A randomized, double-blind, placebo-controlled study of RAD001 in the treatment of patients with subependymal giant cell astrocytomas (SEGA) associated with Tuberous Sclerosis Complex (TSC)

TSC is an autosomal dominant genetic disorder caused by inactivating mutations
in the TSC1 or TSC2 genes, and characterized by benign, highly vascular,
hamartoma growth. Lesions occur in the brain, kidneys, heart, liver, lungs and
skin, leading to renal complications, pulmonary failure, autism, mental
retardation, seizures and epilepsy.

Measures of childhood prevalence range from 1 in 6,800 to 1 in 17,300 but full
ascertainment is difficult to achieve. Brain lesions are the primary cause of
morbidity and mortality in this disorder in childhood. The incidence of
subependymal giant cell astrocytoma in TSC varies from 5 to 15%. These are slow
growing lesions that are typically unapparent clinically until they reach
sufficient size to produce ventricular obstruction and hydrocephalus. By the
time symptoms are noted they are often irreversible even by emergent surgical
intervention. They arise deep within the brain in the region of the foramen of
Monro, which hampers their surgical resection, as the approach to the lesion
entails removal of substantial amounts of viable cerebral tissue. Surgery, even
when successful, often results in significant morbidity. The TSC1/TSC2 protein
complex is a negative regulator of the mTOR pathway. Hence, mutation or loss of
either of these gene products in preclinical models is associated with
increased mTOR pathway activation and heightened sensitivity to mTOR inhibitors
mTOR pathway upregulation has also been observed in lesions derived from TSC
patients and TSC1
or TSC2 defective experimental animal models exist which recapitulate the
pathology, behavioral and neurological aspects of the tuberous sclerosis
disease and are sensitive to mTOR inhibition In this respect, experiments are
in progress aimed at analyzing the effects of RAD001 in animal models of TSC.
Preliminary data indicate that gross kidney lesion scores can be significantly
reduced by RAD001 treatment in both TSC1+/- and TSC2+/- mouse models (p = 0.02
compared to untreated controls, unpaired ttest). mTOR inhibition is associated
with a dramatic inhibition of the phosphorylation of the ribosomal S6 protein
in treated kidney lesions (S6 phosphorylation is an established pharmacodynamic
marker of mTOR pathway activation status). Furthermore, a dramatic improvement
in survival has been observed in a mouse brain model of TSC (genotype : Tsc1cc
syn-cre+), with a highly statistically significant improvement in survival (p <
0.0001) associated with RAD001 treatment The investigator also noted an
improvement in behavior, weight gain and neurological phenotype. Assessment of
brain pathology is currently ongoing. Finally, both estrogen and vascular
endothelial growth factor (VEGF)
signaling have been implicated in the pathogenesis and vascularization of TSC
lesions In this respect, RAD001 has been shown to inhibit both estrogen and
VEGF-dependent signaling events Taking all these data into account, there is a
strong rationale for using RAD001 for the treatment of patients.
with tuberous sclerosis.

This study will evaluate the antitumor activity of RAD001 versus placebo in
patients with subependymal giant cell astrocytomas (SEGA) associated with
Tuberous Sclerosis Complex (TSC).

This is a prospective, double-blind, randomized, parallel group,
placebo-controlled, multi-center phase III study evaluating treatment with
RAD001 versus placebo in 99 patients with TSC-associated SEGA.

Screening/Baseline Phase:
Screening/baseline evaluations will be performed within 28 days prior to
treatment day 1. An MRI of the brain should be performed for the baseline tumor
assessment.

Blinded Treatment Phase/Duration of Treatment:
Patients will be randomized to receive either RAD001 or matching placebo.
Patients will be treated with blinded
study treatment until SEGA progression, unacceptable toxicity or
discontinuation for any other reason.

Open Label Treatment Phase:
If SEGA progression is documented by central radiology review during the
blinded treatment phase, then the treating physician may proceed to unblind the
patient.

Follow-Up (for patients who discontinue study treatment):
Patients who have not had SEGA progression at the time of study treatment
discontinuation will be followed up with MRIs of the brain (and MRIs of the
kidney if angiomyolipomata with longest diameter * 1.0 cm were present at
baseline) annually until eventual SEGA progression, or until the start of any
non-study systemic anti-TSC therapy, whichever occurs soonest.

Extension phase:
The data cutoff date for the final analysis will be 6 months after the last
patient is randomized. Once the final trial results are known, and if these
results favor RAD001, then an extension phase will be launched. All patients
still receiving study treatment at this time, as well as those being followed
for posttreatment evaluation, will be given the option of starting open-label
RAD001, which will be provided.

During treatment phase patients will receive 4.5 mg/m2/day RAD001 or placebo.
Dose adjustments will be permitted based on safety findings and blood trough
measurements.

Additional side effects of RAD001 occurring in more than 5% of treated patients
include fatigue, weaknes nausea and vomiting, dry mouth, skin or nail changes
(including acne, rash, redness, itching, dryness or irritation), diarrhea, loss
of appetite (anorexia) resulting in weight loss, abdominal pain, swelling of
the extremities- usually lower limbs, fever abnormal or loss of taste,
inflammation of the throat, bleeding of the nose, inflammation of the lining of
the digestive system, inflammation of the throat, feeling tired, pain in arms
and legs, shortness of breath, dry skin and headache. In some cases RAD001
could change sleep patterns.

There could be a lowering of the number of blood cells, which help fight
infection. This could lead to an infection (which could be potentially life
threatening). In addition, there could be a lowering of the blood cells that
help the blood to clot and the lowering of the protein (hemoglobin) that helps
carry oxygen in the blood. This is not expected to be severe enough to have an
impact on the patients health.
Drugs given to patients like chemotherapy and the study drug, everolimus, can
cause the patient*s immune system to not work as well. A patient with hepatitis
B or hepatitis C could have the virus become more active.

Rarely (less than 1% of patients) RAD001 is associated with a blood clot
trapped in a blood vessel (embolism).

The tests done at each visit are standard medical tests. The most unpleasant is
often having blood samples taken. The risks of taking blood may include
fainting, pain and/or bruising. Rarely, there may be a small blood clot or
infection at the site of the needle puncture. The blood pressure cuff may also
cause discomfort or bruising to the upper arm.
The sticky patches applied to the chest during an ECG can occasionally cause a
rash or redness of the skin when removed.

The risk from a CT scan, for any patients that need to have one if clinically
indicated, is small.
*There is a slight risk of developing an allergic reaction to the contrast
material. The reaction can be mild (itching, rash) or severe (difficulty
breathing or sudden shock). Death resulting from an allergic reaction is rare.
Most reactions can be controlled using medication.
* The contrast material used during CT scanning can cause water loss or damage
to the kidneys that may lead to kidney failure.
* If contrast material is used, patients may be at risk for kidney problems if
they have diabetes, especially if tjey take metformin (Glucophage).
* There is always a slight risk of damage from being exposed to any radiation,
including the low levels of X-rays used for a CT scan. However, the risk of
damage from the X-rays is usually very low compared with the potential benefits
of the test.