Canakinumab for the Treatment of Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis

Inclusion Criteria

• Subjects must voluntarily sign informed consent form (ICF) and be willing and able to adhere to the study visit schedule and all protocol requirements
• Subjects must be >= 18 years of age at the time of signing the ICF
• Subjects must have a pathologically confirmed diagnosis of primary myelofibrosis (PMF) as per the World Health Organization (WHO) diagnostic criteria or post-essential thrombocythemia (ET) MF or post-polycythemia vera (PV) MF according to IWG-MRT criteria
• Subjects must have at least one of the following: * Hemoglobin < 10 g/dL * Transfusion-dependency (at least 6 units of packed red blood cells [PRBC] in the 12 weeks prior to study enrollment, for a hemoglobin < 8.5 g/dL, in the absence of bleeding or treatment-induced anemia with the most recent transfusion having occurred in the 28 days prior to study enrollment) * Splenomegaly palpated >= 5 cm below the left costal margin (LCM) or spleen volume ≥ 450cc * MFSAF v4.0 total symptom score (TSS) >= 10
• A bone marrow biopsy must be performed within the 30-day screening period; however, a bone marrow biopsy obtained within 90 days of signing ICF without intervening treatments and approved by the study chair may suffice
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Life expectancy of at least 6 months
• Recovery to ≤ grade 1 or baseline of any toxicities due to prior systemic treatments excluding alopecia
• Women of childbearing potential (WCBP) must have a negative urine or serum pregnancy test within 28 days of starting the study drug. Men and women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence, tubal ligation, vasectomy) prior to cycle 1 day 1 and for 130 days after stopping study treatment. Vasectomy must be performed a minimum of 3 months before study start
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3.0 x upper limit of normal (ULN), or =< 4 x ULN (unless if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis [EMH] related to MF)
• Direct bilirubin =< 1.5 x ULN or =< 2.0 x ULN (unless if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis (EMH) related to MF or documented Gilbert’s syndrome)
• Serum creatinine =< 2.0 mg/dL
• Platelet count >= 25 x 10^9/L (subject must not have had platelet transfusion in the 14 days prior to signing ICF)
• Absolute neutrophil count (ANC) >= 1000/uL
• Subject must be willing to receive red blood cell and/or platelet transfusions if indicated
• Bone marrow and peripheral blood blast count < 10%
• PART 1 ONLY: At least two weeks must have elapsed between the last dose of any MF-directed drug treatments (including investigational therapies and excluding hydroxyurea) and study enrollment
• PART 1 ONLY: Not eligible for available, approved JAKi therapy due to a platelet count of < 50 x 10^9/L, or previously treated and lack/loss of response per investigator discretion
• PART 2 ONLY: Current treatment with a JAKi (inclusive of ruxolitinib, fedratinib, momelotinib, or pacritinib) for at least 16 weeks and on a stable or decreased dose for at least 12 weeks prior to study enrollment

Exclusion Criteria

• Prior malignancy active within the previous <1 year, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
• Any of the following cardiac abnormalities * Uncontrolled, symptomatic congestive heart failure as designated by the treating physician * Myocardial infarction =< 6 months prior to enrollment * Unstable angina pectoris designated by treating physician * Serious uncontrolled cardiac arrhythmia as designated by treating physician * Uncontrolled hypertension as designated by treating physician
• Known history of human immunodeficiency virus (HIV) (no laboratory testing is required), or active infection with hepatitis B or hepatitis C
• Active tuberculosis (TB) infection or documented, untreated latent TB infection (all subjects should undergo TB risk evaluation prior to enrollment with TB screening performed as per local guidelines.)
• Active, uncontrolled infection at the time of enrollment, except in cases of localized infections that are unlikely to lead to a systemic infection such as onychomycoses or dental caries. * Subjects with a new fever (temperature [T] > 38.0 degrees Celsius [C]) or respiratory symptoms are required to undergo laboratory screening for COVID-19
• Have undergone prior allogeneic hematopoietic stem cell transplant (allo-HSCT) for treatment of any hematological disorder or prior solid organ transplant
• Any serious or uncontrolled psychiatric or medical disorder that, in the opinion of the investigator, may increase the risk associated with the study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
• Women who are pregnant or breastfeeding
• Subjects undergoing concurrent treatment with agents targeting tumor necrosis factor alpha (TNFalpha) or IL-1 within 28 days of study enrollment
• Subjects who have received a live vaccination within 90 days before study drug administration (subjects should not be treated with live-virus vaccine while undergoing therapy and 130 days after canakinumab discontinuation)
• Subjects with a condition requiring systemic treatment with corticosteroids within 14 days of study drug administration (i.e. prednisone at doses of > 10 mg). Inhaled or topical steroids and adrenal/pituitary replacement doses =< 10mg daily of prednisone or equivalent are permitted