A Trial of Fedratinib 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:

Main Study Inclusion Criteria

1. Subject is at least 18 years of age at the time of signing the informed consent form (ICF)

2. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2

3. Subject has diagnosis of primary myelofibrosis (PMF) according to the 2016 WorldHealth Organization (WHO) criteria, or diagnosis of post-ET or post-PV myelofibrosisaccording to the IWG-MRT 2007 criteria, confirmed by the most recent local pathologyreport

4. Subject has a DIPSS Risk score of Intermediate or High

5. Subject has a measurable splenomegaly during the screening period as demonstrated byspleen volume of ≥ 450 cm3 by MRI or CT-scan assessment or by palpable spleenmeasuring ≥ 5 cm below the left costal margin.

6. Subject has been previously exposed to ruxolitinib, while diagnosed with MF (PMF,post-ET MF or post-PV MF), and must meet at least one of the following criteria (aor b)

7. Treatment with ruxolitinib for ≥ 3 months

8. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following:

• Development of a red blood cell transfusion requirement (at least 2units/month for 2 months) or
• Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhagewhile on treatment with ruxolitinib

7. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to fedratinibtreatment.

8. Subject must understand and voluntarily sign an ICF prior to any study-relatedassessments/procedures being conducted

9. Subject is willing and able to adhere to the study visit schedule and other protocolrequirements

10. Participants must agree to use effective contraception

Exclusion Criteria:

Main Study Exclusion Criteria

1. Any of the following laboratory abnormalities:

2. Platelets < 50,000/μL

3. Absolute neutrophil count (ANC) < 1.0 x 109/L

4. White blood count (WBC) > 100 x 10^9/L

5. Myeloblasts > 5 % in peripheral blood

6. Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per theModification of Diet in Renal Disease [MDRD] formula)

7. Serum amylase or lipase > 1.5 x ULN (upper limit of normal)

8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN

9. Total bilirubin > 1.5 x ULN, subject's total bilirubin between 1.5 - 3.0 x ULNare eligible if the direct bilirubin fraction is < 25% of the total bilirubin

10. Subject is pregnant or lactating female

11. Subject with previous splenectomy

12. Subject with previous or planned hematopoietic cell transplant

13. Subject with prior history of encephalopathy, including Wernicke's

14. Subject with signs or symptoms of encephalopathy including Wernicke's (eg, severeataxia, ocular paralysis or cerebellar signs)

15. Subject with thiamine deficiency, defined as thiamine levels in whole blood belownormal range according to institutional standard and not corrected prior toenrollment on the study

16. Subject with concomitant treatment with or use of pharmaceutical, herbal agents orfood known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), ordual CYP2C19 and CYP3A4 inhibitors

17. Subject on any chemotherapy, immunomodulatory drug therapy (eg, thalidomide,interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids > 10 mg/day prednisone or equivalent. Subjects who have had prior exposure tohydroxyurea (eg, Hydrea) in the past may be enrolled into the study as long as ithas not been administered within 14 days prior to the start of fedratinib treatment

18. Subject has received ruxolitinib within 14 days prior to the start of fedratinib

19. Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulatingfactor [G-CSF]) within 14 days prior to the start of fedratinib treatment

20. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1cycle other than ruxolitinib treatment

21. Subject on treatment with aspirin with doses > 150 mg daily

22. Subject with major surgery within 28 days before starting fedratinib treatment

23. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liverdisease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis,hemochromatosis, non-alcoholic steatohepatitis)

24. Subject with prior malignancy other than the disease under study unless the subjecthas not required treatment for the malignancy for at least 3 years prior toenrollment. However, subject with the following history/concurrent conditions providedsuccessfully 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 isfree of disease and on hormonal treatment only

25. Subject with uncontrolled congestive heart failure (New York Heart AssociationClassification 3 or 4)

26. Subject with known human immunodeficiency virus (HIV), known active infectiousHepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)

27. Subject with serious active infection

28. Subject with presence of any significant gastric or other disorder that wouldinhibit absorption of oral medication

29. Subject is unable to swallow capsule

30. Subject has any significant medical condition, laboratory abnormality, orpsychiatric illness that would prevent the subject from participating in the study

31. Subject has any condition including the presence of laboratory abnormalities, whichplaces the subject at unacceptable risk if he/she were to participate in the study

32. Subject has any condition that confounds the ability to interpret data from thestudy

33. Subject with participation in any study of an investigational agent (drug, biologic,device) within 30 days prior to start of fedratinib treatment

34. Subject with life expectancy of less than 6 months.