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Trial record 1 of 1 for:    LDE225 + INC424 in Patients With MF
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A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

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ClinicalTrials.gov Identifier: NCT01787552
Recruitment Status : Completed
First Posted : February 8, 2013
Results First Posted : April 15, 2020
Last Update Posted : April 15, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 6, 2013
First Posted Date  ICMJE February 8, 2013
Results First Submitted Date  ICMJE April 8, 2019
Results First Posted Date  ICMJE April 15, 2020
Last Update Posted Date April 15, 2020
Actual Study Start Date  ICMJE May 8, 2013
Actual Primary Completion Date April 10, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 3, 2020)
  • Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b) [ Time Frame: 6 weeks (42 days) ]
    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.
  • 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 ]
    Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients
Original Primary Outcome Measures  ICMJE
 (submitted: February 6, 2013)
  • Phase Ib: Dose Limiting Toxicities (DLTs) [ Time Frame: 6 weeks (42 days) ]
    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 ]
    Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 3, 2020)
  • 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 ]
    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]
  • 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 ]
    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].
  • 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 ]
    Cmax: Maximum observed plasma concentration after drug administration [mass x volume- 1].
  • 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 ]
    Tmax: Time to reach Cmax [time]
  • 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 ]
    CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-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 [ Time Frame: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48) ]
    The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.
  • 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) ]
    Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden
  • 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) ]
    Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1
  • Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores [ Time Frame: Week 24, Week 48 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]
  • 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 ]
    T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]
  • 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 ]
    Vss/F: Apparent volume of distribution at steady state after oral administration [volume]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 6, 2013)
  • 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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
  • Phase ll: Change in cytokine levels [ Time Frame: Baseline, Week 24, Week 48 ]
  • 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 ]
    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 ]
    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 ]
    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 ]
    EORTC QLQ- 30 = European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-30
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis
  • Thrombocytosis
  • Essential Thrombocythemia
  • Polycythemia Vera
  • Myeloproliferative Disorders
  • Bone Marrow Diseases
  • Hematologic Diseases
  • Blood Coagulation Disorders
  • Blood Platelet Disorders
  • Hemorrhagic Disorders
Intervention  ICMJE
  • Drug: LDE225
  • Drug: INC424
Study Arms  ICMJE Experimental: LDE225 + INC424
LDE225 and INC424 in combination
Interventions:
  • Drug: LDE225
  • Drug: INC424
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 12, 2016)
50
Original Estimated Enrollment  ICMJE
 (submitted: February 6, 2013)
82
Actual Study Completion Date  ICMJE April 10, 2018
Actual Primary Completion Date April 10, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Denmark,   France,   Germany,   Ireland,   Italy,   Netherlands,   Spain,   United Kingdom
Removed Location Countries Russian Federation
 
Administrative Information
NCT Number  ICMJE NCT01787552
Other Study ID Numbers  ICMJE CLDE225X2116
2012-004023-20 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP