Phase 1b/2 Study Of The Efficacy And Safety Of Sonidegib (Lde225) In Combination With Ruxolitinib (Inc424) In Patients With Myelofibrosis

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.