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Title A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept (ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With and Without Red Blood Cell-Transfusion Dependence

IRB CLGN1917

CC 17-1133

Hospital Main Campus

Phase Phase 2

Disease Myelofibrosis, Myeloproliferative Neoplasms

Drug ACE-536

Description

• To evaluate the efficacy and safety of luspatercept for the treatment of anemia in subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis with and without red blood cell (RBC)-transfusion dependence.

• To evaluate the safety of luspatercept in MPN-associated myelofibrosis
• To evaluate the effect of luspatercept in MPN-associated myelofibrosis
• To evaluate population pharmacokinetics of luspatercept in subjects with MPNassociated myelofibrosis with and without RBC-transfusion dependence

• To explore the relationship between luspatercept exposure and measures of efficacy and toxicity
• To explore biomarkers related to efficacy parameters and markers related to mechanism of action of luspatercept
• To explore MPN-associated myelofibrosis-related mutations relative to disease progression and/or drug response

Inclusion Criteria

1. Subject is ≥18 years of age at the time of signing the informed consent form (ICF).
2. Subject has MPN-associated myelofibrosis (PMF, post-PV MF, and/or post-ET MF) as confirmed from the local pathology report.
3. Subject has anemia defined as:
   • Cohorts 1 and 3A
     • Obtain ≥ 3 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. No subjects with an interval ≥ 42 days between hemoglobin measurements will be enrolled.
     • There must not be any RBC transfusions within the 84-day period immediately up to the C1D1 date.
   • 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 chemotherapyinduced 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 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:
   • 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.
   • 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:
   • 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. True abstinence is acceptable when it is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.] Agreement to use highly effective methods of contraception that alone or in combination resulting in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.
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

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.
   • 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 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
    • Platelets
      • Cohorts 1 and 2: < 25 x 10⁹/L
      • Cohort 3A and 3B: < 50 x 10⁹/L
    • Estimated glomerular filtration rate < 45 mL/min/1.73 m2 (via the 4-variable 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 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.