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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01787552




Registration number
NCT01787552
Ethics application status
Date submitted
6/02/2013
Date registered
8/02/2013
Date last updated
15/04/2020

Titles & IDs
Public title
A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
Scientific 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
Secondary ID [1] 0 0
2012-004023-20
Secondary ID [2] 0 0
CLDE225X2116
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary Myelofibrosis 0 0
Thrombocytosis 0 0
Essential Thrombocythemia 0 0
Polycythemia Vera 0 0
Myeloproliferative Disorders 0 0
Bone Marrow Diseases 0 0
Hematologic Diseases 0 0
Blood Coagulation Disorders 0 0
Blood Platelet Disorders 0 0
Hemorrhagic Disorders 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system
Blood 0 0 0 0
Clotting disorders
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Experimental: LDE225 + INC424 - LDE225 and INC424 in combination
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
Timepoint [1] 0 0
6 weeks (42 days)
Primary outcome [2] 0 0
Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
Timepoint [2] 0 0
Week 24 and Week 48
Secondary outcome [1] 0 0
Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)
Timepoint [1] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Secondary outcome [2] 0 0
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast
Timepoint [2] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Secondary outcome [3] 0 0
Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)
Timepoint [3] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Secondary outcome [4] 0 0
Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)
Timepoint [4] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Secondary outcome [5] 0 0
Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)
Timepoint [5] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Secondary outcome [6] 0 0
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
Timepoint [6] 0 0
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Secondary outcome [7] 0 0
Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1
Timepoint [7] 0 0
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Secondary outcome [8] 0 0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers
Timepoint [8] 0 0
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Secondary outcome [9] 0 0
Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores
Timepoint [9] 0 0
Week 24, Week 48
Secondary outcome [10] 0 0
Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores
Timepoint [10] 0 0
Baseline, Week 25, Week 49
Secondary outcome [11] 0 0
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48
Timepoint [11] 0 0
Week 24, Week 48
Secondary outcome [12] 0 0
Phase Ib and Phase II: LDE225: PK Parameter: Racc
Timepoint [12] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1
Secondary outcome [13] 0 0
Phase Ib and Phase II: INC424: PK Parameter: T1/2
Timepoint [13] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
Secondary outcome [14] 0 0
Phase Ib and Phase II: INC424: PK Parameter: Vss/F
Timepoint [14] 0 0
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1

Eligibility
Key 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).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/05/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
10/04/2018
Sample size
Target
Accrual to date
Final
50
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 0 0
Novartis Investigative Site - Camperdown
Recruitment hospital [2] 0 0
Novartis Investigative Site - Woolloongabba
Recruitment postcode(s) [1] 0 0
NSW - Camperdown
Recruitment postcode(s) [2] 0 0
4102 - Woolloongabba
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Leuven
Country [2] 0 0
Canada
State/province [2] 0 0
Ontario
Country [3] 0 0
Canada
State/province [3] 0 0
Quebec
Country [4] 0 0
Denmark
State/province [4] 0 0
Roskilde
Country [5] 0 0
France
State/province [5] 0 0
Marseille
Country [6] 0 0
Germany
State/province [6] 0 0
Aachen
Country [7] 0 0
Germany
State/province [7] 0 0
Magdeburg
Country [8] 0 0
Ireland
State/province [8] 0 0
Galway
Country [9] 0 0
Italy
State/province [9] 0 0
FI
Country [10] 0 0
Italy
State/province [10] 0 0
RC
Country [11] 0 0
Netherlands
State/province [11] 0 0
Amsterdam
Country [12] 0 0
Netherlands
State/province [12] 0 0
Rotterdam
Country [13] 0 0
Spain
State/province [13] 0 0
Catalunya
Country [14] 0 0
Spain
State/province [14] 0 0
Madrid
Country [15] 0 0
United Kingdom
State/province [15] 0 0
Scotland
Country [16] 0 0
United Kingdom
State/province [16] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01787552
Trial related presentations / publications
Gupta V, Wolleschak D, Hasselbalch H, Vannucchi AM, Koschmieder S, Cervantes F, Li Y, Dong T, Wroclawska M, Bharathy S, Harrison C. Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study. Blood Adv. 2020 Jul 14;4(13):3063-3071. doi: 10.1182/bloodadvances.2019001212.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01787552