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

Medulloblastoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01708174
• Other study ID #: CLDE225C2301
• Status: Completed
• Phase: Phase 2
• First received: October 11, 2012
• Last updated: August 7, 2017
• Start date: May 6, 2013
• Est. completion date: October 5, 2016

Study information

• Verified date: August 2017
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: October 5, 2016
• Est. primary completion date: October 5, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Months and older

Eligibility

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.

Related Conditions & MeSH terms

• Medulloblastoma

Intervention

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.
• TMZ
Temozolomide capsules were obtained locally by the Investigator

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Herston	Queensland
Australia	Novartis Investigative Site	Perth	Western Australia
Brazil	Novartis Investigative Site	Sao Paulo	SP
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
France	Novartis Investigative Site	Angers Cedex 1
France	Novartis Investigative Site	Bordeaux	Aquitaine
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Toulouse Cedex 9
France	Novartis Investigative Site	Vandoeuvre les Nancy
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Hamburg
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Torino	TO
Netherlands	Novartis Investigative Site	Rotterdam
Netherlands	Novartis Investigative Site	Rotterdam
Russian Federation	Novartis Investigative Site	Moskow	Russia
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Esplugues de Llobregat	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Goteborg
Switzerland	Novartis Investigative Site	Zürich
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	Sutton	Surrey
United States	Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Dept Onc	Baltimore	Maryland
United States	Dana Farber Cancer Institute SC-7	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children Dept of Oncology	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center Division of Hema/Onco.	Cincinnati	Ohio
United States	University of Texas/MD Anderson Cancer Center SC-3	Houston	Texas
United States	Columbia University Medical Center- New York Presbyterian Dept of Oncology	New York	New York
United States	Children's Hospital of Pittsburgh Dept of Oncology	Pittsburgh	Pennsylvania
United States	Seattle Cancer Care Alliance Dept Oncology	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  France,  Germany,  Italy,  Netherlands,  Russian Federation,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	Progression Free Survival (PFS) According to IRC 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
Secondary	PFS According to Local Investigator Assessment 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
Secondary	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	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
Secondary	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	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
Secondary	Overall Survival (OS) 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
Secondary	Pharmacokinetics (PK): Summary of Plasma Trough Concentrations for Sonidegib (LDE225)	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

External Links

•   Results for CLDE225C2301 from the Novartis Clinical Trial Results Website