A Safety and Efficacy Study to Evaluate Luspatercept in Subjects With Myeloproliferative Neoplasm-associated Myelofibrosis Who Have Anemia With and Without Red Blood Cell-transfusion Dependence

NCT ID: NCT03194542

Last Updated: 2023-08-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 95 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-15
• Study Completion Date: 2022-07-18

Brief Summary

This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of luspatercept in subjects with MPN-associated myelofibrosis and anemia with and without RBC-transfusion dependence. The study is divided into a Screening Period, a Treatment Period (consisting of a Primary Phase, a Day 169 Disease Response Assessment, and an Extension Phase), followed by a Posttreatment Follow-up Period.

Detailed Description

Subjects satisfying the eligibility criteria will be assigned to 1 of the following cohorts (which are enrolling in parallel) based on their eligibility:

• Cohort 1 (subjects with anemia only that are not currently receiving RBC transfusions) - Cohort 2: (subjects that are RBC-transfusion dependent)
• Cohort 3A: (subjects on ruxolitinib as part of their standard of care therapy that have anemia only)
• Cohort 3B: (subjects on ruxolitinib as part of their standard of care therapy that are RBC-transfusion dependent) Overall, the study will enroll approximately 100 subjects worldwide.

Conditions

Primary Myelofibrosis; Anemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Luspatercept in subjects with MPN-associated myelofibrosis

Subjects across each of the cohorts (Cohort 1, Cohort 2, Cohort 3A, and Cohort 3B) will receive luspatercept.

Group Type: EXPERIMENTAL

Luspatercept

Intervention Type: DRUG

Luspatercept is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human active in receptor type IIB linked to the IgG1 Fc domain. Luspatercept, through a mechanism of action different from erythropoietin, works to correct ineffective erythropoiesis by promoting late-stage maturation of erythroblasts.

Interventions

Luspatercept

Luspatercept is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human active in receptor type IIB linked to the IgG1 Fc domain. Luspatercept, through a mechanism of action different from erythropoietin, works to correct ineffective erythropoiesis by promoting late-stage maturation of erythroblasts.

Intervention Type: DRUG

Other Intervention Names

ACE-536

Eligibility Criteria

Inclusion Criteria

Subjects must satisfy the following criteria to be enrolled in the study (with the enrollment date defined as the date in which the subject is assigned a cohort in Integrated Response Technology [IRT]) and receive their first dose of luspatercept:

1. Subject is ≥18 years of age at the time of signing the informed consent form (ICF).

2. Subject has Myeloproliferative neoplasm (MPN)-associated myelofibrosis (PMF, post- Post-polycythemia vera myelofibrosis (PV MF), and/or Post-essential thrombocythemia myelofibrosis (post-ET MF)) as confirmed from the most recent local bone marrow biopsy report according to the World Health Organization 2016 criteria.

3. Subject has anemia defined as:

1. Cohorts 1 and 3A

• Obtain ≥ 3 Hemoglobin (Hgb) levels of ≤ 9.5 g/dL recorded on ≥ 3 different days, including the day of dosing, in the 84-day period immediately up to the C1D1 date. There must be ≥ 14 days in between each Hgb measurement. No subjects with an interval ≥ 42 days between hemoglobin measurements will be enrolled.
• There must not be any Red blood cell (RBC) transfusions within the 84-day period immediately up to the C1D1 date.

2. Cohorts 2 and 3B

• Average RBC-transfusion frequency: 4 to 12 RBC units/84 days immediately up to the C1D1 date. There must be no interval > 56 days without ≥ 1 RBC-transfusion.
• Subjects must have a Hgb value of < 13 g/dL on C1D1 prior to luspatercept administration.
• Only RBC transfusions given when the Hgb ≤ 9.5 g/dL are scored in determining eligibility.

4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

5. Subject is not anticipated during the 6 months from the C1D1 date to receive a hematopoietic cell transplant.

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 (ie, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must:

1. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact.

2. 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 investigational product, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal halflife of luspatercept based on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy.

7. Male subjects must:

a. 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 luspatercept based on multiple-dose PK data) following investigational product discontinuation, even if he has undergone a successful vasectomy

8. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.

9. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria

The presence of any of the following will exclude a subject from enrollment (with the enrollment date defined as the date in which the subject is assigned a cohort in Integrated Response Technology (IRT)):

1. Subject use of hydroxyurea or other drugs with potential effects on hematopoiesis or ongoing adverse events from previous treatment ≤ 112 days immediately up to the enrollment date.

a. Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a stable or decreasing dose for ≥ 84 days immediately up to enrollment and is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 28 days immediately up to enrollment.

2. Cohort 1 and 2 only: subjects treated with Janus kinase 2 gene (JAK2) inhibitors ≤ 112 days immediately up to the enrollment date or if anticipated/substantial likelihood for subject to receive ruxolitinib within the first 168 days on the study.

3. Cohort 3 only: subjects not receiving ruxolitinib:

1. for at least 280 days (40 weeks) without interruptions exceeding 2 consecutive weeks

2. on a stable daily dose for at least 112 days (16 weeks) immediately up to the enrollment date as part of their standard-of-care therapy.

4. Subject use of ESAs or androgenic steroids ≤ 112 days immediately up to the enrollment date.

5. Initiation of iron chelation therapy (ICT) or change with ICT dose within ≤ 112 days up to the enrollment date.

6. Subject with anemia from iron deficiency, B12 and folate deficiencies, hemolytic anemia, infection, or bleeding.

7. Pregnant or breastfeeding females.

8. Subject with blood myeloblasts ≥ 5%.

9. Subject with major surgery within 8 weeks up to the enrollment date. Subject must have completely recovered from any previous surgery immediately up to the enrollment date.

10. Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for ≥ 5 years. However, subject with the following history/concurrent conditions is allowed:

• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)

11. Subject with prior therapy of luspatercept or sotatercept.

12. Subject participation in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices within 30 days immediately up to the enrollment date.

13. Subject with prior hematopoietic cell transplant.

14. Subject with any of the following laboratory abnormalities:

• Neutrophils < 1 x 109/L
• White blood count (WBC) > 100 x 109/L
• Platelets

• Cohorts 1 and 2: < 25 x 109/L
• Cohort 3A and 3B: < 50 x 109/L
• All Cohorts: > 1000 x 109/L
• Estimated glomerular filtration rate < 45 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [Modification of diet in renal disease (MDRD)] formula)
• Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN)
• 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 (ie, ineffective erythropoiesis)
• Uncontrolled hyperthyroidism or hypothyroidism

15. Subject with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the enrollment date.

16. Subject with diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mmHg measured during the Screening Period despite appropriate treatment.

17. Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction <35%.

18. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see luspatercept Investigator's Brochure (IB)).

19. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).

20. Subject with human immunodeficiency virus (HIV), evidence of active infectious Hepatitis B (HepB), and/or evidence of active Hepatitis C (HepC).

21. Subject with any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study.

22. Subject with any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

23. Subject with any condition or concomitant medication that confounds the ability to interpret data from the study.

24. Subject on anticoagulant therapy not under appropriate control or subject not on a stable dose of anticoagulant therapy for ≥ 8 weeks up to the enrollment date.

25. Subject on anagrelide within 28 days immediately up to the enrollment date.

26. Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in hemoglobin of ≥ 2g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 6 months prior to enrollment.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bristol-Myers Squibb

Role: STUDY_DIRECTOR

Bristol-Myers Squibb

Locations

Local Institution - 102

Phoenix, Arizona, United States

Mayo Clinic - Arizona

Phoenix, Arizona, United States

Local Institution - 103

Stanford, California, United States

Stanford Cancer Center

Stanford, California, United States

Local Institution - 101

Jacksonville, Florida, United States

Mayo Clinic - Jacksonville

Jacksonville, Florida, United States

Local Institution - 107

Orange City, Florida, United States

Mid Florida Hematology and Oncology Centers, PA

Orange City, Florida, United States

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Local Institution - 108

Tampa, Florida, United States

Local Institution - 104

New York, New York, United States

Mount Sinai Medical Center

New York, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

Local Institution - 109

Cleveland, Ohio, United States

Avera Research Institute

Sioux Falls, South Dakota, United States

Local Institution - 105

Sioux Falls, South Dakota, United States

Local Institution - 100

Houston, Texas, United States

MD Anderson Cancer Center The University of Texas

Houston, Texas, United States

Local Institution - 106

San Antonio, Texas, United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

CHRU de Brest - Hopital Morvan

Brest, , France

Local Institution - 203

Brest, , France

Centre Hospitalier de Lens

Lens, , France

Local Institution - 201

Lens, , France

Hopital Saint Louis

Paris, , France

Local Institution - 200

Paris, , France

Gustave Roussy

Villejuif, , France

Local Institution - 202

Villejuif, , France

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, , Italy

Local Institution - 304

Bergamo, , Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

Local Institution - 300

Florence, , Italy

Fondazione IRCCS Policlinico San Matteo

Pavia, , Italy

Local Institution - 301

Pavia, , Italy

Istituto Clinico Humanitas

Rozzano (MI), , Italy

Local Institution - 303

Rozzano (MI), , Italy

Local Institution - 302

Varese, , Italy

Ospedale di Circolo di Varese

Varese, , Italy

Belfast Health and Social Care Trust

Belfast Northern Ireland, , United Kingdom

Local Institution - 404

Cardiff, , United Kingdom

University Hospital of Wales

Cardiff, , United Kingdom

Local Institution - 400

Headington, Oxford, , United Kingdom

University of Oxford

Headington, Oxford, , United Kingdom

Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital

London, , United Kingdom

Local Institution - 403

London, , United Kingdom

Imperial College London

London, , United Kingdom

Local Institution - 402

London, , United Kingdom

Countries

United States; France; Italy; United Kingdom

References

Gerds AT, Harrison C, Kiladjian JJ, Mesa R, Vannucchi AM, Komrokji R, Bose P, Kremyanskaya M, Mead AJ, Gotlib J, Rose S, Sanabria F, Marsousi N, Giuseppi AC, Jiang H, Palmer JM, McCaul K, Ribrag V, Passamonti F. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis. Blood Adv. 2024 Sep 10;8(17):4511-4522. doi: 10.1182/bloodadvances.2024012939.

Reference Type: DERIVED

PMID: 38820422 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html

BMS Clinical Trial Information

https://www.bmsstudyconnect.com/s/US/English/USenHome

BMS Clinical Trial Patient Recruiting

Other Identifiers

2017-000322-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1197-1202

Identifier Type: REGISTRY

Identifier Source: secondary_id

ACE-536-MF-001

Identifier Type: -

Identifier Source: org_study_id