A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms

Inclusion Criteria:

Must be diagnosed with 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 CML with ≥ 5% blasts
* MPN-NOS with ≥ 5% blasts
* MDS/MPN Overlap Syndromes with ≥ 5% blasts including 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. Because no dosing or adverse event data are currently available on the use of fedratinib in combination with IDH inhibitors in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* Eastern Cooperative Oncology Group performance status ≤2 (see Appendix A).

Patients must have normal organ and marrow function as defined below:

* Creatinine clearance ≥30 mL/min, determined by the Cockroft-Gault formula, OR serum creatinine ≤ 1.5 x ULN
* AST and 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)

Other eligibility criteria includes the following:

* Patients must be at least 2 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
* Patients must be willing to use appropriate contraception. 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 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 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 PI. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. 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 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.
* 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.