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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01787552
First Posted: February 8, 2013
Last Update Posted: July 26, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
February 6, 2013
February 8, 2013
July 26, 2017
May 8, 2013
December 29, 2017   (Final data collection date for primary outcome measure)
  • 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).
Same as current
Complete list of historical versions of study NCT01787552 on ClinicalTrials.gov Archive Site
  • 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
Same as current
Not Provided
Not Provided
 
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
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.
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.
Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Primary Myelofibrosis
  • Thrombocythemia, Essential
  • Thrombocytosis
  • Myeloproliferative Disorders
  • Bone Marrow Diseases
  • Hematologic Diseases
  • Blood Coagulation Disorders
  • Blood Platelet Disorders
  • Hemorrhagic Disorders
  • Drug: LDE225
  • Drug: INC424
Experimental: LDE225 + INC424
LDE225 and INC424 in combination
Interventions:
  • Drug: LDE225
  • Drug: INC424
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
50
December 29, 2017
December 29, 2017   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Belgium,   Canada,   Denmark,   France,   Germany,   Ireland,   Italy,   Netherlands,   Spain,   United Kingdom
Russian Federation
 
NCT01787552
CLDE225X2116
2012-004023-20 ( EudraCT Number )
No
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
July 2017

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