The purpose of this study is to test the drug RAD001 in combination with other chemotherapy drugs, Carboplatin and Cetuximab. Because RAD001 has not been used in this combination before, it is not clear which dose will be best when used in combination.

The investigators will test the safety of RAD001 in combination with Carboplatin and Cetuximab and see what effects (good and/or bad) it has on your cancer, and find the highest dose of RAD001 that can be given without causing bad side effects. The doses of Carboplatin and Cetuximab will not be varied as both these drugs are considered to be part of the current standard of care for patients with your condition.

Inclusion Criteria:

• Patients must have at least one measurable site of disease according to Response Evaluation Criteria in Solid Tumors (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.

• Histologically or cytologically proven squamous cell carcinoma of the head and neck (SCCHN).

• Patients with recurrent, refractory or metastatic squamous cell carcinoma of oral cavity, oropharynx and larynx, hypopharynx or paranasal sinus, and unknown primary SCCHN who failed to respond to, or relapsed from prior chemoradiotherapy for definitive treatment of disease.

• Evaluable locoregional and/or metastatic disease according to RECIST criteria (see Section 6) that is not appropriate for treatment by primary surgical resection or radiotherapy.

• Patients may not have had prior chemotherapy for recurrent or metastatic disease.

• Patients must not be candidates for curative therapy.

• Age ≥ 18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• Life expectancy of ≥ 4 months.

• Adequate bone marrow, liver and renal function as assessed by the following:

  • Hemoglobin ≥ 9.0/dl
  • Absolute-neutrophil count (ANC ) ≥ 1500/mm3
  • Platelet count ≥ 100,000/mm3
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement)
  • International normalized ratio (INR) ≤ 1.5 or a prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight (LMW) heparin for > 2 weeks at time of randomization)
  • 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.

• Women of childbearing potential must have a negative pregnancy test within 7 days prior to first receiving investigational product. Sexually active women of childbearing potential (WOCBP) must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control. All WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study participation.

• Signed informed consent prior to beginning protocol specific procedures. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial.

Exclusion Criteria:

• History of prior malignancy within the past 5 years except for curatively treated basal cell carcinoma and squamous cell carcinoma of the skin, cervical intraepithelial neoplasia (CIN) or localized prostate cancer with a current prostate-specific antigen (PSA) < 1.0 mg/dL on 2 successive evaluations at least 3 months apart, with the most recent evaluation within 4 weeks of study entry.

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.

• 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.).

• Prior treatment with any investigational drug within the preceding 4 weeks.

• Any unresolved toxicity (except alopecia) greater than NCI-Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0 grade 2 from prior systemic anticancer therapy.

• Patients who have received prior treatment with a mammalian target of rapamycin (mTOR) inhibitor (sirolimus, temsirolimus, everolimus).

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

• Prior therapy with Cetuximab will be allowed provided it was part of definitive therapy and not part of treatment for recurrent or metastatic disease.

• Prior severe infusion reaction to a monoclonal antibody.

• 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.

• 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.

• 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 diffusing capacity of lung for carbon monoxide (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

• Abnormal liver function tests (LFTs) as follows: total bilirubin (TB) > 1.5x ULN, alanine aminotransferase (ALT) > 1.25x ULN, and/or alkaline phosphatase > 2.5 x ULN (except when LFTs attributed to metastatic SCCHN, in which case, TB, ALT and alkaline phosphatase must be ≤ NCI-CTCAE, v3.0 grade 1).

• Absolute neutrophil count < 1000/mm3 or platelets < 100,000/mm3.

• 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. (WOCBP must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001).

• History of noncompliance to medical regimens.

• Patients unwilling to or unable to comply with the protocol.

Up to 25 months

Limitations of this analysis include the small sample size in this phase 1b study, a patient population with mixed primary sites of disease, and variable doses of everolimus.