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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

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ClinicalTrials.gov Identifier: NCT03194542
Recruitment Status : Recruiting
First Posted : June 21, 2017
Last Update Posted : June 25, 2018
Sponsor:
Information provided by (Responsible Party):
Celgene

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 Intervention/treatment Phase
Primary Myelofibrosis Anemia Drug: Luspatercept 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: will contain up to 20 subjects with anemia only that are not currently receiving RBC transfusions (these subjects will be referred to as "anemia only" throughout the protocol, defined as 0 RBC units/84 days immediately up to the C1D1 date)
  • Cohort 2: will contain up to 20 subjects that are RBC-transfusion dependent (these subjects will be referred to as "RBC-transfusion dependent" throughout the protocol, defined as an average RBC transfusion frequency of 2 to 4 RBC units/28 days over at least the 84 days immediately up to the C1D1 date)
  • Cohort 3A: will contain ≥ 10 subjects (Cohort 3 contains 30 subjects in total) who meet the eligibility criteria for Cohort 1 (anemia only) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date
  • Cohort 3B: will contain ≥ 10 subjects (Cohort 3 contains 30 subjects in total) who meet the eligibility criteria for Cohort 2 (RBC-transfusion dependent) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date Overall, the study will enroll approximately 70 subjects worldwide.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 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 15, 2017
Estimated Primary Completion Date : June 15, 2019
Estimated Study Completion Date : November 21, 2023


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.
Other Name: ACE-536




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



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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: 2 to 4 RBC units/28 days over at least the 84 days immediately up to the C1D1 date. There must be no interval > 42 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.
      • RBC transfusions given because of bleeding, infection, or chemotherapy induced anemia are not 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 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 a stable dose of ruxolitinib as part of their standard-of-care therapy for 112 days immediately up to the enrollment date.
  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

      o 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03194542


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

Locations
United States, Arizona
Mayo Clinic - Arizona Recruiting
Phoenix, Arizona, United States, 85054
United States, California
Stanford Cancer Center Recruiting
Stanford, California, United States, 94305
United States, Florida
Mayo Clinic - Jacksonville Recruiting
Jacksonville, Florida, United States, 32224
Mid Florida Hematology and Oncology Centers, PA Recruiting
Orange City, Florida, United States, 32763
H. Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
United States, New York
Mount Sinai Medical Center Recruiting
New York, New York, United States, 10029
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
United States, South Dakota
Avera Research Institute Recruiting
Sioux Falls, South Dakota, United States, 57105
United States, Texas
MD Anderson Cancer Center The University of Texas Recruiting
Houston, Texas, United States, 77030
University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
France
CHRU de Brest - Hopital Morvan Recruiting
Brest Cedex, France, 29609
Centre Hospitalier de Lens Recruiting
Lens Cedex, France, 62307
Hopital Saint Louis Recruiting
Paris, France, 75010
Institut Gustave Roussy Recruiting
Villejuif, France, 94805
Italy
Azienda Ospedaliera Papa Giovanni XXIII Recruiting
Bergamo, Italy, 24127
Azienda Ospedaliera Universitaria Careggi Recruiting
Firenze, Italy, 50134
Fondazione IRCCS Policlinico San Matteo Recruiting
Pavia, Italy, 27100
Istituto Clinico Humanitas Recruiting
Rozzano (MI), Italy, 20089
Ospedale di Circolo di Varese Recruiting
Varese, Italy, 21100
United Kingdom
Belfast Health and Social Care Trust Not yet recruiting
Belfast Northern Ireland, United Kingdom, BT9 7AB
University Hospital of Wales Recruiting
Cardiff, United Kingdom, CF14 4XW
University of Oxford Recruiting
Headington, Oxford, United Kingdom, OX3 7LE
Guys Hospital Recruiting
London, United Kingdom, SE1 9RT
Imperial College London Recruiting
London, United Kingdom, W12 0HS
Sponsors and Collaborators
Celgene
Investigators
Study Director: Torsten Gerike, MD Celgene

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03194542     History of Changes
Other Study ID Numbers: ACE-536-MF-001
2017-000322-35 ( EudraCT Number )
U1111-1197-1202 ( Registry Identifier: WHO )
First Posted: June 21, 2017    Key Record Dates
Last Update Posted: June 25, 2018
Last Verified: June 2018

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
Myeloproliferative Neoplasm-Associated Myelofibrosis
Primary Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
Post-Essential Thrombocythemia
Anemia
Red Blood Cell (RBC) Transfusion
Ruxolitinib

Additional relevant MeSH terms:
Neoplasms
Anemia
Primary Myelofibrosis
Myeloproliferative Disorders
Hematologic Diseases
Bone Marrow Diseases