- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01787552
A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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New South Wales
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Camperdown, New South Wales, Australia, NSW
- Novartis Investigative Site
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Queensland
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Woolloongabba, Queensland, Australia, 4102
- Novartis Investigative Site
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Leuven, Belgium, 3000
- Novartis Investigative Site
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Ontario
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Toronto, Ontario, Canada, M5G 2M9
- Novartis Investigative Site
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Quebec
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Montreal, Quebec, Canada, H3T 1E2
- Novartis Investigative Site
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Roskilde, Denmark, 4000
- Novartis Investigative Site
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Marseille, France, 13273
- Novartis Investigative Site
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Aachen, Germany, 52074
- Novartis Investigative Site
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Magdeburg, Germany, 39120
- Novartis Investigative Site
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Galway, Ireland
- Novartis Investigative Site
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FI
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Firenze, FI, Italy, 50134
- Novartis Investigative Site
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RC
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Reggio Calabria, RC, Italy, 89124
- Novartis Investigative Site
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Amsterdam, Netherlands, 1081 HV
- Novartis Investigative Site
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Rotterdam, Netherlands, 3015 GD
- Novartis Investigative Site
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Madrid, Spain, 28034
- Novartis Investigative Site
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Catalunya
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Barcelona, Catalunya, Spain, 08036
- Novartis Investigative Site
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London, United Kingdom, SE1 9RT
- Novartis Investigative Site
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Scotland
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Glasgow, Scotland, United Kingdom, G12 0YN
- Novartis Investigative Site
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: LDE225 + INC424
LDE225 and INC424 in combination
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
Time Frame: 6 weeks (42 days)
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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.
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6 weeks (42 days)
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Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
Time Frame: Week 24 and Week 48
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Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients
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Week 24 and Week 48
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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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]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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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].
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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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
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Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Tmax: Time to reach Cmax [time]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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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
Time Frame: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.
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Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1
Time Frame: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden
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Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers
Time Frame: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1
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Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores
Time Frame: Week 24, Week 48
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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.
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Week 24, Week 48
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Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores
Time Frame: Baseline, Week 25, Week 49
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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.
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Baseline, Week 25, Week 49
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Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48
Time Frame: Week 24, Week 48
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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.
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Week 24, Week 48
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Phase Ib and Phase II: LDE225: PK Parameter: Racc
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1
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Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1
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Phase Ib and Phase II: INC424: PK Parameter: T1/2
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
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T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
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Phase Ib and Phase II: INC424: PK Parameter: Vss/F
Time Frame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
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Vss/F: Apparent volume of distribution at steady state after oral administration [volume]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
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Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
- Safety
- Efficacy
- Myelofibrosis
- Dose escalation
- JAK inhibitor
- Maximum Tolerated Dose
- MTD
- Safety Expansion
- 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
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Neoplasms
- Neoplasms by Site
- Bone Marrow Neoplasms
- Hematologic Neoplasms
- Hemostatic Disorders
- Blood Coagulation Disorders
- Primary Myelofibrosis
- Disease
- Thrombocytosis
- Thrombocythemia, Essential
- Hematologic Diseases
- Bone Marrow Diseases
- Hemorrhagic Disorders
- Myeloproliferative Disorders
- Polycythemia Vera
- Polycythemia
- Blood Platelet Disorders
Other Study ID Numbers
- CLDE225X2116
- 2012-004023-20 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
IPD Sharing Supporting Information Type
- Study Protocol
- Statistical Analysis Plan (SAP)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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