Ruxolitinib Prior to Transplant in Patients With Myelofibrosis
Condition: Primary Myelofibrosis; Post Polycythemia Vera Myelofibrosis; Post Essential Thrombocythemia Myelofibrosis
MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential
Intervention: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)
Intervention description: Ruxolitinib (INC424) tablets will be started 60 days (day -65) prior to start of conditioning chemotherapy. The starting dose of Ruxolitinib will be determined according to baseline platelet count and will be modified according to platelet count at follow-up. The drug will be given in the maximum tolerated dose as defined in the protocol for 56 days, followed by 4 days of taper, and will be stopped completely at the planned start of conditioning therapy (starting on day -5) i.e. 5 days prior to stem cell infusion. The drug will be supplied as 5 mg tablets.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Myelofibrosis; Stem cell transplant; Ruxolitinib

Summary:

      The purpose of this study is to find out if giving the study drug Ruxolitinib (INC424) prior
      to a combination of other chemotherapeutic drugs (Fludarabine and Busulfan) before infusing
      another person's hematopoietic stem cells (bone marrow transplantation) will be successful in
      people who have advanced primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis
      (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF), collectively known as
      myelofibrosis (MF). MF is a disorder in which bone marrow tissue develops in abnormal sites
      because the bone marrow itself undergoes fibrosis or scarring. This study plans to evaluate
      whether adding the drug Ruxolitinib will further aid in reducing pre-transplant spleen size,
      improve physical performance levels and reduce adverse events (side effects) related to the
      transplant. Ruxolitinib is a drug that is approved by the FDA for the treatment of patients
      with advanced forms of myelofibrosis. Using Ruxolitinib prior to stem cell transplantation is
      experimental.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Documented diagnosis of primary myelofibrosis according to WHO criteria or post PV
             myelofibrosis or post ET myelofibrosis as per IWG-MRT criteria

          -  Age 18-70 years

          -  Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria OR
             Intermediate-1 risk disease with one of the following additional unfavorable features
             known to impact the survival adversely

               1. Red cell transfusion dependency

               2. Unfavorable Karyotype

               3. Platelet count <100 x 109/l

          -  Blasts in the PB and BM ≤10% prior to study enrollment

          -  Availability of a suitable matched related (6/6 or 5/6) or unrelated donor (10/10 or
             9/10 antigen or allele matched).

          -  Able to give informed written consent

          -  ECOG Performance status of 0-2.

          -  Life expectancy >3 months

          -  Off all MF-directed therapy including investigational agents for at least 2 weeks
             prior to study enrollment and recovered from all toxicities*

          -  Adequate organ function

               -  Adequate renal function - creatinine <1.5 x IULN

               -  Adequate hepatic function - AST/ALT <2.5 x IULN, Total Bilirubin <1.5 x IULN

               -  Adequate hematopoietic function - Platelet ≥50 x 109/l and ANC ≥1.0 x 109/l

               -  LVEF >40% (MUGA or echocardiogram) Normal per Institutional standard

               -  Adequate pulmonary function with DLCO >50%

                    -  A patient who has been on stable dose of Ruxolitinib and has received
                       ruxolitinib ≤6 months prior to the study entry will be considered
                       potentially eligible for the study with the caveat that there is no evidence
                       of loss of response (>5cm increase in spleen size from the nadir).

        Exclusion Criteria:

          -  Any previous JAK2 inhibitor treatment prior to study enrollment, with the exception of
             Ruxolitinib

          -  Hypersensitivity to JAK inhibitor

          -  Clinical or laboratory evidence of cirrhosis

          -  Prior allogeneic transplant for any hematopoietic disorder

          -  >20% blast in the PB or BM prior to HCT or had leukemic transformation (>20% blasts in
             PB or BM any time prior to HCT)

          -  Syngeneic donor

          -  Cord Blood transplant

          -  Active uncontrolled infection

          -  H/o another malignancy within 5-years of date of HCT except h/o basal cell or squamous
             cell carcinoma of skin or PV or ET

          -  Known HIV positive

          -  Pregnancy at the time of BMT

          -  Any other concurrent illness which in investigator's opinion puts the patient at
             excessive risk of treatment related toxicities

          -  Unable to give informed consent

          -  Active infection with hepatitis A,B or C virus

          -  Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment to
             this study