A Study of Itacitinib in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Participants With Myelofibrosis
Condition: MPN (Myeloproliferative Neoplasms)
MeSH terms: Primary Myelofibrosis; Myeloproliferative Disorders
Intervention: Itacitinib; Ruxolitinib
Intervention description: Itacitinib self-administered orally once daily .; Ruxolitinib self-administered orally at the stable dose of < 20 mg daily established before entering the study.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Myelofibrosis; Janus kinase (JAK) inhibitor; itacitinib; ruxolitinib

Summary:

      The purpose of this study is to evaluate the efficacy and safety of itacitinib combined with
      low-dose ruxolitinib or itacitinib alone in participants with myelofibrosis (MF).
    

Eligibility criteria:

        Inclusion Criteria:

        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:

          -  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 participants

          -  Confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis, or
             post-essential thrombocythemia myelofibrosis according to revised World Health
             Organization 2016 criteria.

          -  Must have palpable spleen of greater than or equal to (≥) 5 centimeter (cm) below the
             left subcostal margin on physical examination at the screening visit.

          -  Eastern Cooperative Oncology Group 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

        Exclusion Criteria:

          -  Lack of recovery from all toxicities from previous therapy (except ruxolitinib) to
             Grade 1 or better.

          -  Previous treatment with itacitinib or Janus kinase (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.

          -  Recent history of inadequate bone marrow reserve as demonstrated by protocol-defined
             criteria.

          -  Inadequate liver function at screening and baseline visits as demonstrated by
             protocol-defined criteria.

          -  Inadequate renal function at screening and baseline visits as demonstrated by
             protocol-defined criteria.

          -  Active bacterial, fungal, parasitic, or viral infection that requires therapy.

          -  Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of
             reactivation: HBV deoxyribonucleic acid (DNA) and HCV ribonucleic acid (RNA) must be
             undetectable. Participants cannot be positive for hepatitis B surface antigen or
             anti-hepatitis B core antibodies. Participants 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.

          -  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. Participants
             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
             participants treated in Cohort A only).

          -  Inadequate recovery from toxicity and/or complications from a major surgery before
             starting therapy.

          -  Currently breastfeeding or pregnant.