A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)

August 7, 2017 updated by: Novartis Pharmaceuticals

A Phase II, Multi-center, Open-label, Single-arm Study of the Efficacy and Safety of Oral LDE225 in Patients With Hh-pathway Activated Relapsed Medulloblastoma

This Phase II study evaluated the safety and efficacy of LDE225 in adult and pediatric patients with Hh-pathway activated, relapsed MB.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This study was a single-arm study of the efficacy and safety of oral sonidegib in patients with Hh-pathway activated relapsed medulloblastoma. It was initially designed as a randomized, controlled, open-label phase III study of adults and children with Hh-pathway activated MB whose disease had failed standard of care therapy, including radiation therapy (RT). The original study consisted of a randomized controlled part and a non-randomized uncontrolled part. Approximately 69 patients were to be randomized in a 2:1 ratio to receive sonidegib oral suspension or the active control, temozolomide (TMZ) capsules. Randomization was to be stratified according to age, <18 years versus ≥ 18 years. Approximately 40 patients were to receive sonidegib in the non-randomized uncontrolled part of the study. Following the enrollment of 11 patients, the study was amended to become a phase II single-arm study with only sonidegib, and the target enrollment was changed to 20 patients. Prior to the study amendment, TMZ participants whose disease progressed while on TMZ were permitted to crossover to sonidegib. After the amendment, participants receiving TMZ were crossed over to sonidegib.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
22

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • Queensland
      • Herston, Queensland, Australia, 4029
        • Novartis Investigative Site
    • Western Australia
      • Perth, Western Australia, Australia, 6840
        • Novartis Investigative Site
  • Brazil
    • SP
      • Sao Paulo, SP, Brazil
        • Novartis Investigative Site
  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 1X8
        • Novartis Investigative Site
      • Toronto, Ontario, Canada, M5G 1Z6
        • Novartis Investigative Site
  • France
      • Angers Cedex 1, France, 49033
        • Novartis Investigative Site
      • Lille Cedex, France, 59020
        • Novartis Investigative Site
      • Paris, France, 75231
        • Novartis Investigative Site
      • Toulouse Cedex 9, France, 31059
        • Novartis Investigative Site
      • Vandoeuvre les Nancy, France, 54511
        • Novartis Investigative Site
      • Villejuif Cedex, France, 94805
        • Novartis Investigative Site
    • Aquitaine
      • Bordeaux, Aquitaine, France, 33076
        • Novartis Investigative Site
  • Germany
      • Augsburg, Germany, 86156
        • Novartis Investigative Site
      • Essen, Germany, 45147
        • Novartis Investigative Site
      • Hamburg, Germany, 20246
        • Novartis Investigative Site
  • Italy
    • BO
      • Bologna, BO, Italy, 40139
        • Novartis Investigative Site
    • MI
      • Milano, MI, Italy, 20133
        • Novartis Investigative Site
    • RM
      • Roma, RM, Italy, 00165
        • Novartis Investigative Site
    • TO
      • Torino, TO, Italy, 10126
        • Novartis Investigative Site
      • Torino, TO, Italy, 101126
        • Novartis Investigative Site
  • Netherlands
      • Rotterdam, Netherlands, 3075 EA
        • Novartis Investigative Site
      • Rotterdam, Netherlands, 3015 CN
        • Novartis Investigative Site
  • Russian Federation
    • Russia
      • Moskow, Russia, Russian Federation, 117198
        • Novartis Investigative Site
  • Spain
      • Madrid, Spain, 28046
        • Novartis Investigative Site
      • Madrid, Spain, 28009
        • Novartis Investigative Site
    • Andalucia
      • Sevilla, Andalucia, Spain, 41013
        • Novartis Investigative Site
    • Catalunya
      • Barcelona, Catalunya, Spain, 08035
        • Novartis Investigative Site
      • Esplugues de Llobregat, Catalunya, Spain, 08950
        • Novartis Investigative Site
    • Comunidad Valenciana
      • Valencia, Comunidad Valenciana, Spain, 46026
        • Novartis Investigative Site
  • Sweden
      • Goteborg, Sweden, 413 45
        • Novartis Investigative Site
  • Switzerland
      • Zürich, Switzerland, 8032
        • Novartis Investigative Site
  • United Kingdom
      • Leeds, United Kingdom, LS9 7TF
        • Novartis Investigative Site
    • Surrey
      • Sutton, Surrey, United Kingdom, SM2 5PT
        • Novartis Investigative Site
  • United States
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Ann & Robert H. Lurie Children Dept of Oncology
    • Maryland
      • Baltimore, Maryland, United States, 21231
        • Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Dept Onc
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Dana Farber Cancer Institute SC-7
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center- New York Presbyterian Dept of Oncology
    • Ohio
      • Cincinnati, Ohio, United States, 45229-3039
        • Cincinnati Children's Hospital Medical Center Division of Hema/Onco.
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213-2583
        • Children's Hospital of Pittsburgh Dept of Oncology
    • Texas
      • Houston, Texas, United States, 77030-4009
        • University of Texas/MD Anderson Cancer Center SC-3
    • Washington
      • Seattle, Washington, United States, 98105
        • Seattle Cancer Care Alliance Dept Oncology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

4 months and older (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with histologically confirmed diagnosis of MB, who have experienced relapse or progression after standard-of-care therapy including radiotherapy. Patients currently receiving steroids must have been on a stable (or decreasing) dose for at least 5 days before initiating study therapy.
  • Only patients with a test result, using the 5-gene Hh signature assay, indicating Hhpathway activated MB are eligible for this study. All available tumor material obtained at any time during the course of the patient's disease should be submitted for these analyses
  • At least one measurable lesion defined as lesion(s) that can be accurately measured in at least two dimensions and is ≥ 10 mm in each dimension by Gadolinium (Gd)-MRI, irrespective of slice thickness/reconstruction interval, for CNS lesions and CT or MRI (with or without contrast) for non-CNS lesions. All patients with CNS lesions must have a brain MRI with and without gadolinium and a spine MRI with gadolinium within 2 weeks prior to first dose of study treatment.

  • Performance Status corresponding to ECOG score of 0, 1, or 2:

    1. Karnofsky performance status score ≥ 50 for patients >16 years of age
    2. Lansky performance status score ≥ 50 for patients ≤ 16 years of age

  • Adequate bone marrow function as defined as:

    1. Peripheral absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    2. Platelet count ≥ 80 x 109/L
    3. Hemoglobin (Hgb) ≥ 9 g/dL
  • Serum CK ≤1.5 ULN

Exclusion Criteria:

  • Prior treatment with a Smoothened inhibitor Systemic anticancer treatment within 2 weeks before first dose of study treatment (6 weeks for nitrosourea, mitomycin, and monoclonal antibodies).
  • Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months before first dose of study treatment.
  • Patients who have neuromuscular disorders that are associated with elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
  • Patients receiving treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5 or are metabolized by CYP2B6 and CYP2C9, that have narrow therapeutic indices that cannot be discontinued at least 2 weeks before first dose of study treatment and for the duration of the study
  • Patients receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms, dose must have been stabilized (or decreasing) for at least 5 days before first dose of study treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Sonidegib (LDE225)
600 mg orally for adults and 500 mg/m2 orally for children
Drug: LDE225
Sonidegib for oral suspension was supplied in amber glass bottles. Sonidegib oral suspension was combined with the supplied reconstitution vehicle to a final concentration of 50 mg/mL.
ACTIVE_COMPARATOR: Temozolamide (TMZ)
150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.
Drug: TMZ
Temozolomide capsules were obtained locally by the Investigator

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Percentage of Participants With Overall Response Rate (ORR) According to Independent Review Committee (IRC) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
Time Frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). Assessments after crossover were not included for TMZ participants.
from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS) According to IRC From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
Time Frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). TMZ participants without event prior to crossover were censored.
from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
PFS According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
Time Frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause. PFS was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma.
from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
Percentage of Participants With ORR According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
Time Frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR). ORR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. Assessments after crossover were not included for TMZ patients.
from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
Duration of Response (DoR) According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
Time Frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
DoR was defined as the time from the first documented onset of confirmed PR or CR to the date of PD/relapse or death due to medulloblastoma. DoR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. TMZ participants without an event prior to crossover were censored.
from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
Overall Survival (OS) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
Time Frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
OS was defined as the time from date of randomization to date of death due to any cause. All deaths are considered, including deaths occurred after crossover for TMZ participants.
from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
Pharmacokinetics (PK): Summary of Plasma Trough Concentrations for Sonidegib (LDE225)
Time Frame: Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and 53
Blood samples were collected for assessment. The children's group was analyzed up until week 25 only.
Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and 53

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Novartis Pharmaceuticals

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 6, 2013

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 5, 2016

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 5, 2016

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 11, 2012

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 15, 2012

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 16, 2012

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 11, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 7, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CLDE225C2301

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