A study to evaluate the benefit and safety of Luspatercept (ACE-536) in adults with myeloproliferative neoplasm-associated myelofibrosis on concomitant JAK2 inhibitor therapy and who require red blood cell transfusions

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celgene Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

22 Feb 2021 → ongoing

Decision date (initial)

2024-03-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Celgene Corporation

External identifiers

EU CT number

2023-507890-17-00

EudraCT number

2020-000607-36

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Others, Therapy, Efficacy

To evaluate the efficacy of luspatercept compared with placebo for the treatment of anemia in subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) with concomitant JAK2 inhibitor therapy and who require red blood cell transfusions.

Secondary objectives 1

1. - To evaluate additional efficacy parameters of luspatercept compared with placebo; - To evaluate the the safety of luspatercept compared to placebo in subjects with MPN-associated MF as measured by the frequency and severity of adverse events (AEs), serious adverse events (SAEs), antidrug antibodies (ADA), and transformation to blast phase; - To evaluate pharmacokinetics (PK) for luspatercept in MPN-associated MF.

Conditions and MedDRA coding

Anemia associated with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF)

Regulatory references

Scientific advice from competent authorities

EMA Regulatory Submissions Expediter Limited

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. 1. Subject is ≥18 years of age at the time of signing the informed consent form (ICF). 2. Subject has a diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria or diagnosis of postET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report. 3. Subject is requiring RBC transfusions as defined as: a. Average RBC-transfusion frequency: 4 to 12 RBC units/12 weeks immediately up to randomization. There must be no interval > 6 weeks (42 days) without ≥ 1 RBC transfusion. b. RBC transfusions are scored in determining eligibility when given for treatment of: - Symptomatic (ie, fatigue or shortness of breath) anemia with a pretransfusion Hgb ≤ 9.5 g/dL or- Asymptomatic anemia with a pretransfusion Hgb ≤ 7 g/dL c. RBC transfusions given for worsening of anemia due to bleeding or infections are not scored in determining eligibility. 4. Subjects on continuous (eg, absent of dose interruptions lasting ≥ 2 consecutive weeks) JAK2 inhibitor therapy as approved in the country of the study site for the treatment for MPN-associated MF as part of their standard-of-care therapy for at least 32 weeks, on stable daily dose for at least 16 weeks immediately up to the date of randomization and anticipated to be on a stable daily dose of that JAK2 inhibitor for at least 24 weeks after randomization. 5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.
2. 6. A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (eg, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must: a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the study, and after end of IP. This applies even if the subject practices true abstinence* from heterosexual contact. b. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) 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 half-life of IP based on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy.
3. 7. Male subjects must: Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential** while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy.

Exclusion criteria 3

1. 1. Subject with anemia from cause other than MPN-associated MF or JAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration). 2. Subject use of hydroxyurea, immunomodulatory compounds such as pomalidomide, thalidomide, ESAs, androgenic steroids or other drugs with potential effects on hematopoiesis ≤ 8 weeks immediately up to the date of randomization. a. Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 4 weeks immediately up to randomization. b. Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable dose for the 8 weeks immediately up to randomization.
2. 3. Subject with any of the following laboratory abnormalities at screening: a. Neutrophils: < 1 x 10^9/L b. White blood count (WBC): > 100 x 10^9/L c. Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not < 25 x 10^9/L or > 1000 x 10^9/L d. Peripheral blood myeloblasts: > 5% e. Estimated glomerular filtration rate: < 30 mL/min/1.73 m2 (via the 4variable modification of diet in renal disease [MDRD] formula) or nephrotic subjects (eg, urine albumin-tocreatinine ratio> 3500 mg/g) f. Aspartate aminotransferase (AST) or alanine aminotransferase: (ALT) > 3.0 x upper limit of normal (ULN) g. Direct bilirubin: ≥ 2 x ULN - Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis) 4. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, that is not resolved at the time of randomization.
3. 5. Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for ≥ 3 years. However, subject with the following history/concurrent conditions is allowed: a. Basal or squamous cell carcinoma of the skin b. Carcinoma in situ of the cervix c. Carcinoma in situ of the breast d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) 6. Subject with prior hematopoietic cell transplant or subject anticipated to receive a hematopoietic cell transplant during the 24 weeks from the date of randomization. 7. Subject with stroke, myocardial infarction, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the date of randomization.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The Primary end point of RBC-transfusion is defined as the proportion of subjects who become RBC transfusion free during any consecutive 12-week period

Secondary endpoints 2

1. The key secondary endpoint, defined as the proportion of subjects who become RBC-transfusion free over any consecutive 16-week period starting during the Blinded Core Treatment Period (the time from randomization up to and including Week 24) and referred to as RBC-TI 16...
2. .....will be tested in the same manner as the primary efficacy endpoint once superiority ofluspatercept on the primary endpoint is demonstrated.

Investigational products

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

Test 2

Placebo 1

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 8

Locations

12 EU/EEA countries · 58 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 105 files

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

Application history

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