Fedratinib in Combination With Ivosidenib or Enasidenib for the Treatment of IDH Mutated Ph-Negative Advanced Blood Cancer

Inclusion Criteria

• Advanced-phase IDH-mutated Ph-neg MPNs (both untreated and relapsed/refractory) including any of the following: * Polycythemia vera with (PV) >= 5% blasts * Essential thrombocythemia (ET) with >= 5% blasts * Primary myelofibrosis (PMF) with >= 5% blasts * Atypical chronic myeloid leukemia (CML) with >= 5% blasts * MPN-not otherwise specified (NOS) with >= 5% blasts * Myelodysplastic syndrome (MDS)/MPN overlap syndromes with >= 5% blasts including chronic myelomonocytic leukemia (CMML) * Post-PV myelofibrosis with >= 5% blasts * Post-ET myelofibrosis with >= 5% blasts
• Patients can be on cytoreduction at time of study enrollment with hydroxyurea or steroids
• Age >=18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Creatinine clearance >= 30 mL/min, determined by the Cockcroft-Gault formula, OR serum creatinine =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN and bilirubin =< 1.5 x ULN (unless considered due to Gilbert’s syndrome, leukemic involvement, or extravascular hemolysis in the spleen)
• Patients must be at least 4 weeks from major surgery, radiation therapy, or participation in other investigational trials, and must have recovered from clinically significant toxicities related to these prior treatments
• Female patients of childbearing potential must have negative results for a pregnancy test and must be willing to utilize appropriate contraception. A female of childbearing potential 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. Male subjects must practice true abstinence or agree to use an acceptable method of birth control during sexual contact with a pregnant female or female of childbearing potential while on study and for at least 4 months after discontinuation of the investigational product(s)
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients cannot be on concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in this protocol. Patients cannot have had prior treatment with an IDH1 inhibitor, IDH2 inhibitor, or fedratinib
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for >= 3 years or they are not currently requiring treatment for an indolent malignancy. Patients with acute promyelocytic leukemia (APL) and active central nervous system (CNS) disease would also be excluded
• Patients with prior history of encephalopathy, including Wernicke’s (WE). If a patient has signs/symptoms of encephalopathy, including WE (eg 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. Patients with thiamine deficiency that has not been corrected before proceeding to the dose finding phase of the study
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to fedratinib, ivosidenib, or enasidenib
• Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 should have eligibility and alternative medications reviewed by site principal investigator (PI). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active chronic liver disease (eg chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cholangitis, hemochromatosis) or psychiatric illness/social situations that would limit compliance with study requirements
• Subject has a history of progressive multifocal leukoencephalopathy (PML)
• Subject has corrected QT interval (QTc) interval (ie, Fridericia’s correction [QTcF]) >= 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g. family history of long QT interval syndrome) at screening unless due to bundle branch block or pacemaker with approval of the principal investigator
• Pregnant women are excluded from this study because fedratinib, ivosidenib, and enasidenib carry the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with fedratinib, ivosidenib, and enasidenib, breastfeeding should be discontinued if the mother is treated with any of these agents
• Human immunodeficiency virus (HIV)-positive patients, patients with active hepatitis B, and patients with active Hepatitis C on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with fedratinib, ivosidenib, and enasidenib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally