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

NCT ID: NCT01708174

Last Updated: 2017-08-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-06
• Study Completion Date: 2016-10-05

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.

Conditions

Medulloblastoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sonidegib (LDE225)

600 mg orally for adults and 500 mg/m2 orally for children

Group Type: EXPERIMENTAL

LDE225

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

TMZ

Intervention Type: DRUG

Temozolomide capsules were obtained locally by the Investigator

Interventions

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.

Intervention Type: DRUG

TMZ

Temozolomide capsules were obtained locally by the Investigator

Intervention Type: DRUG

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.

• Minimum Eligible Age: 4 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Ann & Robert H. Lurie Children Dept of Oncology

Chicago, Illinois, 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

Columbia University Medical Center- New York Presbyterian Dept of Oncology

New York, New York, United States

Cincinnati Children's Hospital Medical Center Division of Hema/Onco.

Cincinnati, Ohio, United States

Children's Hospital of Pittsburgh Dept of Oncology

Pittsburgh, Pennsylvania, United States

University of Texas/MD Anderson Cancer Center SC-3

Houston, Texas, United States

Seattle Cancer Care Alliance Dept Oncology

Seattle, Washington, United States

Novartis Investigative Site

Herston, Queensland, Australia

Novartis Investigative Site

Perth, Western Australia, Australia

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Bordeaux, Aquitaine, France

Novartis Investigative Site

Angers, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Toulouse, , France

Novartis Investigative Site

Vandœuvre-lès-Nancy, , France

Novartis Investigative Site

Villejuif, , France

Novartis Investigative Site

Augsburg, , Germany

Novartis Investigative Site

Essen, , Germany

Novartis Investigative Site

Hamburg, , Germany

Novartis Investigative Site

Bologna, BO, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Roma, RM, Italy

Novartis Investigative Site

Torino, TO, Italy

Novartis Investigative Site

Torino, TO, Italy

Novartis Investigative Site

Rotterdam, , Netherlands

Novartis Investigative Site

Rotterdam, , Netherlands

Novartis Investigative Site

Moscow, Russia, Russia

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Esplugues de Llobregat, Catalonia, Spain

Novartis Investigative Site

Valencia, Valencia, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Gothenburg, , Sweden

Novartis Investigative Site

Zurich, , Switzerland

Novartis Investigative Site

Sutton, Surrey, United Kingdom

Novartis Investigative Site

Leeds, , United Kingdom

Countries

United States; Australia; Brazil; Canada; France; Germany; Italy; Netherlands; Russia; Spain; Sweden; Switzerland; United Kingdom

Other Identifiers

CLDE225C2301

Identifier Type: -

Identifier Source: org_study_id