Phase II Study of RAD001 Head and Neck Cancer

The study of the efficacy of RAD001 will proceed in two stages after the method of Simon . In
the first stage 15 patients will be accrued and treated. If 9 or fewer patients show clinical
benefit the study will be terminated. If 10 or more patients show clinical benefit the study
will proceed to the second stage, accruing an additional 26 patients. If the second stage is
complete and a total of 29 or more patients show clinical benefit among the 41 patients
treated, the treatment CBR for will be considered high enough to warrant further study.
Conversely, if the evaluation of RAD001 concludes at the first stage, or if 28 or fewer
patients experience a clinical benefit after completing the second stage, the therapy will
not be considered for further study.

Current knowledge about the molecular mechanisms of cancer-related pathways involved in
cellular signaling, cell cycle regulation and cell death is yielding therapies directed at
specific components of these pathways, such as the epidermal growth factor receptor (EGF-R),
the mammalian target of rapamycin (mTOR), the vascular endothelial growth factor receptor
(VEGF-R) and the insulin-like growth factor receptor (IFG-R). Both small molecule and
monoclonal antibody therapies directed against these targets are available. Furthermore,
immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and mutation analysis
are available for profiling expression of pathway components, raising the possibility of
individualized prognosis and therapy.

One receptor in particular, is both a prognostic factor and a therapeutic target in HNSCC.
Upregulation of EGF-R expression and aberrant activation of kinase cascades downstream of
this receptor occur early in the process of carcinogenesis and play a major role in malignant
progression.1 The level of EGF-R expression correlates with recurrence and poor prognosis in
HNSCC. A well tolerated anti-EGF-R monoclonal antibody, cetuximab, has shown remarkable
activity against HNSCC, including statistically significant improvement in survival for
patients with locally advanced disease treated with radiotherapy, leading to its regulatory
approval for this disease.2 Unfortunately, despite survival advances achieved with EGF-R
inhibitors, the majority (~60%) of patients with advanced disease are refractory to EGF-R
directed therapies.3 One anticipated mechanism by which the current regimen may fail in some
patients is the upregulation of escape pathways downstream of the EGF-R. A pathway of
particular interest is the PI3/AKT/mTOR axis, within which the mTOR protein may be targeted
by the tyrosine kinase inhibitor RAD001.

In order to investigate pathway components that may act as an escape mechanism while
concurrently targeting a downstream kinase that may enable rescue from resistance to EGF-R
directed therapies, we propose this prospective, phase II, single-arm, single-agent
interventional clinical trial of RAD001 for patients with refractory SCCHN. The primary
outcome is activity of RAD001 while secondary outcomes include safety, toxicity and extensive
laboratory correlates to be performed on tumor tissues. By carrying out this
clinic-translational trial of the novel mTOR inhibitor, RAD001, in patients with refractory
SCCHN, we aim to explore mechanisms of activity of and resistance to inhibitors of the EGF-R
pathway components while measuring the clinical activity of RAD001.

Inclusion Criteria:

- Histologically or cytologically documented squamous cell CA of the head and neck

- Metastatic and/or recurrent head and neck cancer (not eligible for curative intent
surgical or radiation therapy)

- Patients must have at least one measurable site of disease according to RECIST
criteria that has not been previously irradiated. If the patient has had previous
radiation to the marker lesion(s), there must be evidence of progression since the
radiation

- Performance status 0-2

- Age ≥18 years

- Non-pregnant

- Prior treatment:

- Prior treatment for recurrent or metastatic disease required (at least one): up to but
no more than 2 regimens (chemotherapy and/or biologic) allowed.

- Prior induction and concomitant chemoradiotherapy with a curative intent (with or
without biologic agents) is allowed

- No other serious medical or psychiatric disease

- Required Lab Values:

Granulocytes ≥ 1,500/µl Platelets ≥ 100,000/µl Bilirubin ≤ 1.5 x ULN INR ≥ 1.3 (or < 3 if
on anticoagulation) AST or ALT ≤ 2.5 x ULN (< 5 x ULN in patients with liver metastases)
Creatinine ≤ ULN or Creatinine Clearance >= 60 mL/min, if creatinine above ULN

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x
ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only
be included after initiation of appropriate lipid lowering medication.

- Patients with accessible tumor tissue must agree to a pre-treatment biopsy at
screening. If available, original diagnostic tissue may be submitted in place of the
pre-treatment biopsy.

- Signed informed consent

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of study drug (including chemotherapy, radiation
therapy, antibody based therapy, etc.)

- Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

- Prior treatment with any investigational drug within the preceding 4 weeks

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent, except corticosteroids with a daily dosage equivalent to
prednisone ≤ 20 mg. However, patients receiving corticosteroids must have been on a
stable dosage regimen for a minimum of 4 weeks prior to the first treatment with
RAD001. Topical or inhaled corticosteroids are allowed.

- Patients should not receive immunization with attenuated live vaccines within one week
of study entry or during study period

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or IV

- unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any
other clinically significant cardiac disease

- severely impaired lung function as defined as spirometry and DLCO that is 50% of the
normal predicted value and/or 02 saturation that is 88% or less at rest on room air.
PFTs as clinically indicated.

- uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

- active (acute or chronic) or uncontrolled severe infections

- liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis

- A known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

- Patients with an active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. If barrier contraceptives
are being used, these must be continued throughout the trial by both sexes. Hormonal
contraceptives are not acceptable as a sole method of contraception. (Women of
childbearing potential must have a negative urine or serum pregnancy test within 7
days prior to administration of RAD001)

- Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus).

- Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins
(sirolimus, temsirolimus) or to its excipients

- Patients unwilling to or unable to comply with the protocol