Fedratinib in Combination with Decitabine for the Treatment of Myeloproliferative Neoplasms in Accelerated and Blast Phase

Inclusion Criteria

• Subjects must have MPN-AP as defined by 10%-19% blasts in the peripheral blood or bone marrow and evidence of dysplastic marrow features with a concomitant diagnosis of essential thrombocythemia (ET), polycythemia vera (PV) or primary myelofibrosis (PMF) or a diagnosis of MPN-BP as defined by 20% blasts in the blood or bone marrow following a previous diagnosis of ET, PV or PMF.
• Estimated creatinine clearance (by Cockcroft-Gault Equation) of >= 50 mL/min (within 14 days of study entry)
• Serum total bilirubin =< 1.5 x upper limit of normal (ULN) (unless attributable to Gilbert’s disease or hemolysis, in which case the direct bilirubin level must be =< 1.5 x ULN) (within 14 days of study entry)
• Alkaline phosphatase, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 14 days of study entry)
• >= 18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2. Patients with ECOG performance status of 3 will be eligible if the lower performance status is deemed by the investigator to be due entirely to MPN-AP/BP and not due to another comorbidity
• Subject must have a white blood cell count < 25 x 10^9/L * Note: Hydroxyurea use is permitted to meet this criterion
• Serum thiamine level in the normal range (supplementation is permitted)
• Women of childbearing potential and males must agree to use adequate contraception (i.e., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately
• Patients who are not immediate candidates for or have declined a hematopoietic stem cell transplant
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

• Receipt of chemotherapy or investigational therapy, with the exception of hydroxyurea, within 4 weeks of study entry. Previous treatment at any time with decitabine, fedratinib or ruxolitinib as single agents will not exclude eligibility. Previous stem cell transplant will not exclude eligibility as long as other inclusion/exclusion criteria have been met and subjects do not have grade >= II graft versus host disease (GVHD) requiring systemic immunosuppressive therapy
• Subjects with a human leukocyte antigen (HLA)-compatible donor or stem cell source who are immediate candidates for allogeneic hematopoietic cell transplantation (HCT)
• Subjects who are receiving any concurrent treatment for AML, including other investigational agents
• Diagnosis of acute myelofibrosis
• Uncontrolled intercurrent illness including, but not limited to hepatitis, human immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral therapy, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class 3 or 4), unstable angina pectoris, ventricular arrhythmia, Child-Pugh Class C cirrhosis, or psychiatric illness/social situations that would limit compliance with study requirements
• Subjects with a prior history of Wernicke’s encephalopathy (WE) will be excluded. If a subject has signs or symptoms of encephalopathy, including Wernicke’s encephalopathy (e.g. severe ataxia, ocular paralysis or cerebellar signs), thiamine deficiency must be excluded and a brain magnetic resonance imaging (MRI) should be obtained prior to study initiation to evaluate for WE
• Other medications, severe acute/chronic medical or psychiatric conditions, or laboratory abnormalities that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, that in the judgment of the investigator would make the subject inappropriate for entry into this study.
• Pregnant women are excluded because of the potential for teratogenic or abortifacient effects