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

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.

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.

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.