Phase 1b Dose-Escalation Study of Sonidegib (LDE225) in Combination with Ruxolitinib (INC424) in Patients with Myelofibrosis
Authors: Gupta Vikas , Koschmieder Steffen , Harrison Claire N. , Cervantes Francisco , Heidel Florian H , Drummond Mark , Rey Jerome , Hurh Eunju , Bao Weichao , Rampersad Anita , Kalambakas Stacey , Vannucchi Alessandro Maria 
Published: October 2019

Abstract
Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has been shown to effectively reduce splenomegaly, manage myelofibrosis (MF)-related symptoms, and improve survival, but has limited anticlonal activity. Inhibition of hedgehog signaling via therapy with sonidegib, a selective inhibitor of smoothened (SMO), in combination with ruxolitinib reduced white blood cell (WBC) and platelet counts, JAK2 mutant allele burden, and bone marrow (BM) fibrosis in preclinical MF models more than ruxolitinib alone (Bhagwat, ASH 2013). The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of sonidegib in combination with ruxolitinib for patients (pts) with MF is being assessed in the phase 1b portion of this phase 1b/2 study (NCT01787552). The safety-expansion cohort is currently ongoing; updated data will be presented.
Methods: Adults with primary or secondary (post–polycythemia vera or –essential thrombocythemia) intermediate- or high-risk MF with palpable splenomegaly not previously treated with JAK or SMO inhibitors were eligible. Pts received oral doses of sonidegib once daily (QD) and ruxolitinib twice daily (BID). The first dose level enrolled was sonidegib 400 mg QD + ruxolitinib 10 mg BID. Dose escalations were guided by a Bayesian logistic regression model. In addition to safety and pharmacokinetics (PK), spleen length was assessed by palpation at screening, wk 1, every 2 wk until wk 13, monthly after wk 13, and at the end of treatment. BM fibrosis was assessed in biopsies collected every 24 wk.
Results: As of March 26, 2014, 23 pts (16 male) with a median age of 67 y (range, 42-77 y) were treated at 3 dose levels (1: sonidegib 400 mg QD + ruxolitinib 10 mg BID [n = 8]; 2: sonidegib 400 mg QD + ruxolitinib 15 mg BID [n = 10]; 3: sonidegib 400 mg QD + ruxolitinib 20 mg BID [n = 5]). Median (range) levels for hemoglobin, platelet count, and WBC count at baseline (BL) were 102 g/L (64-142 g/L), 232 × 109/L (81-900 × 109/L) and 21 x 109/L (2-59 x 109/L), respectively. Median (range) palpable spleen size at BL was 13 cm (5-38 cm) below costal margin. According to the International Prognosis Scoring System, 5, 7, and 11 pts were intermediate-1, intermediate-2, and high-risk, respectively. At data cutoff, 4 pts had discontinued treatment due to an adverse event (AE), physician decision, progressive disease, or patient decision (n = 1 each). PK parameters and trough levels for both agents generally aligned with single-agent data. Fatigue was the most commonly reported AE regardless of causality (Table). Six serious AEs were reported, 4 at dose level 1 (face edema, hyponatremia, pyrexia, right ventricular failure; n = 1 each) and 2 at dose level 2 (blood creatine kinase [CK] increased; n = 2). Dose-limiting toxicities of grade 3 and 4 CK elevations were reported in 2 pts at dose level 2. At data cutoff, 65% of pts achieved a ≥ 50% reduction in palpable spleen length from BL and 9 pts had resolution of splenomegaly.
Conclusions: The evaluated combination doses of sonidegib and ruxolitinib were generally well tolerated in pts with MF, and preliminary efficacy data appear promising. Sonidegib and ruxolitinib in combination did not appear to affect the PK of either agent. Once the MTD and/or RP2D are determined, the safety and efficacy of this combination will be further evaluated in the phase 2 study. Abstract 712. Table.Dose Level 1Sonidegib 400 mg QD +Ruxolitinib 10 mg BID(n = 8)Dose Level 2Sonidegib 400 mg QD +Ruxolitinib 15 mg BID(n = 10)Dose Level 3Sonidegib 400 mg QD +Ruxolitinib 20 mg BID(n = 5)All(N = 23)AEs of any cause reported in > 10% of all pts, n (%)AllGrade 3/4AllGrade 3/4AllGrade 3/4AllGrade 3/4Fatigue5 (63)1 (13)3 (30)0008 (35)1 (4)Anemia5 (63)5 (63)00005 (22)5 (22)Dysgeusia3 (38)02 (20)0005 (22)0Abdominal pain2 (25)02 (20)01 (20)05 (22)0Alopecia1 (13)04 (40)0005 (22)0Muscle spasms1 (13)04 (40)1 (10)005 (22)1 (4)Thrombocytopenia2 (25)1 (13)1 (10)01 (20)04 (17)1 (4)Diarrhea3 (38)01 (10)0004 (17)0Hyponatremia2 (25)2 (25)1 (10)1 (10)003 (13)3 (13)Blood CK increased1 (13)02 (20)2 (20)003 (13)2 (9)Muscular weakness1 (13)02 (20)1 (10)003 (13)1 (4)Aspartate aminotransferase increased002 (20)1 (10)1 (20)03 (13)1 (4)Decreased appetite3 (38)000003 (13)0Nausea2 (25)01 (10)0003 (13)0Constipation2 (25)01 (10)0003 (13)0Asthenia1 (13)02 (20)0003 (13)0Upper respiratory tract infection1 (13)02 (20)0003 (13)0Headache003 (30)0003 (13)0Myalgia003 (30)0003 (13)0Alanine aminotransferase increased002 (20)01 (20)03 (13)0

Disclosures
Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel, Accomodation, Expenses Other; Novartis Foundation: Research Funding. Harrison:SBio: Consultancy; Gilead: Honoraria; CTI: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire: Speakers Bureau. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Heidel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Drummond:Novartis: Consultancy, Honoraria, Speakers Bureau. Rey:Novartis: Consultancy. Hurh:Novartis NIBR: Employment. Bao:Novartis Pharmaceuticals Corporation: Employment. Rampersad:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Kalambakas:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.