Abstract Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has been approved for the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis (MF), post-polycythemia vera (PPV) MF, and post-essential thrombocythemia (PET) MF. In a murine model of MF, ruxolitinib in combination with the hedgehog pathway inhibitor (HPI) sonidegib, improved splenomegaly and bone marrow (BM) fibrosis more than ruxolitinib monotherapy (Bhagwat, ASH 2013). Building on these data, ruxolitinib and sonidegib combination therapy is being assessed in a phase 1b/2 study in patients (pts) with MF (NCT01787552). Findings from the phase 1b portion of this study determined the recommended phase 2 dose (RP2D) to be sonidegib 400 mg once daily and ruxolitinib 20 mg twice daily (Gupta, ASH 2014). Combination treatment was generally well tolerated; the maximum tolerated dose was not reached, and the only observed dose-limiting toxicity was creatine kinase (CK) elevation. In this report, safety and efficacy data from the analysis performed 24 weeks after the last pt enrollment (data cutoff, 08 May 2015) are presented for pts treated at the RP2D. Methods: Eligible pts includedadults with primary or secondary (PPV or PET) intermediate (Int)- or high-risk MF with palpable splenomegaly who were not previously treated with a JAK inhibitor or HPI. The primary objective was to assess the efficacy of co-administration of ruxolitinib and sonidegib determined by reduction in spleen volume per MRI/CT by central review at the end of weeks 24 and 48. Results: Overall, 27 pts with primary MF (n = 16; 59.3%), PET-MF (n = 7; 25.9%), and PPV-MF (n = 4; 14.8%) were treated at the RP2D (median exposure, 28.6 weeks). The median age was 69 years (range, 44 to 83 years), 70.4% of pts were male, and 85.2% were JAK2 V617F positive. According to the International Prognosis Scoring System, 1 pt (3.7%) was low risk, 4 pts (14.8%) were Int-1, 4 pts (14.8%) were Int-2, and 18 pts (66.7%) were high risk. At data cutoff, 20 pts (74.1%) remained on treatment; 5 pts discontinued treatment due to an adverse event (AE), and 1 pt each due to pt decision and death (multi-organ failure unrelated to study treatment occurring 2 days after discontinuation). Overall, the most common AEs regardless of causality (all grade; grade 3/4; Table) were anemia (52%; 33%) and muscle spasms (48%; 4%). AEs requiring dose adjustment or interruption were experienced by 17 pts (63%), with the most common being increased CK (19% [n = 5]) and myalgia (19% [n = 5]). The mean hemoglobin level at baseline (BL) was ≈ 100 g/L and it remained relatively stable throughout treatment. Mean platelet count decreased from BL levels of ≈ 300 × 109/L to ≈ 150 × 109/L by week 4, and then remained relatively stable at ≈ 200 × 109/L. At the end of week 24, 12 pts (44.4%) had a ≥ 35% reduction in spleen volume as measured by MRI/CT and 15 pts (55.6%) achieved a ≥ 35% reduction in spleen volume at any time on treatment (Figure 1). A ≥ 50% reduction in palpable spleen length was achieved by 15 pts (55.6%) at the end of week 24; a best response of ≥ 50% reduction in spleen length at any time on treatment was achieved by 25 pts (92.6%), with 15 pts (55.6%) having a non-palpable spleen (Figure 2). The mean change in JAK2 V617F allele burden was -9.0% (range, -56.5% to 7.0%) from BL to the end of week 24. Investigator-assessed changes in BM fibrosis in pts with BL and post-BL values indicated that 2 pts had an improvement (from grade 3 to grade 2), 8 pts remained stable, and 3 pts had a worsening from BL by the end of week 24. Pharmacokinetics of the combination will be presented. Conclusions: The combination of ruxolitinib and sonidegib has activity in pts with MF and may provide improved benefit over ruxolitinib monotherapy. Combination treatment was generally well tolerated, with ≈ 74% of pts remaining on treatment at data cutoff. Table. Most Common Adverse Events Sonidegib 400 mg Once Daily + Ruxolitinib 20 mg Twice Daily(n = 27) AEs of any cause in ≥ 10% of pts, n (%) All Grade 3/4 Anemia 14 (52) 9 (33) Muscle spasms 13 (48) 1 (4) Increased CK 10 (37) 5 (19) Myalgia 8 (30) 2 (7) Dysgeusia 8 (30) - Thrombocytopenia 7 (26) 3 (11) Diarrhea 7 (26) 1 (4) Fatigue 7 (26) 0 Pyrexia 6 (22) 1 (4) Alopecia 6 (22) - Constipation 5 (19) 0 Nausea 5 (19) 0 Abdominal pain 4 (15) 0 Dizziness 4 (15) 0 Headache 4 (15) 0 Decreased platelet count 3 (11) 1 (4) Asthenia 3 (11) 0 Cough 3 (11) 0 Decreased weight 3 (11) 0 Dry mouth 3 (11) 0 Dyspnea 3 (11) 0 Extremity pain 3 (11) 0 Increased creatinine 3 (11) 0 Disclosures Gupta: Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Ruxolitinib is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Sonidegib is approved for the treatment of locally advanced basal cell carcinoma. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Shire: Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hasselbalch:Novartis: Research Funding. Koschmieder:Novartis Foundation: Research Funding; Baxalta/CTI: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences ; Janssen Cilag: Other: Travel reimbursement for scientific conferences ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences , Research Funding. Cervantes:Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy. Bao:Novartis Pharmaceuticals Corporation: Employment. Kalambakas:Novartis: Employment, Equity Ownership. Atienza:Novartis Pharmaceuticals Corporation: Employment. Gopalakrishna:Novartis Pharma AG: Employment. Heidel:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.