The purpose of this research is to gather information on the safety and effectiveness of
fedratinib (a drug called a "jak inhibitor" ) in combination with ivosidenib or enasidenib
(two anti-cancer drugs). While all three drugs are FDA-approved for various conditions, the
US Food and Drug Administration (FDA) has not approved the combination of these drugs for the
treatment of rare blood cancers that present Isocitrate dehydrogenase (IDH) mutations, and
therefore these drugs can only be given in a research study.
Doctors leading this study hope to learn about the safety of combining fedratinib (a type of
drug called a "JAK inhibitor" whichblocks the activity of janus kinase enzymes in your body)
with anti-cancer drugs ivosidenib and enasidenib in participants who have rare blood cancers
that show Isocitrate dehydrogenase (IDH) mutations (a type of genetic mutation). Your
participation in this research will last about 24 months.
The purpose of this research is to gather information on the safety and effectiveness of
fedratinib in combination with ivosidenib or enasidenib. While all three drugs are
FDA-approved for various conditions, the US Food and Drug Administration (FDA) has not
approved the combination of these drugs for the treatment of IDH-mutated blood cancers (known
as myeloproliferative neoplasms), and therefore these drugs can only be given in a research
study.
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.
