An Open-Label Phase 2 Study of Itacitinib (INCB039110) in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Subjects With Myelofibrosis

Cohort A only
• Receiving ruxolitinib dose of less than 20 mg daily with no dose increase or
no dose modification in the last 8 weeks before screening visit.
Cohort B only
• Must have had initial reduction in spleen on ruxolitinib treatment (response
is defined by any spleen length or volume reduction, by palpation or MRI/CT
assessment, from baseline while on previous ruxolitinib treatment per IWG-MRT
ELN 2013 guidelines):
- Followed by documented evidence of progression in spleen length or volume OR
- Discontinued ruxolitinib for hematologic toxicities, after the initial
reduction in spleen length or volume.
All subjects
• Men and women, aged 18 years or older.
• Confirmed diagnosis of PMF, PPV-MF, or PET-MF according to revised WHO 2016
criteria.
• Must have palpable spleen of >= 5 cm below the left subcostal margin on
physical examination at the screening visit. (If spleen is not palpable due to
body habitus, spleen enlargement must be documented by other means [eg,
ultrasound or MRI] and study sponsor medical monitor be contacted for
acceptance).
• ECOG performance status of 0, 1, or 2.
• Screening bone marrow biopsy specimen available or willingness to undergo a
bone marrow biopsy at screening/baseline; willingness to undergo bone marrow
biopsy at Week 24.
• Life expectancy of at least 24 weeks.
• Willingness to avoid pregnancy or fathering children based on the following
criteria:
- Woman of nonchildbearing potential (ie, surgically sterile with a
hysterectomy and/or bilateral oophorectomy OR >= 12 months of amenorrhea and at
least 50 years of age).
- Woman of childbearing potential who has a negative serum pregnancy test at
screening and negative urinary test before the first dose on Day 1 and who
agrees to take appropriate precautions to avoid pregnancy (with at least 99%
certainty) from screening through safety follow-up. Permitted methods that are
at least 99% effective in preventing pregnancy should be communicated to the
subject and their understanding confirmed.
- Man who agrees to take appropriate precautions to avoid fathering children
(with at least 99% certainty) from screening through safety follow-up.
Permitted methods that are at least 99% effective in preventing pregnancy
should be communicated to the subject and their understanding confirmed.

All subjects
• Lack of recovery from all toxicities from previous therapy (except
ruxolitinib) to Grade 1 or better.
• Previous treatment with itacitinib or JAK1 inhibitors (JAK1/JAK2 inhibitor
ruxolitinib is permitted).
• Inability to swallow food or any condition of the upper gastrointestinal
tract that precludes administration of oral medications.
• Unwillingness to be transfused with blood components.
• Recent history of inadequate bone marrow reserve as demonstrated by the
following:
- Platelet count < 50 × 109/L in the 4 weeks before screening or platelet
transfusion within 8 weeks before screening.
- Absolute neutrophil count levels < 0.5 × 109/L in the 4 weeks before
screening.
- Peripheral blood blast count of > 10% at the screening or baseline hematology
assessments.
• Inadequate liver function at screening and baseline visits as demonstrated by
the following:
- Direct bilirubin >= 2.0 × the upper limit of laboratory normal (ULN). (NOTE:
direct bilirubin may be assumed to be within limits if total bilirubin is <= 2.0
× ULN).
- Alanine aminotransferase or aspartate aminotransferase > 2.5 × ULN.
• Inadequate renal function at screening and baseline visits as demonstrated by
creatinine clearance < 40 mL/min measured or calculated by Cockroft-Gault
equation, or glomerular filtration rate < 40 mL/min/1.73 m2 as calculated using
the Modification of Diet in Renal Disease formula.
• Active bacterial, fungal, parasitic, or viral infection that requires
therapy. Subjects with acute infections requiring treatment should delay
screening/enrollment until the course of therapy has been completed and the
event is considered resolved. Prophylactic antibiotics will be permitted.
• Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or
risk of reactivation: HBV DNA and HCV RNA must be undetectable. Subjects cannot
be positive for hepatitis B surface antigen or anti-hepatitis B core
antibodies. Subjects who have positive anti-HBs as the only evidence of prior
exposure may participate in the study provided that there is both 1) no known
history of HBV infection and 2) verified receipt of hepatitis B vaccine.
• Known human immunodeficiency virus infection.
• Clinically significant or uncontrolled cardiac disease, including unstable
angina; acute myocardial infarction within 6 months of Day 1 of study drug
administration; New York Heart Association Class III or IV congestive heart
failure; and arrhythmia requiring therapy unless approved by medical
monitor/sponsor.
• Active invasive malignancy over the previous 2 years except treated basal or
squamous carcinomas of the skin, completely resected intraepithelial carcinoma
of the cervix, and completely resected papillary thyroid and follicular thyroid
cancers. Subjects with malignancies with indolent behavior such as prostate
cancer treated with radiation or surgery may be enrolled as long as they have a
reasonable expectation to have been cured with the treatment modality received.
• Splenic irradiation within 6 months before receiving the first dose of
itacitinib.
• Use of any prohibited concomitant medications.
• Active alcohol or drug addiction that would interfere with their ability to
comply with the study requirements.
• Use of any potent/strong cytochrome P450 3A4 inhibitors within 14 days or 5
half-lives (whichever is longer) before the first dose of itacitinib or
anticipated during the study.
• Use of concomitant treatment of fluconazole at a dose > 200 mg (for
ruxolitinib subjects treated in Cohort A only).
• Inadequate recovery from toxicity and/or complications from a major surgery
before starting therapy.
• Currently breastfeeding or pregnant.
• Inability to comprehend or unwilling to sign the informed consent form.
• Any condition that would, in the investigator's judgment, interfere with full
participation in the study, including administration of study drug and
attending required study visits; pose a significant risk to the subject; or
interfere with interpretation of study data.