Study of LusPACercept in Participants With Myelofibrosis Associated Anemia and Thrombocytopenia

Inclusion Criteria:

• Patients with myelofibrosis as defined by WHO criteria - either primary or secondary myelofibrosis with:

  • Anemia:

    • Transfusion Dependent: ≥3 units transfused in the 12 weeks immediately preceding C1D1.
    • Non-Transfusion Dependent: had ≥3 Hb level measurements of ≤10 g/dL recorded on ≥3 different days with no RBC transfusions in the 12 weeks immediately preceding C1D1.

  • Thrombocytopenia: Platelet count of ≤150 at any time after signing informed consent.

• Age ≥18 years

• Participant has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

• 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 (eg, has had menses at any time in the preceding 24 consecutive months). Females of childbearing potential (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 study, and after end of IP. This applies even if the participant 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# 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) after discontinuation of study therapy.

    • Subjects must avoid concomitant use of pacritinib with hormonal contraceptives except for intrauterine systems containing levonorgestrel. The effectiveness of hormonal contraceptives, except for intrauterine systems containing levonorgestrel, may be reduced when used with pacritinib. If contraception is needed or desired, an alternate contraceptive that is not affected by CYP3A4 inducers (e.g., an intrauterine system) or additional nonhormonal contraceptive (e.g., condoms) should be used when treated concomitantly with pacritinib, and for 30 days after last dose of pacritinib

• Male participants 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 who is or is not using contraception** while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) following IP 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 participant. [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 result 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: Placement of an intrauterine device (IUD); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.

    • Participant is willing and able to adhere to the study visit schedule and other protocol requirements including the use of the electronic patient reported outcomes device.
    • Participants must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior use of Luspatercept, Sotatercept, Elritercept or any other activin ligand traps, pacritinib or Momelotinib for any duration. Prior Ruxolitinib or Fedratinib are permissible with a wash out period of 2 weeks prior to C1D1.
• Participant participation in any other clinical protocol or investigational trial that involves use of experimental therapy (including investigational agents) and/or therapeutic devices within 30 days or for investigational agents within five half-lives, whichever comes later, by the end of the screening period.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to luspatercept or pacritinib.
• Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, gastrointestinal (GI) disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

4.2.5. Participant with anemia from cause other than MF or JAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration).

• Participant use of hydroxyurea, immunomodulatory compounds such as pomalidomide, thalidomide, ESAs, androgenic steroids, strong CYP3A4 inhibitors and inducers, or other drugs with potential effects on hematopoiesis ≤ 2 weeks up to the end of the screening period.

  • Systemic corticosteroids are permitted for nonhematological conditions providing the participant is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 4 weeks immediately up to the end of the screening period. Use of topical steroids (drops, inhaler, ointment etc.) are permitted.
  • Iron chelation therapy (ICT) is permitted providing the participant is receiving a stable dose for the 8 weeks up to the end of the screening period.

• Participant with any of the following laboratory abnormalities at screening:

  • Neutrophils: < 0.5 x 109/L
  • White blood count (WBC): > 100 x 109/L
  • Peripheral blood myeloblasts: > 10%
  • PT or INR and PTT or aPTT >=1.5x ULN (this exclusion criteria would not apply for patients on anticoagulation).
  • Estimated glomerular filtration rate: < 30 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [MDRD] formula) or nephrotic participants (eg, urine albumin-to-creatinine ratio > 3500 mg/g)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): > 3.0 x upper limit of normal (ULN)
  • Direct bilirubin: ≥ 2 x ULN
  • Severe hepatic impairment defined as Child-Pugh Class C (score ≥10)
  • Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis) or due to pre-existing Gilbert's disease.

• Participant with prior history of malignancies, other than disease under study, unless the participant has been free of the disease for ≥ 3 years. However, participants with the following history/concurrent conditions are allowed (if they have already undergone treatment with curative intent):

  • 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)

• Participant with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 3 months prior to the end of the screening period.

• Participant 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).

• Pregnant or breastfeeding females.

• Subjects with QTc >480 (unless QRS prolongation >120 msec, in which case QTC up to 500 is acceptable)

• Subjects who have experienced a thrombotic or embolic event during 6 months prior to first planned dose of luspatercept.

• Subjects who have experienced a major cardiac event within 6 months prior to enrollment, including but not limited to hospitalization for congestive heart failure (CHF), myocardial infarction (MI), or clinically significant arrhythmia requiring medical intervention

• Subjects who have experienced symptomatic heart failure defined as New York Heart Association (NYHA) Class II or greater at the time of enrollment