Background: Momelotinib (MMB) is a JAK1/2 inhibitor, and displays potent in vitro inhibitory activity against cells dependent on JAK2 including cells with the JAK2V617F mutation. Dosing of ruxolitinib (RUX), the first JAK inhibitor approved for myelofibrosis (MF), is based on platelet count, with dose reduction indicated for various degrees of hematologic toxicity. In the phase III study of RUX versus placebo (PBO) in MF (COMFORT-1), 70% of subjects in the RUX arm experienced thrombocytopenia of any grade compared to 31% of subjects in the PBO arm, with rates of Grade 3 and 4 thrombocytopenia of 13% and 1% on the RUX and PBO arms, respectively. Grade 3 and 4 anemia rates were 45% and 19% for the RUX and PBO arms, respectively (Verstovsek et al, NEJM 2012). For those patients who experience significant hematologic toxicities while on RUX, no approved alternative JAK inhibitor therapy is currently available. Methods: 150 subjects with primary, post-polycythemia vera, or post-essential thrombocythemia MF will be randomized in a 2:1 manner to receive either MMB or best available therapy (BAT) for 24 weeks, with the option for eligible subjects to continue open-label MMB in an extended treatment phase for up to an additional 168 weeks. Treatment on the BAT arm may include RUX. Key inclusion criteria are palpable splenomegaly ≥ 5 cm, currently or previously treated with RUX and characterized by either requirement for red blood cell transfusion while on RUX, or dose adjustment of RUX to < 20 mg twice daily at start of or during RUX treatment plus either ≥ Grade 3 thrombocytopenia, ≥ Grade 3 anemia, and/or ≥ Grade 3 hemorrhage. The primary endpoint is Splenic Response Rate at Week 24, defined as the proportion of subjects who achieve ≥ 35% reduction in spleen volume from baseline at Week 24, as measured by MRI or CT scan. Secondary endpoints include Response Rate in Total Symptom Score, defined as the proportion of subjects who achieve ≥ 50% reduction in total symptom score from baseline to Week 24 as measured by the modified MPNSAF TSS diary. The DMC last reviewed the trial in Nov 2014 and recommended that the trial continue as planned. Clinical trial registry number: NCT02101268. Clinical trial information: NCT02101268