Inclusion Criteria:

1. Patients must be ≥ 18 years of age and have a histologically confirmed diagnosis of R/M SCCHN which is no longer amenable to curative surgical or radiation therapy.
2. Patients must sign a written informed consent form and HIPAA statement.
3. Patients must undergo biopsy for confirmation of R/M disease within 6 weeks (42 days) of study entry and be willing and able to comply with peripheral blood collections for the purpose of correlative studies. Biopsy of primary or metastatic site(s) is allowed, provided the site has not been previously irradiated.
4. Patients must have measurable disease as defined by RECIST.
5. Patients must have ECOG PS 0 or 1.
6. Patients must have adequate hematologic function as defined by an ANC ≥ 1,500, hemoglobin ≥ 10 g/dL, and a platelet count ≥ 75,000 obtained within 14 days prior to treatment.
7. Patients must have adequate hepatic function as defined by a total bilirubin ≤ 1.5 mg/dL and AST (SGOT) and ALT (SGPT) ≤ 2 times the ULN obtained within 14 days prior to treatment.
8. Patients must have adequate renal function defined as a serum creatinine ≤ 1.5 mg/dL or calculated CrCl ≥ 55 mL/minute (calculations should be conducted using the Cockroft-Gault equation).
9. Patients must have adequate lipid control defined as a serum cholesterol ≤ 350 mg/dL and serum triglycerides ≤ 300 mg/dL obtained within 14 days prior to treatment.
10. Patients must not have received previous chemotherapy for the treatment of R/M SCCHN. Previous curative-intent treatment with chemotherapy, radiation therapy, chemoradiotherapy, or surgery for locoregional disease is allowed provided at least 3 months have elapsed since the completion of previous therapies and the patient has recovered from all treatment related toxicities.
11. Patients may have received prior radiation therapy for symptomatic sites of disease progression provided that ≥ 21 days have elapsed since treatment and the patient has recovered from any treatment related toxicities.
12. Males and females of reproductive potential must agree to use effective contraception for the duration of study participation.

Exclusion Criteria:

1. Patients with active or prior CNS metastases.
2. Patients with a history of previous hypersensitivity reaction to study drugs.
3. Patients with other active malignancies are excluded. Patients with a history of non-melanoma skin cancers, in-situ cervical cancer, definitively treated stage I or II cancers from which the patient is in remission, or a history of other malignancies from which the patient has been disease free for ≥ 5 years are permitted.
4. Concurrent therapy with any other anti-cancer treatments.
5. Ongoing or active clinically serious infection requiring IV antibiotics or active HIV infection.
6. Patients with a history of symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any medical condition that could compromise the safety of the patient.
7. Patients with, in the best judgment of the investigator, psychosocial, family, sociological, or geographical limitations which could impact the patient's ability to comply with study procedures.
8. Pregnant or lactating females.
9. Employees of the investigator or study center with direct involvement in this or other studies under the direction of the investigative team.
10. Patients currently taking any of the following medications are ineligible: phenytoin, carbamazepine, phenobarbitor, and/or rifampin as these are all strong Cyp3A4/5 inducers.