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
Condition: Primary Myelofibrosis; Anemia
MeSH terms: Neoplasms; Anemia; Primary Myelofibrosis; Myeloproliferative Disorders
Intervention: Luspatercept
Intervention description: 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 MeSH terms: Luspatercept
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 95.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Luspatercept; ACE-536; Myeloproliferative Neoplasm-Associated Myelofibrosis; Primary Myelofibrosis; Post-Polycythemia Vera Myelofibrosis; Post-Essential Thrombocythemia; Anemia; Red Blood Cell (RBC) Transfusion; Ruxolitinib

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.
    

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.