A Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab In Patients With Recurrent Or Metastatic Head and Neck Cancer

Inclusion Criteria:

- Histologically or cytologically confirmed squamous cell carcinoma of the head and
neck (SCCHN) from any primary site, including unknown primary cancers of the head and
neck

- No nasopharyngeal carcinoma of histologic types World Health Organization (WHO)
2 or 3

- No squamous cell carcinoma that originated in the skin

- Recurrent disease, incurable disease as determined by surgery or radiation, or
metastatic disease

- A second primary SCCHN allowed if eligibility is based on a recurrent or
metastatic first primary SCCHN

- Patients who refuse radical resection for recurrent disease are eligible

- Patients must have measurable disease based on Response Evaluation Criteria in Solid
Tumors (RECIST)

- Disease in previously irradiated sites is considered measurable if there has
been unequivocal disease progression or biopsy-proven residual carcinoma after
radiotherapy

- Persistent disease after radiotherapy must be biopsy proven at least 8 weeks
after completion of radiotherapy (radiographic findings are acceptable providing
that clear cut measurements can be made)

- Patients must be progression-free for at least 6 months after completion of
chemotherapy or chemoradiotherapy or radiotherapy plus cetuximab given as part of
initial potential curative therapy (if received such prior therapy)

- At least 6 months since completion of prior concurrent radiotherapy plus
cetuximab (8 weeks for cetuximab given as part of adjuvant regimen post
radiotherapy)

- Patients having progression after 2 courses of induction chemotherapy are not
eligible

- No tumors that invade major vessels (e.g., the carotid) as shown unequivocally by
imaging studies

- No known brain metastases

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Hemoglobin >= 8.0 g/dL

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

- Creatinine clearance >= 60 mL/min

- Total bilirubin normal

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and alkaline
phosphatase must meet one of the following criteria:

- Alkaline phosphatase normal AND AST or ALT =< 5 x upper limit of normal (ULN)

- Alkaline phosphatase > 1 but =< 2.5 x ULN AND AST or ALT > 1 but =< 1.5 x ULN

- Alkaline phosphatase > 2.5 but =< 5 x ULN AND AST or ALT normal

- Urine dipstick must be < 0-1+ within 2 weeks (14 days) of randomization; if urine
dipstick result is > 1+, a calculation of Urine Protein Creatinine (UPC) ratio is
required; patients must have a UPC ratio < 1.0 to participate in the study

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Patients who meet the following criteria will be excluded due to the possibility of
increased risk for tumor bleeding with bevacizumab therapy:

- Tumors that invade major vessels (e.g. the carotid) as shown unequivocally by
imaging studies

- Central (i.e. within 2 cm from the hilum) lung metastases that are cavitary as
shown unequivocally by imaging studies

- Any prior history of bleeding related to the current head and neck cancer

- History of gross hemoptysis (bright red blood of 0.5 teaspoon or more per
episode of coughing) =< 3 months prior to enrollment

- No history of coagulopathy or hemorrhagic disorders

- No history of thrombosis (e.g., pulmonary embolism or deep venous thrombosis)
currently requiring therapeutic anticoagulation (prophylactic use of warfarin 1
mg/day is allowed)

- International normalized ratio (INR) < 1.5 at registration

- No hypercalcemia related to head and neck cancer

- Patients with a prior history of squamous cell or basal cell carcinoma of the skin or
in situ carcinoma of the cervix must have been curatively treated

- Patients with a history of other prior malignancy must have been treated with
curative intent and must have remained disease free for 5 years post diagnosis

- No current peripheral neuropathy >= grade 2

- Patients must not have any co-existing condition that would preclude full compliance
with the study

- No history of severe hypersensitivity reaction to docetaxel or other drugs formulated
with polysorbate 80 (if the physician's choice of chemotherapy is docetaxel)

- Patients must have a blood pressure (BP) =< 150/90 mm Hg within 2 weeks prior to
randomization

- Patients with a history of hypertension must be well-controlled upon study entry
(BP =< 150/90 mm Hg) on a stable regimen of anti-hypertensive therapy

- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to registration

- No significant traumatic injury within the past 28 days

- No serious nonhealing wound, ulcer, or bone fracture

- No unstable angina or myocardial infarction within the past 6 months

- No symptomatic congestive heart failure or New York Heart Association (NYHA) class
II-IV heart disease

- No history of aortic dissection or presence of aneurysm > 6 cm (or at high risk for
rupture)

- No serious cardiac arrhythmia requiring medication (history of chronic atrial
fibrillation or other atrial arrhythmia with controlled rate on medication is
allowed)

- No clinically significant peripheral vascular disease manifested by intermittent
claudication or need for vascular intervention

- No history of any central nervous system (CNS) cerebrovascular ischemia or stroke
within the past 6 months

- No active serious infection

- No history of a serious human anti-human antibody (HAHA) reaction

- Patients with known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human antibodies are not eligible

- Chronic latex xerostomia, speech and swallowing abnormalities, resulting from prior
radiation or surgery, allowed provided nutritional status is stable

- No other prior malignancy except curatively treated squamous cell or basal carcinoma
of the skin, in situ cervical cancer, or malignancy for which the patient has been
curatively treated and remains disease-free for the past 3 years

- No concurrent bisphosphonates for bone metastasis unless initiated > 3 months before
study entry

- Patients must have recovered to grade 1 or better from the effects of any prior
surgery, chemotherapy, or radiotherapy AND > 4 weeks post-surgery

- A maximum of one prior radiotherapy regimen, curative or palliative, to the head and
neck is allowed; if the radiation is combined with chemotherapy and/or cetuximab, a
minimum of 4 months must elapse between the end of radiotherapy and registration; if
the radiation is given alone, a minimum of 8 weeks must elapse between the end of
radiotherapy and registration; a minimum of 3 weeks must elapse between prior
radiation to other areas and registration

- No prior bevacizumab

- No prior chemotherapy or biologic/molecular-targeted therapy for recurrent or
metastatic SCCHN

- Patients may have received one regimen of induction, concurrent
chemoradiotherapy, and/or adjuvant chemotherapy as part of initial potential
curative therapy

- A minimum of 6 months is required between last dose of chemotherapy or
chemoradiotherapy and study treatment

- No major surgical procedure or open biopsy within 28 days prior to study enrollment,
or anticipation of need for major surgical procedure during the course of the study

- More than 4 weeks since prior surgery

- No other concurrent investigational agent

- Patients must not be receiving chronic daily treatment with aspirin (> 325 mg/day) or
nonsteroidal anti-inflammatory agents (NSAIDs) known to inhibit platelet function

- The use of anti-platelet agents (e.g., dipyridamole [Persantine], ticlopidine
[Ticlid], or clopidogrel [Plavix]) is allowed only if patient is not receiving
aspirin or NSAIDs known to inhibit platelet function

- No human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy

- No other concurrent chemotherapy, immunotherapy, antitumor hormonal therapy
(excluding contraceptives and replacement steroids), radiotherapy, or experimental
medications

- No concurrent amifostine