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

Study Overview
=================
Brief Summary
-----------------
The purpose of this phase Ib/II clinical trial was 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.

Detailed Description
-----------------
The study is considered to have been completed because the participants completed the study as per study design at the time of trial termination. If participants were already in extension phase until discontinuation criteria were met or alternative setting was available, they were considered as completed. The study was terminated due to one of the compounds being divested.

Official Title
-----------------
A Phase Ib/II, Open-label, Multi-center, Dose-finding Study to Assess the Safety and Efficacy of the Oral Combination of LDE225 and INC424 (Ruxolitinib) in Patients With Myelofibrosis

Conditions
-----------------
Primary Myelofibrosis, Thrombocytosis, Essential Thrombocythemia, Polycythemia Vera, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases, Blood Coagulation Disorders, Blood Platelet Disorders, Hemorrhagic Disorders

Intervention / Treatment
-----------------
* Drug: LDE225
* Drug: INC424


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with PMF per 2008 WHO criteria, post-PV MF or post-ET MF per IWG-MRT criteria. Ineligible or unwilling to undergo stem cell transplantion. PLT counts > or = 75X 10^9/L not reached with the aid of transfusions. ECOG performance status ≤ 2. Palpable splenomegaly defined as ≥ 5 cm below the left costal margin. Intermediate risk level 1 (1 prognostic factor which is not age), Intermediate risk level 2, or high risk. Active symptoms of MF as demonstrated by one symptom score of at least 5 (0 to10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) on the MF Symptom Assessment Form (MFSAF). Exclusion Criteria: Previous therapy with JAK or Smoothened inhibitors. Patient is currently on medications that interfere with coagulation (including warfarin) or platelet function with the exception of low dose aspirin (up to 100 mg) and LMWH. Impairment of GI function or GI disease that may significantly alter the absorption of INC424 or LDE225 (e.g., uncontrolled nausea, vomiting, diarrhea; malabsorption syndrome; small bowel resection). Splenic irradiation within 12 months prior to Screening. Pregnant or nursing women. WOCBP not using highly effective methods of contraception Sexually active males who refuse condom use Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. Pravastatin may be used if necessary, with extra caution.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDE225 + INC424<br>LDE225 and INC424 in combination | Drug: LDE225<br> <br> Drug: INC424<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b) | A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol. | 6 weeks (42 days) | 
| Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1 | Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients | Week 24 and Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h) | Plasma Concentration Time Curve: AUC0-24h: Area under the concentration-time curve from time zero to 24 hours extrapolate from AUClast[mass x time x volume-1] | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1 | 
| Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast | AUC0-12h: Area under the concentration-time curve from time zero to 12 hours extrapolate from AUClast[mass x time x volume-1]. AUCinf: Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase [mass x time x volume-1]. AUClast: Area under the concentration-time curve from time zero to the time of last measurable concentration [mass x time x volume-1]. | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1 | 
| Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax) | Cmax: Maximum observed plasma concentration after drug administration [mass x volume- 1]. | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1 | 
| Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax) | Tmax: Time to reach Cmax [time] | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1 | 
| Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F) | CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1] | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1 | 
| Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 | The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity. | Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48) | 
| Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1 | Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden | Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48) | 
| Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers | Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1 | Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48) | 
| Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores | The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score. | Week 24, Week 48 | 
| Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores | The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score. | Baseline, Week 25, Week 49 | 
| Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 | EORTC QLQ-C30 is the European Organization for Research & Treatment of Cancer, Quality of Life (QoL) Questionnaire & is one of the most widely used & validated instruments to measure health-related QoL in subjects with cancer. The scale includes 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning & social functioning), global health status/QoL & 9 symptom scale/items (fatigue, nausea & vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, & financial difficulties). This instrument asks the subject to respond according to the past week, with the exception of the first 5 questions that represent physical functioning & capture the subject's current status. The range of scores for all of the scales is from 0 to 100. For functional & global health status/QoL scales, higher scores indicate better QoL & level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties. | Week 24, Week 48 | 
| Phase Ib and Phase II: LDE225: PK Parameter: Racc | Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold] | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1 | 
| Phase Ib and Phase II: INC424: PK Parameter: T1/2 | T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time] | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 | 
| Phase Ib and Phase II: INC424: PK Parameter: Vss/F | Vss/F: Apparent volume of distribution at steady state after oral administration [volume] | 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Safety Expansion, Safety, Efficacy, Myelofibrosis, Post-polycythemia vera myelofbrosis (Post PV-PMF), Post essential thrombocythemia myelofibrosis (Post ET-MF), Primary myelofibrosis (PMF), Intermediate risk myelofibrosis, High risk myelofibrosis, Combination Treatment, Hedgehog Signaling Pathway, Smoothened inhibitor, JAK inhibitor, Dose escalation, Maximum Tolerated Dose, MTD