Maintenance Fedratinib for the Prevention of Post-Transplant Relapse in Myeloproliferative Neoplasms

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 must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements
• Philadelphia chromosome negative myeloproliferative disease (including polycythemia vera, myelofibrosis, and essential thrombocytosis, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, myelodysplastic syndrome/myeloproliferative neoplasm-unclassified, MPN not otherwise specified) having undergone first allogeneic (allo) hematopoietic cell transplant (HCT)
• Engraftment including > 95% myeloid cell donor chimerism and Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Platelets >= 30 x 10^9/L with no platelet transfusions in the prior 7 days
• Absence of disease progression as defined by International Working Group (IWG) Myeloproliferative Neoplasm Response Criteria
• Acute graft versus host disease (GVHD) of the skin is permitted if prednisone has been tapered to =< 0.25 mg/kg with continued response
• A female of childbearing potential (FCBP) must: * Have a negative pregnancy tests as verified by the Investigator during screening prior to enrollment (a second pregnancy test will be collected prior to therapy as below). 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 * 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). ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). *** Agreement to use highly effective methods of contraception that alone or in combination resulting 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: Combined (estrogen and progestogen containing) hormonal contraception: Oral; intravaginal; transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; placement of an intrauterine device; placement of an intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner.
• 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 ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
• CRITERIA TO INITIATE THERAPY:
• All patients enrolled on the study must initiate therapy between days 60-100 post-transplant (where the day of transplant infusion is day 0)
• History and physical exam by medical provider (confirmed within 7 days prior to taking the first dose)
• ECOG performance status of 0, 1, or 2 (confirmed within 7 days prior to taking the first dose)
• Platelets >= 30 x 10^9/L with no platelet transfusions in the prior 7 days (confirmed within 7 days prior to taking the first dose)
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (confirmed within 7 days prior to taking the first dose)
• Serum creatinine clearance >= 45 ml/min (by Cockroft-Gault equation) (confirmed within 7 days prior to taking the first dose)
• Serum amylase and lipase =< 1.5 x ULN (confirmed within 7 days prior to taking the first dose)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN (confirmed within 7 days prior to taking the first dose)
• Total bilirubin =< 1.5 x ULN (Subjects with a total bilirubin between 1.5 –3.0 x ULN are eligible if the direct bilirubin fraction is < 25% of the total bilirubin) (confirmed within 7 days prior to taking the first dose)
• Absence of skin GVHD or skin GVHD on prednisone =< 0.25 mg/kg with continued response (confirmed within 7 days prior to taking the first dose)
• Absence of GVHD of the gastrointestinal (GI) tract requiring systemic therapy (confirmed within 7 days prior to taking the first dose)
• Absence of GVHD of the liver requiring systemic therapy (confirmed within 7 days prior to taking the first dose)
• For females of child-bearing potential, a negative pregnancy test verified by the Investigator (confirmed within 7 days prior to taking the first dose)

Exclusion Criteria

• Acute GVHD of the gut or liver currently on systemic therapy. Patients who have completed systemic therapy and are asymptomatic may be enrolled
• Treatment with JAK2 inhibitor within 14 days prior to enrollment
• Serum creatinine clearance < 45 ml/min (as per Cockroft-Gault Equation)
• Serum amylase and lipase > 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
• Total bilirubin =< 1.5 x ULN (Subjects with a total bilirubin between 1.6–3.0 x ULN are eligible if the direct bilirubin fraction is < 25% of the total bilirubin)
• Subject is pregnant or a lactating female
• Subject with prior history of Wernicke’s encephalopathy (WE)
• Subject has signs or symptoms of encephalopathy, including Wernicke’s encephalopathy (e.g. severe ataxia, ocular paralysis or cerebellar signs) in which case thiamine deficiency needs to be excluded and a brain magnetic resonance imaging (MRI) might be required to exclude possible Wernicke’s encephalopathy
• Subject with concomitant treatment with or use of pharmaceutical or herbal agents known to be strong inducers of CYP3A4. However, if a patient is started on a strong CYP3A4 inducer while on fedratinib, the dose must be adjusted
• Thiamine levels below the normal range, per institutional standard, may enroll but must be corrected to the normal range before initiating treatment with fedratinib. Normalized thiamine level must be confirmed within 10 days of starting fedratinib therapy
• Subject on any chemotherapy, immunomodulatory drug therapy (e.g., thalidomide, interferon-alpha), Anagrelide, or concurrent JAK2 inhibitor. Patients who have had exposure to hydroxyurea (e.g., hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to initiation of fedratinib
• Subject on treatment with myeloid growth (e.g. granulocyte colony-stimulating factor [G-CSF]) factor within 14 days prior to initiation of fedratinib
• Subject on treatment with aspirin with doses > 150 mg daily
• Subject with major surgery within 28 days before starting fedratinib
• Subject with diagnosis of chronic liver disease (e.g., chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis
• Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
• Subject with known human immunodeficiency virus (HIV), evidence of active infectious hepatitis B (Hep B), and/or evidence of active hepatitis C (Hep C)
• Subject with serious active infection
• Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
• Concurrent active malignancy requiring therapy. Localized skin basal cell or squamous cell carcinomas are permitted
• Bone marrow blast percentage greater than 10%.
• Subject is unable to swallow capsule
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
• Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to start of fedratinib
• 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