The presence of IDH mutation is associated with worse survival in patients with
myelofibrosis. Moreover IDH mutations are among the most frequently encountered events in
MPNs that have progressed to acute myeloid leukemia. Ruxolitinib, a JAK1/2 inhibitor, and
enasidenib an IDH2 inhibitor are effective and tolerable treatments for patients with
myelofibrosis (MF) and acute myeloid leukemia (AML), respectively. The study team hypothesize
that the combination of these agents in patients with MPN with an IDH2 mutation will improve
the overall clinical response to therapy.
At this time, there is no standard medical treatment for MPN-AP/BP and most patients with
accelerated and blast phase MPN do not respond well to treatment This is a phase II
open-label study to evaluate the safety and efficacy of combined ruxolitinib and enasidenib
in patients with accelerated/blast-phase myeloproliferative neoplasm or chronic phase
myelofibrosis with high risk features and IDH2 mutation.
Ruxolitinib (Jakafi/Jakavi) is FDA approved for myelofibrosis and was shown to reduce
splenomegaly and improve symptoms. Enasidenib is a potent inhibitor of the IDH2 mutant enzyme
and is FDA approved for relapsed refractory AML where it showed effectivity.
Pre-clinical studies indicate increased disease mitigating effects with the combination of
enasidenib and ruxolitinib.
This study will enroll up to 32 patients. Ruxolitinib and enasidenib will be given orally in
28-day cycles.
INCLUSION CRITERIA:
- Subjects must be ≥ 18 years at the time of signing the Informed Consent Form (ICF).
- Understanding and voluntary signing an IRB-approved informed consent form.
- Diagnosis of:
1. Accelerated-phase (≥ 10% blasts in PB or BM) or blast-phase (≥ 20% blasts in PB
or BM) myeloproliferative neoplasm (with history of prior myelofibrosis,
polycythemia vera, or essential thrombocythemia)
2. Previously treated patients with myelofibrosis with persistent disease or
progressive disease (persistent or progressive splenomegaly, leukocytosis,
anemia, or thrombocytopenia) with intermediate-1 or greater risk disease
according to 2013 International Working Group (IWG) criteria, and 4-9%
circulating blasts.
- Demonstration of an IDH2 mutation.
- Platelet count > 75,000 X 109/L for chronic phase myelofibrosis patients.
- Prior therapy with either ruxolitinib or enasidenib is permitted, but not a
combination of ruxolitinib and enasidenib.
- Patients with chronic phase myelofibrosis on ruxolitinib must be on the drug for at
least 3 months and on a stable dose for at least one month.
- Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 2. ECOG 3 status will be allowed if attributable to MPN.
- Patients must have adequate organ function as demonstrated by the following: a. Direct
bilirubin < 2.0mg/dL, unless due to Gilbert's disease or current elevations in direct
bilirubin associated with existing enasidenib use. b. Serum creatinine< 2.0 mg/dL. c.
ALT and AST ≤ 3x upper limit of normal (unless transaminitis is considered to be
related to MF).
- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to starting
enasidenib and must either commit to continued abstinence from heterosexual
intercourse or begin TWO acceptable methods of birth control, one highly effective
method and one additional effective method AT THE SAME TIME, at least 4 weeks before
she starts taking enasidenib. FCBP must also agree to ongoing pregnancy testing. Men
must agree to use a condom during sexual contact with a female of child bearing
potential even if they have had a successful vasectomy. All patients must be counseled
at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
- All study participants must be able to swallow oral medication.
- Ability to adhere to the study visit schedule and all protocol requirements.
EXCLUSION CRITERIA:
- Use of any other standard anti-neoplastic drug or growth factor (e.g., anagrelide,
G-CSF, lenalidomide, thalidomide clofarabine) except hydroxyurea or experimental
drugs, with the exception of ruxolitinib or enasidenib, less than 14 days or
5-half-lives, whichever is longer, prior to starting study therapy and/or lack of
recovery from all toxicity (except for alopecia) from previous therapy to Grade 1 or
better.
a. Patients will be permitted to receive hydroxyurea while on study for up to a total
of 3 cycles of combined therapy.
- Known prior clinically relevant hypersensitivity reaction to ruxolitinib or
enasidenib.
- Prior therapy with enasidenib in combination with ruxolitinib.
- Concurrent use of strong inducers of CYP3A4 (Rifampin, St. John's Wort, Carbamazepine,
Phenytoin) and/or the following strong inhibitors of CYP3A4 (protease inhibitor
containing HIV anti-retrovirals, cobicistat, clarithromycin, itraconazole,
ketoconazole, nefazodone, and telithromycin) are prohibited. Also prohibited are
CYP2C9 substrate medications that have a narrow therapeutic range: phenytoin and
warfarin.
- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form, which places the
subject at unacceptable risk if he/she were to participate in the study or which
confounds the ability to interpret data from the study.
- Lactating females.
- Active uncontrolled infections.
- Patients with active malignancy of other type than required for this study are not
eligible with the exception of currently treated basal cell, squamous cell carcinoma
of the skin, or carcinoma "in situ" of the cervix or breast. Patients with
malignancies with indolent behavior such as prostate cancer treated with radiation or
surgery can be enrolled in the study as long as they have a reasonable expectation to
have been cured with the treatment modality received.
- Subject has significant active cardiac disease within 6 months prior to the start of
study treatment, including New York Heart Association (NYHA) Class III or IV
congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or left
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment.
- QTc interval (Fridericia's correction [QTcF]) > 450 ms
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified
designee to ensure that the patient qualifies for the trial.
