A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
This Phase II study evaluated the safety and efficacy of LDE225 in adult and pediatric
 patients with Hh-pathway activated, relapsed MB.
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.
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.