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
Condition: Primary Myelofibrosis; Post-Polycythemia Vera; Myelofibrosis
MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential
Intervention: FEDRATINIB; Best Available Therapy (BAT)
Intervention description: A potent and selective inhibitor of JAK2 kinase activity; Best available therapy (BAT)
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 202.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MF; myeloproliferative neoplasms; MPN; myelofibrosis; PMF; post-PV; Post-Polycythemia Vera; post-ET MF; Post-Essential Thrombocythemia Myelofibrosis

Summary:

      A Phase 3, multicenter, open-label, randomized study to evaluate the efficacy and safety of
      fedratinib compared to best available therapy (BAT) in subjects with DIPSS (Dynamic
      International Prognostic Scoring System)-intermediate or high-risk primary myelofibrosis
      (PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia
      myelofibrosis (post-ET MF) and previously treated with ruxolitinib. The primary objective of
      the study is to evaluate the percentage of subjects with at least 35% spleen volume reduction
      in the fedratinib and the BAT arms.
    

Eligibility criteria:

        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 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

          4. Subject has a DIPSS Risk score of Intermediate-2 or High

          5. 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

          6. Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis
             Symptom Assessment Form (MFSAF)

          7. Subject has been previously exposed to ruxolitinib, and must meet at least one of the
             following criteria (a and/or b)

               1. Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response
                  (refractory) defined as < 10% spleen volume reduction by MRI or < 30% decrease
                  from baseline in spleen size by palpation or regrowth (relapsed) to these
                  parameters following an initial response

               2. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following
                  (intolerant):

                    -  Development of a red blood cell transfusion requirement (at least 2
                       units/month for 2 months) or

                    -  Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while
                       on treatment with ruxolitinib

          8. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1
             or pretreatment baseline before start of last therapy prior to randomization

          9. Subject must understand and voluntarily sign an ICF prior to any study-related
             assessments/procedures being conducted

         10. Subject is willing and able to adhere to the study visit schedule and other protocol
             requirements

         11. A female of childbearing potential (FCBP) must:

               1. Have 2 negative pregnancy tests as verified by the Investigator during screening
                  prior to starting study treatment. 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.

               2. 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 highly effective contraception without interruption, -14 days prior
                  to starting investigational product, during the study treatment (including dose
                  interruptions), and for 30 days after discontinuation of study treatment.

             Note: A female of childbearing potential (FCBP) is 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).

         12. A male subject 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 30 days
        following investigational product discontinuation, or longer if required for each compound
        and/or by local regulations, even if he has undergone a successful vasectomy

        Exclusion Criteria:

          1. Any of the following laboratory abnormalities:

               1. Platelets < 50 x 109/L

               2. Absolute neutrophil count (ANC) < 1.0 x 109/L

               3. White blood count (WBC) > 100 x 109/L

               4. Myeloblasts ≥ 5 % in peripheral blood

               5. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification
                  of Diet in Renal Disease [MDRD] formula)

               6. Serum amylase or lipase > 1.5 x upper limit of normal (ULN)

               7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper
                  limit of normal (ULN)

               8. 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 < 25% of the total bilirubin

          2. Subject is pregnant or lactating female

          3. Subject with previous splenectomy

          4. Subject with previous or planned hematopoietic cell transplant

          5. Subject with prior history of encephalopathy, including Wernicke's (WE)

          6. Subject with signs or symptoms of encephalopathy, including WE (eg, severe ataxia,
             ocular paralysis or cerebellar signs)

          7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below
             normal range according to the central laboratory and not demonstrated to be corrected
             prior to randomization

          8. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or
             food known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), or dual
             CYP2C19 and CYP3A4 inhibitors

          9. 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 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

         10. Subject has received ruxolitinib within 14 days prior to randomization

         11. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than
             ruxolitinib treatment

         12. Subject on treatment with aspirin with doses > 150 mg daily

         13. Subject with major surgery within 28 days prior to randomization

         14. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease,
             autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis,
             hemochromatosis, non-alcoholic steatohepatitis)

         15. 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

         16. Subject with uncontrolled congestive heart failure (New York Heart Association
             Classification 3 or 4)

         17. Subject with known human immunodeficiency virus (HIV), known active infectious
             Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)

         18. Subject with serious active infection

         19. Subject with presence of any significant gastric or other disorder that would inhibit
             absorption of oral medication

         20. Subject is unable to swallow capsule

         21. Subject with any significant medical condition, laboratory abnormality, or psychiatric
             illness that would prevent the subject from participating in the study

         22. 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

         23. Subject has any condition that confounds the ability to interpret data from the study

         24. Subject with participation in any study of an investigational agent (drug, biologic,
             device) within 30 days prior to randomization

         25. Subject with a life expectancy of less than 6 months