Phase II Randomized Trial of the Combination of Cetuximab and Sorafenib or Single Agent Cetuximab

PRIMARY OBJECTIVES:

I. Compare the progression free survival (PFS) of the combination of cetuximab and sorafenib
to that of cetuximab alone in patients with recurrent, refractory or metastatic squamous cell
carcinoma of the head and neck (SCCHN).

SECONDARY OBJECTIVES:

I. To evaluate the response rate, overall survival (OS) and toxicity of the combination of
cetuximab and sorafenib and of cetuximab alone.

II. To evaluate the presence of EGFRvIII mutation, increased EGFR gene copy number and
activated EGFR gene expression signature, and correlate with clinical parameters (RR, OS and
PFS) in the cetuximab alone and cetuximab/sorafenib arms.

III. To evaluate whether VEGF receptor family and their ligand expression can predict
response to cetuximab/sorafenib.

IV. To determine the proteomic profiles in serum and tumors that can predict the response and
survival upon the treatment with cetuximab or cetuximab/sorafenib.

V. To evaluate the effect of therapy on both general and head and neck specific
functionality, symptom burden and QOL.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral
placebo twice daily on days 1-21. (oral placebo closed as of 02/18/2010).

ARM II: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral
sorafenib tosylate twice daily on days 1-21.

In both arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Paraffin embedded tissue samples are collected at baseline for pharmacogenomic studies and
blood samples are collected at baseline and for the first 3 courses for research purposes.
Quality of life and symptom burden are assessed by Vanderbilt Head and Neck Symptom Survey,
FACT-HN, and Fatigue and Pain Inventory questionnaires at baseline, at day 43, and at 3 and 6
months.

After completion of study treatment, patients are followed periodically for 3 years.

Inclusion Criteria:

- Patients with recurrent, refractory or metastatic squamous cell carcinoma of oral
cavity, oropharynx and larynx, hypopharynx or paranasal sinus, head and neck unknown
primary or nasopharyngeal carcinoma WHO type 1; patients with recurrent, refractory or
metastatic squamous cell carcinoma of oral cavity, oropharynx and larynx, hypopharynx
or paranasal sinus, head and neck unknown primary or nasopharyngeal carcinoma WHO type
1; patients may have had up to 1 prior palliative chemotherapy for recurrent or
metastatic disease; please note that chemotherapy given as part of a regimen for
curative intent for recurrent disease does not count as "prior chemotherapy;" patients
must not presently be candidates for curative therapy

- ECOG performance status 0, 1 or 2

- Hemoglobin >= 9.0/dl

- Absolute-neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 x ULN

- ALT and AST =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement)

- INR < 1.5 or a PT and PTT within normal limits

- Creatinine =< 1.5 x ULN

- If primary therapy was given for curative intent, at least 4 weeks must have elapsed
after completion of primary therapy prior to enrollment on this clinical trial;
however, toxicities from prior treatment must have resolved to grade 1 or less

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of the treatment; women of childbearing potential and
men must agree to use adequate contraception prior to study entry and for the duration
of study participation (i.e, a hormonal contraceptive, intra-uterine device, diaphragm
with spermicide, condom with spermicide, or abstinence) for the duration of the study
and for a minimum of 3 months following the last dose of chemotherapy; male subject
agrees to use an acceptable method for contraception for the duration of the study and
for a minimum of 3 months following the last dose of chemotherapy

- Patients must have a measurable disease defined by RECIST criteria

- 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:

- Prior treatment with sorafenib or cetuximab

- Patients with active clinically significant infection or with a fever >= 38.5º C
within 3 days of the first scheduled day of protocol treatment

- History of prior malignancy within the past 3 years except for curatively treated
basal cell carcinoma and squamous cell carcinoma of the skin, CIN or localized
prostate cancer with a current 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

- Patients with known hypersensitivity to sorafenib or cetuximab

- Prior severe infusion reaction to a monoclonal antibody

- History of hand-foot syndrome

- Pregnant or lactating; sexually active women of childbearing potential must use an
effective method of birth control during the course of the study, in a manner such
that risk of failure is minimized

- Known untreated brain metastasis; patients with neurological symptoms must undergo a
CT scan/MRI of the brain to exclude brain metastasis or progression of brain
metastasis; patients with treated brain metastasis are eligible for study as long as
no evidence of progression of CNS disease; hemorrhagic brain metastases are not
allowed on study

- Uncontrolled comorbid illness

- Patients with HIV who are taking antiretroviral mediations will be excluded because of
the potential interactions of anti-retroviral medications with these agent; however,
given the potential immune modulating effects of sorafenib, investigators should still
be very cautious about placing HIV positive patients on this trial as the effects of
these medications on the HIV virus itself are not know

- History of allogeneic transplant

- Patient has received other investigational drugs within 28 days before enrollment

- Cardiac disease: congestive heart failure > class II NYHA; patients must not have
unstable angina (anginal symptoms at rest) or new onset angina (began within the last
3 months) or myocardial infarction within the past 6 months; significant history of
uncontrolled cardiac disease; i.e., uncontrolled hypertension (defined as defined as
systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal
medical management), uncontrolled congestive heart failure, and cardiomyopathy with
decreased ejection fraction will also be excluded from study; cardiac ventricular
arrhythmias requiring anti-arrhythmic therapy will also be excluded from study

- Thrombotic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event > CTCAE grade 2 within 4 weeks of first dose of
study drug

- Any other hemorrhage/bleeding event > CTCAE grade 3 within 4 weeks of first dose of
study drug

- Tumor that invades the carotid artery as shown unequivocally by imaging studies

- Serious non-healing wound, ulcer, or bone fracture

- Evidence or history of bleeding diathesis or coagulopathy

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
study drug

- Use of St. John's Wort or rifampin (rifampicin)

- Use of the following medications will not be allowed within 4 weeks prior to
enrollment on the study and during the study: ketoconazole, itraconazole, ritonavir,
cyclosporine, carbamazepine, phenytoin, phenobarbital; products containing grapefruit
juice will not be allowed while on study

- Known or suspected allergy to sorafenib or any agent given in the course of this trial

- Any malabsorption problem

- Known HIV positive patients will be excluded from trial due to the potential immune
modulation that these agents may cause