7. Female children of childbearing potential (FCCBP), individuals of childbearing potential (IOCBP), and male (as assigned at birth) 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.
8. 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 IOCBP 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/IOCBP, including those who commit to complete abstinence*. Female children of childbearing potential/IOCBP 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/IOCBP must agree to ongoing pregnancy testing during the course of the study at the 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.
9. 9. Male (as assigned at birth) 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/IOCBP 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.

Exclusion criteria 29

1. 1. Not applicable as per Protocol Amendment 4.
2. 18. Participant is pregnant or breastfeeding female or plan to get pregnant during the study.
3. 19. 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.
4. 10. Participant has platelet count > 1000 x 109/L.
5. 20. Participant has major organ damage, including: a) Symptomatic splenomegaly b) Liver disease with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3× 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 of Grade ≥ 3 according to NCI-CTCAE version 5.0. e) Renal insufficiency
6. 21. 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.
7. 22. Participant use high dose long-term therapy with systemic glucocorticoids (defined as > 0.2 mg/kg/day or > 10 mg/day of prednisone equivalent for > 14 days) ≤ 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 (≤ 14 days), single doses of systemic glucocorticoids (eg, for prevention or treatment of transfusion reactions), inhaled, intranasal and topical corticosteroids are allowed.
8. 2. Not applicable as per Protocol Amendment 4.
9. 3. Not applicable as per Protocol Amendment 4.
10. 4. Participant has a diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); βthalassemia combined with α-thalassemia is allowed
11. 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). 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.
12. 9. Not applicable as per Protocol Amendment 4.
13. 6. Not applicable as per Protocol Amendment 4.
14. 7. Not applicable as per Protocol Amendment 4.
15. 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.
16. 23. Not applicable as per Protocol Amendment 4.
17. 24. Participant has history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IP (refer to the IB).
18. 25. Participant use of cytotoxic agents, immunosuppressants ≤ 28 days prior to enrollment (ie, antithymocite globulin [ATG] or cyclosporine).
19. 26. Participant has history of malignancy with the exception of: a) Curatively resected nonmelanoma skin cancer. b) Curatively treated carcinoma in situ. c) Other solid tumor with no known active disease in the opinion of the Investigator.
20. 27. Participant who has EMH complications or requires treatment to control the growth of EMH masse(s) during the screening period.
21. 28. Any medical or psychiatric condition (including active infections, recent surgery, sequelae of diseases or interventions, clinically significant laboratory abnormalities or concurrent treatment) 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.
22. 29. Use of 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.
23. 11. Not applicable as per Protocol Amendment 4.
24. 12. Participant has treatment with another investigational drug or device ≤ 28 days prior to enrollment.
25. 13. Participant has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
26. 14. Participant underwent or is scheduled for HSCT or gene therapy (candidates for HSCT or gene therapy with anticipated waiting period of ≥ 12 months are eligible).
27. 15. Not applicable as per Protocol Amendment 4.
28. 16. Participant use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior to enrollment (allowed if initiated > 8 weeks before or during treatment).
29. 17. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. To determine the recommended dose (RD) for TD and NTD β-thalassemia participants
2. To evaluate the pharmacokinetics (PK) for TD and NTD β-thalassemia participants

Secondary endpoints 6

1. • The safety for TD and NTD β-thalassemia participants including: Type,frequency, seriousness, and severity of AEs and relationship to luspatercept (per NCI CTCAE version 5.0)
2. • The immunogenicity in TD andNTD β-thalassemiaparticipants
3. • The mean change in RBC transfusion burden in TDβ-thalassemia participants
4. • The mean change in hemoglobin levels in NTD β-thalassemia participants
5. • The mean change in mean daily dose of iron chelation therapy (ICT) in TD and NTD β-thalassemia participants
6. • The mean change in serum ferritin in TD andNTD β-thalassemia participants

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Celgene Corp.

Sponsor organisation

Celgene Corp.

Address

Route 206 And Province Line Road

City

Princeton

Postcode

08543-4000

Country

United States

Scientific contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Public contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Third parties 7

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 72 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications