Selection of Chemoradiotherapy Based on Response to Induction Chemotherapy - a Randomized Phase II Study in Locally Advanced Squamous Cell Carcinoma of Head and Neck

Inclusion Criteria:

- Treatment naïve stage III (hypopharynx, or nasopharynx primary) or stage IVa/IVb (all
sites) histologically proven SCCHN with no definitive evidence of metastatic disease

- Patients with unknown primary site of tumor and histologically proven squamous cell
carcinoma of a cervical lymph node felt to arise from a site in the head and neck are
eligible

- Patients must have at least one measurable site of disease according to RECIST
criteria

- Age ≥ 18 years

- Karnofsky performance status > 70%

- Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x
109/L, Hb >9 g/dL

- Adequate liver function as shown by:

- Serum bilirubin ≤ 1.5 x ULN

- ALT and AST ≤ 2.5x ULN

- INR and PTT ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose
of warfarin or on a stable dose of LMW heparin for >2 weeks at time of
randomization.)

- Adequate renal function: serum creatinine ≤ 1.5 x 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.

- 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 [defined as requiring general anesthesia but
not including tonsillectomy, neck dissection, or panendoscopy (triple endoscopy or
examination under general anesthesia)], 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; 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. 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

- Unequivocal demonstration of metastatic disease (i.e. M1 disease).

- 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

- 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 everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection)

- Nota bene: subjects that require administration of everolimus through a feeding tube
are allowed to participate

- 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 everolimus)

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

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

- Patients with a know hypersensitivity to cetuximab, cremaphor, paclitaxel,
carboplatin, 5FU, hydroxyurea, or any compounds of similar chemical or biologic
composition

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol

- Baseline neurologic deficit (> grade II neuropathy)

- Prior severe infusion reaction (grade 4) to a monoclonal antibody