Clinical trial NCT01708174: A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Medulloblastoma
Keywords: medulloblastoma,
relapsed,
pediatric,
children,
adults,
Hh pathway inhibitor,
LDE225
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-10-16
Enrollment: 22
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
Secondary outcomes:
measure: Progression Free Survival (PFS) According to IRC From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
timeFrame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
measure: PFS According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
timeFrame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
measure: 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
timeFrame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
measure: 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
timeFrame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
measure: Overall Survival (OS) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
timeFrame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
measure: Pharmacokinetics (PK): Summary of Plasma Trough Concentrations for Sonidegib (LDE225)
timeFrame: Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and 53
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children Dept of Oncology
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Dept Onc
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC-7
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center- New York Presbyterian Dept of Oncology
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center Division of Hema/Onco.
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh Dept of Oncology
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center SC-3
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance Dept Oncology
state: Washington
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Perth
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Bordeaux
country: France
facility: Novartis Investigative Site
state: Aquitaine
city: Angers Cedex 1
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Vandoeuvre les Nancy
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Moskow
country: Russian Federation
facility: Novartis Investigative Site
state: Russia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Esplugues de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Goteborg
country: Sweden
facility: Novartis Investigative Site
city: Zürich
country: Switzerland
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: