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

In the US, between 350 and 500 new cases of pediatric and adult MBs are
diagnosed each year. In general, 30-40% of children with MB will experience
recurrence after primary treatment compared with 50-60% of adult patients.
There is currently no standard therapy after relapse and most patients will die
of the disease. Median survival time after relapse is usually less than 12
months.
Mutations in the Hh pathway have been identified in approximately 20% to 30% of
sporadic MBs. Thus, it is expected that LDE225, an oral Hh-pathway inhibitor,
would most likely provide clinical benefit only in patients with Hh-pathway
activated (Hh+) tumors.

The primary objective is to investigate the safety and efficacy of LDE225 with
respect to overall response rate according to independent central review (ICR).
The key secondary objective is to assess LDE225 with respect to
progression-free survival (PFS) according to ICR.

This study will evaluate the efficacy and safety of LDE225 in adult and
pediatric patients with Hh+ relapsed MB, who have relapsed following prior
standard-of-care therapy, including radiotherapy. Approximately 20 patients
(adults and children combined) with Hh+ relapsed MB, as determined by the
5-gene Hh signature assay, will be included.

LDE225 oral suspension (50mg/mL) will be used for both adult and pediatric
patients and will be given on a daily basis for 4 weeks.

* Study duration in principle until disease progression. Thereafter follow-up
for survival.
* The screening phase with extensive assessments. Weekly visits during the
first 2 cycles and a monthly visit thereafter.
* Extra blood will be drawn during specific visits for PK-analysis,
Coagulation, total CK, pregnancy test (if applicable), bone biomarker, germline
genetic status.
* Urine collection for catilage biomarker (<18 years only)
* Full Physical examination during selected visits.
* Capture age at menarche (girls > 10 years)
* Tanner staging (assessment pubertal development; <18 years only))
* ECG at screening and every other week for the first 2 cycles and once during
every next cycle and at the end of treatment.
* Neurologic exam during the screening, every 2 cycles thereafter and at the
end of study.
* Knee, wrist and fingers x-ray (<18 years only) at screening and at the end of
treatment. Knee x-ray every 8 weeks, and wrist and fingers x-ray every 6 months
while on treatment. X-ray hemiskeleton if > 4months and < 12 months, at
screening and every 8 weeks.
* Panorex or age appropriate dental x-ray (<18 years only) at screening and at
the end of treatment, and yearly while on treatment.
* Dental exam (<18 years only) at screening and at the end of treatment and
every 12 weeks while on treatment.
* Echocardiogram at screening.
* Taste Questionnaire (LDE arms and < 18 years only) on day 5 after starting
LDE225