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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01787552
First received: February 6, 2013
Last updated: August 12, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Primary Myelofibrosis
Thrombocythemia, Essential
Thrombocytosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Drug: LDE225
Drug: INC424
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Phase Ib: Dose Limiting Toxicities (DLTs) [ Time Frame: 6 weeks (42 days) ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT).


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Phase ll: Change in cytokine levels [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    EORTC QLQ- 30 = European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-30


Estimated Enrollment: 82
Study Start Date: May 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LDE225 + INC424
LDE225 and INC424 in combination
Drug: LDE225 Drug: INC424

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01787552

Contacts
Contact: Novartis Pharmaceuticals +41613241111
Contact: Novartis Pharmaceuticals

  Show 24 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01787552     History of Changes
Other Study ID Numbers: CLDE225X2116, 2011-005016-28
Study First Received: February 6, 2013
Last Updated: August 12, 2014
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
Germany: BfArm - Bundesamt für Arzneimittel und Medizinprodukte
Italy:Istituto Superiore di Sanità (National Institute of Health)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Spain: Agencia Espanola de Medicamentos y Productos Sanitarios
Netherlands: Dutch Health Care Inspectorate
Ireland: Ministry of Health
Australia: National Health and Medical Research Council
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Russia: Ministry of Health of the Russian Federation
Denmark: Ministry of Health
Sweden: The National Board of Health and Welfare

Keywords provided by Novartis:
Dose escalation
Maximum Tolerated Dose
MTD
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

Additional relevant MeSH terms:
Myeloproliferative Disorders
Disease
Hematologic Diseases
Bone Marrow Diseases
Blood Coagulation Disorders
Hemostatic Disorders
Hemorrhagic Disorders
Blood Platelet Disorders
Vascular Diseases
Cardiovascular Diseases
Primary Myelofibrosis
Thrombocytosis
Thrombocythemia, Essential
Pathologic Processes

ClinicalTrials.gov processed this record on October 19, 2014