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

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.
 
ClinicalTrials.gov Identifier: NCT01708174
Recruitment Status : Completed
First Posted : October 16, 2012
Results First Posted : June 14, 2017
Last Update Posted : August 11, 2017
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE October 11, 2012
First Posted Date  ICMJE October 16, 2012
Results First Submitted Date  ICMJE March 31, 2017
Results First Posted Date  ICMJE June 14, 2017
Last Update Posted Date August 11, 2017
Actual Study Start Date  ICMJE May 6, 2013
Actual Primary Completion Date October 5, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 16, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 15, 2012)
Overall response rate (ORR) [ Time Frame: 8 weeks ]
ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR). (As per Tumor response guidelines and criteria for Medulloblastoma. ORR will be done by independent central review.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2017)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2012)
  • Progression free survival (PFS) [ Time Frame: 8 weeks ]
    PFS is 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
  • Overall response rate (ORR) [ Time Frame: 8 weeks ]
    As per Tumor response guidelines and criteria for Medulloblastoma. ORR will be done by local investigator assessment.
  • Duration of response (DoR) [ Time Frame: 8 weeks ]
    DoR is 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.
  • Overall survival (OS) [ Time Frame: 4 weeks ]
    OS is defined as the time from date of randomization to date of death due to any cause.
  • Safety and tolerability of LDE225 treatment [ Time Frame: 4 weeks ]
    Adverse and serious adverse events, clinically significant changes in hematology and chemistry values, assessment of physical and/or neurological examinations, vital signs, electrocardiograms, bone x-rays, dental x-rays (e.g., panorex or age appropriate dental x-ray), and dental exams (as appropriate for age)
  • Pharmacokinetics (Pk) - Cmin [ Time Frame: 2 weeks ]
    PK of LDE225 and any relevant metabolites
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
Official Title  ICMJE 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
Brief Summary This Phase II study evaluated the safety and efficacy of LDE225 in adult and pediatric patients with Hh-pathway activated, relapsed MB.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Medulloblastoma
Intervention  ICMJE
  • 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.
  • Drug: TMZ
    Temozolomide capsules were obtained locally by the Investigator
Study Arms  ICMJE
  • Experimental: Sonidegib (LDE225)
    600 mg orally for adults and 500 mg/m2 orally for children
    Intervention: Drug: LDE225
  • 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.
    Intervention: Drug: TMZ
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 9, 2015)
22
Original Estimated Enrollment  ICMJE
 (submitted: October 15, 2012)
109
Actual Study Completion Date  ICMJE October 5, 2016
Actual Primary Completion Date October 5, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Months and older   (Child, 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,   Brazil,   Canada,   France,   Germany,   Italy,   Netherlands,   Russian Federation,   Spain,   Sweden,   Switzerland,   United Kingdom,   United States
Removed Location Countries Belgium,   Hungary,   Israel,   Poland
 
Administrative Information
NCT Number  ICMJE NCT01708174
Other Study ID Numbers  ICMJE CLDE225C2301
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
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 August 2017

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