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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 08/10/2020.

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

Clinicaltrials.gov identifier NCT03194542

Recruitment Status Recruiting

First Posted June 21, 2017

Last update posted February 27, 2020

Study Description

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.

  • Condition or Disease:Primary Myelofibrosis
    Anemia
  • Intervention/Treatment: Drug: Luspatercept
  • Phase: Phase 2
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.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 103 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase-2 Study To Determine Efficacy and Safety of Luspatercept in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With or Without Red Blood Cell-Transfusion Dependence
  • Actual Study Start Date: November 2017
  • Estimated Primary Completion Date: June 2021
  • Estimated Study Completion Date: November 2025
Arms and interventions
Arm Intervention/treatment
Experimental: 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.
Drug: 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.
Outcome Measures
  • Primary Outcome Measures: 1. Anemia response as it relates to hemoglobin (Hgb)increase [ Time Frame: Up to approximately day 168 ]
    Cohorts 1 and 3A - Proportion of subjects achieving ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion
  • 2. Anemia response as it relates to increased red blood cell (RBC)- transfusion independence [ Time Frame: Up to approximately day 168 ]
    Cohorts 2 and 3B - Proportion of subjects who become RBC-transfusion free over any consecutive 84-day period
  • Secondary Outcome Measures: 1. Time to anemia response [ Time Frame: Up to 2 years ]
    Time from first luspatercept dose to first onset of anemia response in each of the cohorts
  • 2. Duration of anemia response [ Time Frame: Up to 2 years ]
    Maximum duration of anemia response in each of the cohorts
  • 3. Frequency of RBC transfusions [ Time Frame: Up to 2 years ]
    Cohorts 2 and 3B - Mean number of RBC units transfused per subject per 28 days
  • 4. Frequency of RBC transfusion dependence [ Time Frame: Up to 2 years ]
    Cohorts 2 and 3B - Proportion of RBC-transfusion dependent subjects who reduce their transfusion burden by ≥ 50% from baseline over any consecutive 84-day period
  • 5. Proportion of subjects who achieve ≥ 50% reduction in fatigue symptom as measured by the Myeloproliferative Neoplasm Symptom Assessment Form, Total Symptom Score (MPN-SAF TSS) [ Time Frame: Up to 2 years ]
    Fatigue, a common symptom among patients with myeloproliferative neoplasm-associated myelofibrosis who have anemia, will be recorded and assessed via the Myeloproliferative Neoplasm Symptom Assessment Form, Total Symptom Score (MPN-SAF TSS)
  • 6. The proportion of subjects who achieve ≥ 50% reduction in total symptom score (TSS) [ Time Frame: Up to 2 years ]
    Myeloproliferative neoplasm (MPN)-associated myelofibrosis-related symptoms (fatigue, night sweats, itchiness, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain) will be recorded using the Myeloproliferative Neoplasm Symptom Assessment Form, Total Symptom Score (MPN-SAF TSS)
  • 7. Health-related quality of life (HRQoL) [ Time Frame: Up to 2 years ]
    Mean changes in HRQoL questionnaire domain scores over the study will be compared to baseline scores
  • 8. Functional Assessment of Cancer Therapy - Anemia (FACT-An) [ Time Frame: Up to 2 years ]
    Mean changes in FACT-An questionnaire domain scores over the study will be compared to baseline scores
  • 9. EQ-5D-5L questionnaires [ Time Frame: Up to 2 years ]
    Mean changes in EQ-5D-5L questionnaire domain scores over the study will be compared to baseline scores
  • 10. Adverse Events (AEs) [ Time Frame: Up to 2 years ]
    Adverse events, including the type, frequency, and severity, will be evaluated
  • 11. Frequency of Antidrug Antibodies (ADA) [ Time Frame: Up to 2 years ]
    Will be collected for assessment of anti-drug antibodies (ADA) against luspatercept in serum in all subjects
  • 12. Pharmacokinetic - AUC [ Time Frame: Up to 1 year ]
    Area under the plasma concentration‐time curve
  • 13. Pharmacokinetic - Cmax [ Time Frame: Up to 1 year ]
    Maximum observed concentration in plasma
  • 14. Changes in Hemoglobin [ Time Frame: Up to 2 years ]
    Assessed via the mean changes in domain scores over the study compared to baseline in the absence of RBC transfusions, calculated from Day 1 through and including Day 168 and Day through end of treatment
  • 15. Mean hemoglobin increase [ Time Frame: Up to 2 years ]
    Proportion of subjects achieving a mean ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
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 100 x 109/L

- Platelets

- Cohorts 1 and 2: < 25 x 109/L - Cohort 3A and 3B: 1000 x 109/L

- Estimated glomerular filtration rate 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.

Contacts and Locations
Contacts

Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations
Show 24 Study Locations
Sponsors and Collaborators

Celgene

Investigators

Study Director: Torsten Gerike, MD Celgene

More Information
  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT03194542 History of Changes
  • Other Study ID Numbers: ACE-536-MF-001, 2017-000322-35, U1111-1197-1202
  • First Posted: June 21, 2017 Key Record Dates
  • Last Update Posted: February 27, 2020
  • Last Verified: February 2020
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: Luspatercept
    ACE-536
    Post-Essential Thrombocythemia
    Anemia
    Ruxolitinib
    Myeloproliferative Neoplasm-Associated Myelofibrosis
    Primary Myelofibrosis
    Post-Polycythemia Vera Myelofibrosis
    Red Blood Cell (RBC) Transfusion
  • Additional relevant MeSH terms: Anemia
    Primary Myelofibrosis
    Myeloproliferative Disorders
    Neoplasms