A Randomized Study of the JAK Inhibitor INC424 Tablets Compared to Best Available Therapy in Subjects with Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF)

INTERVENTION: Product Name: Ruxolitinib Product Code: INC424 Pharmaceutical Form: Tablet INN or Proposed INN: Ruxolitinib CAS Number: 1092939‐17‐7 Current Sponsor code: INC424 Other descriptive name: INCB018424 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ CONDITION: Primary Myelofibrosis (PMF), Post‐Polycythemia Vera‐Myelofibrosis (PPV‐MF) or Post‐Essential Thrombocythemia‐Myelofibrosis (PET‐MF) ; MedDRA version: 14.1 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: To compare the efficacy, safety and tolerability of INCB018424 given twice daily compared to the best‐available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV‐MF) and post essential thrombocythemia myelofibrosis (PET‐MF). ; Primary end point(s): Proportion of subjects achieving 35% reduction in spleen volume from Baseline to Week 48 as measured by MRI (or by CT for subjects unable to undergo MRI). Secondary Objective: To evaluate the population pharmacokinetics of INCB018424. Timepoint(s) of evaluation of this end point: Week 48 SECONDARY OUTCOME: Secondary end point(s): The key secondary efficacy endpoint is defined as: ; • Proportion of subjects achieving a = 35% reduction of spleen size as measured by MRI (or CT scan where applicable) from Baseline to Week 24. ; Other secondary efficacy endpoints are: ; • Duration of maintenance of a = 35% reduction from Baseline in spleen volume. ; • Time to achieve a first = 35% reduction in spleen volume from baseline. ; • Progression free survival. ; •Leukemia free survival. ; • Overall survival. ; • Change in bone marrow histomorphology. ; ; The duration of = 35% reduction from baseline in spleen volume is defined as the longest duration of consecutive measurements of = 35% reduction observed prior to the time of database freeze for subjects who have at least one measured 35% reduction. Specifically: ; 1. If the first MRI showing = 35% reduction from baseline in spleen volume is the last MRI performed on a patient prior to database freeze for the primary analysis then the duration of maintenance will be considered censored with duration of at least one day. ; 2. If the last observed spleen volume value still represents = 35% reduction from Baseline at the time of database freeze and this measure belongs to the longest duration, the duration will be considered as censored with a duration of at least the observed duration plus one day. ; Timepoint(s) of evaluation of this end point: Week 24 (Proportion of subjects achieving a = 35% reduction of spleen size as measured by MRI (or CT scan where applicable) from Baseline to Week 24) INCLUSION CRITERIA: All subjects must meet the following INCLUSION CRITERIA: 1.Subjects 18 years of age or older. 2.Subjects must be diagnosed with PMF, PPV‐MF or PET‐MF, according to the 2008 World Health Organization criteria, irrespective of JAK2 mutation status. •Age > 65 yrs •Presence of constitutional symptoms (weight loss, fever, night sweats) •Marked anemia (Hgb < 10g/dL)* •Leukocytosis (history of WBC > 25 x10 E9/L) •Circulating blasts =1% * A hemoglobin value < 10 g/dL must be demonstrated during the Screening Visit for subjects who are not transfusion dependent. Subjects receiving regular transfusions of packed red blood cells will be considered to have hemoglobi 3.Subjects with myelofibrosis requiring therapy must be classified as high risk (3 or more prognostic factors) OR intermediate risk level 2 (2 or more prognostic factors). The prognostic factors, defined by the International Working Group (Cervantes et al, 2009) are: