An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib

Inclusion Criteria

• Subject is at least 18 years of age at the time of signing the informed consent form (ICF)
• Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2
• Subject has diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report
• Subject has a DIPSS Risk score of Intermediate-2 or High
• Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥ 450 cm3 by MRI or CT-scan and by palpable spleen measuring ≥ 5 cm below the left costal margin
• Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)
• Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b)
• Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response (refractory) defined as 100 x 109/L
• Myeloblasts ≥ 5 % in peripheral blood
• Estimated glomerular filtration rate 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN)
• Total bilirubin > 1.5 x ULN, subject's total bilirubin between 1.5 - 3.0 x ULN are eligible if the direct bilirubin fraction is 10 mg/day prednisone or equivalent. Subjects who have had prior exposure to hydroxyurea (eg, Hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to randomization
• Subject has received ruxolitinib within 14 days prior to randomization
• Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment
• Subject on treatment with aspirin with doses > 150 mg daily
• Subject with major surgery within 28 days prior to randomization
• Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)
• Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to randomization. However, subject with the following history/concurrent conditions provided successfully treated may enroll: non-invasive skin cancer, in situ cervical cancer, carcinoma in situ of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system), or is free of disease and on hormonal treatment only
• Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
• Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
• Subject with serious active infection
• Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
• Subject is unable to swallow capsule
• Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
• Subject has any condition that confounds the ability to interpret data from the study
• Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization
• Subject with a life expectancy of less than 6 months