A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

• Phase Ib: Dose Limiting Toxicities (DLTs) [ Time Frame: 6 weeks (42 days) ] [ Designated as safety issue: Yes ]
  To establish the maximum tolerated dose (MTD) and/or recommended phase II dose (RPllD) of LDE225 in combination with INC424
  
  
• Proportion of patients achieving >= 35% reduction in spleen volume [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT).
  
  

• Phase Ib: Safety of LDE225 in combination with INC424 in myelofibrosis patients [ Time Frame: study start, up to and including 30 days after last dose ] [ Designated as safety issue: Yes ]
  Safety as determined by the number of patients with adverse events, serious adverse events, abnormalities in physical examinations, vital signs and laboratory test values, including electrocardiogram (ECG) data
  
  
• Phase Ib: Plasma pharmacokinetics (PK) parameters [ Time Frame: Week 1 Day 1, Week 1 Day 2, Week 3 Day 1 and then every 2 weeks until Week 9 Day 1, Week 9 Day 2, Week 13 Day 1 and then every 4 weeks until Week 49 Day 1 ] [ Designated as safety issue: Yes ]
  LDE225 and INC424 PK parameters
  
  
• Phase II: Proportion of patients experiencing improvement in bone marrow fibrosis by at least one grade [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  Assessed according to the European consensus on grading bone marrow fibrosis and assessment of cellularity.
  
  
• Phase II: Safety of LDE225 and INC424 [ Time Frame: Study start, up to and including 30 days after last dose ] [ Designated as safety issue: Yes ]
  Safety assessed by number of patients with adverse events, serious adverse events, abnormalities in physical examinations, vital signs and laboratory test values, including ECG data
  
  
• Phase II: Change in total symptom score [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  Change measured by the modified MFSAF (Myelofibrosis Symptom Assessment Form) v2.0
  
  
• Phase ll: Change in JAK2V617F allele burden [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  
• Phase ll: Change in cytokine levels [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  
• Phase II: Plasma pharmacokinetics (PK) parameters [ Time Frame: Week 1 Day 1, Week 1 Day 2, Week 3 Day 1 and then every 2 weeks until Week 9 Day 1, Week 9 Day 2, Week 13 Day 1 and then every 4 weeks until Week 49 Day 1 Day 1 ] [ Designated as safety issue: Yes ]
  Stage 1: LDE225 and INC424 PK parameters
  
  
• Phase II: Plasma pharmacokinetics (PK) parameters [ Time Frame: Week 1 Day 1 and then every 2 weeks until Week 9 Day 1, then every 4 weeks until Week 49 Day 1 ] [ Designated as safety issue: Yes ]
  Stage 2: Ctrough of LDE225 and INC424
  
  
• Phase II: Proportion of patients having >= 50% reduction in total symptom score [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  Change measured by the modified MFSAF (Myelofibrosis Symptom Assessment Form) v2.0
  
  
• Phase II: Change in EORTC QLQ-C30 scores [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  EORTC QLQ- 30 = European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-30
  
  

The purpose of this phase Ib/II clinical trial is to: a) evaluate the safety of the co-administration of LDE225 and INC424 in myelofibrosis patients and establish a maximum tolerated dose and/or Recommended Phase II dose of the combination and b) to assess the efficacy of the co-administration of LDE225 and INC424 on spleen volume reduction. Adult patients, aged ≥ 18 years, with myelofibrosis that meet intermediate or high risk prognostic criteria and exhibit palpable splenomegaly ≥ 5 cm below the left costal margin that have not been previously treated with a JAK or Smo inhibitor will be eligible for this study. Approximately 36 patients will participate in the Phase Ib dose escalation and safety expansion part of the study. Dose escalation will be dependent on the available toxicity information (including adverse events that are not DLTs), PK, PD, and efficacy information, as well as the recommendations from the Bayesian Logistic Regression Model (BLRM). In the Phase II part of the study approximately 46 patients will be enrolled: 18 patients will be enrolled into Stage 1, if following an interim analysis the minimum number of responders are observed, 28 additional patients will be enrolled into stage 2. If less than the minimum number of responders are observed in Stage 1 then further enrollment will be halted. Approximately 82 patients will be enrolled in the entire study.