Bevacizumab, Cisplatin, Radiation Therapy, and Fluorouracil in Treating Patients With Stage IIB, Stage III, Stage IVA, or Stage IVB Nasopharyngeal Cancer

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of bevacizumab and chemoradiotherapy comprising
cisplatin and radiotherapy followed by adjuvant therapy comprising cisplatin, fluorouracil,
and bevacizumab in patients with stage IIB-IVB nasopharyngeal cancer.

SECONDARY OBJECTIVES:

I. Determine the 1- and 2-year rates of locoregional progression-free in patients treated
with this regimen.

II. Determine the 1- and 2-year rates of distant metastases-free in patients treated with
this regimen.

III. Determine the 1- and 2-year rates of progression-free and overall survival of patients
treated with this regimen.

OUTLINE: This is a multicenter study.

BEVACIZUMAB AND CHEMORADIOTHERAPY: Patients receive bevacizumab IV over 30-90 minutes and
cisplatin IV over 20-30 minutes on day 1. Treatment repeats every 21 days for 3 courses in
the absence of disease progression or unacceptable toxicity. Beginning in week 1, patients
also undergo three-dimensional conformal radiotherapy or intensity-modulated radiotherapy
once daily 5 days a week for a total of 33 fractions.

ADJUVANT THERAPY: Beginning in week 10, patients receive fluorouracil IV continuously over 96
hours on days 1-4, cisplatin IV over 20-30 minutes on day 1 OR days 1 and 2, and bevacizumab
IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence
of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Inclusion Criteria:

- Histologically confirmed cancer of the nasopharynx based on biopsy of a primary lesion
and/or lymph nodes

- Histologic WHO types I-IIb/III

- Stage IIB-IVB disease

- No T1-2, N1 disease in which node positivity is based on the presence of
retropharyngeal lymph nodes

- No distant metastases

- Zubrod performance status 0-1

- WBC ? 4,000/mm?

- Hemoglobin ? 9.0 g/dL

- Platelet count ? 100,000/mm?

- Absolute neutrophil count ? 1,500/mm?

- INR ? 1.5

- aPTT ? 1.5 times upper limit of normal (ULN)

- Alkaline phosphatase ? 1.5 times ULN

- ALT and AST ? 1.5 times ULN

- Bilirubin ? 1.5 times ULN

- Creatinine ? 1.5 mg/dL OR creatinine clearance ? 55 mL/min

- Urine protein:creatinine (UPC) ratio < 1.0

- If UPC > 0.5, 24-hour urine protein must be < 1,000 mg

- Hearing loss primarily sensorineural in nature and requiring a hearing aid or
intervention that interferes in a clinically significant way with activities of daily
living allowed

- Conductive hearing loss from tumor-related otitis media is allowed

- No severe, active comorbidity, including any of the following:

- Ongoing bleeding diathesis, hemorrhagic disorder, or coagulopathy within the past
6 months

- Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within the past 6 months

- Esophageal varices, nonhealing wound, nonhealing ulcer, or bone fracture within
the past 6 months

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within the past 30 days

- Unstable angina and/or congestive heart failure or peripheral vascular disease
requiring hospitalization within the past 12 months

- Major medical or psychiatric illness that, in the opinion of the study
investigator, would preclude study compliance

- Active, untreated infection and/or acute bacterial or fungal infection requiring
intravenous antibiotics

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- History of significant weight loss (> 15% from baseline)

- History of arterial thromboembolic events

- Acquired immune deficiency syndrome

- Transmural myocardial infarction

- Cerebrovascular accident

- Transient ischemic attack

- Any other cardiac condition that, in the opinion of the investigator, would
preclude study compliance

- No gross hemoptysis or hematemesis, defined as bright red blood of ? 1 teaspoon per
coughing episode, within the last 4 weeks (incidental blood mixed with phlegm allowed)

- No other invasive malignancy within the past 3 years except nonmelanoma skin cancer or
carcinoma in situ of the breast, oral cavity, or cervix

- Nutritional and physical condition considered suitable for study treatment

- No significant traumatic injury within the past 4 weeks

- No history of allergic reaction to the study drugs

- No baseline blood pressure > 150/100 mm Hg

- No peripheral neuropathy ? grade 2

- Not pregnant or nursing

- Negative serum pregnancy test

- Fertile patients must use effective contraception during and for ? 6 months after
completion of study treatment

- At least 10 days since prior and no concurrent dipyridamole, ticlopidine, clopidogrel
bisulfate, cilostazol, warfarin, heparin, daily treatment with acetylsalicylic acid (>
325 mg/day), or nonsteroidal anti-inflammatory medications known to inhibit platelet
function

- No prior head and neck surgery of the primary tumor or lymph nodes except for
incisional or excisional biopsies

- More than 15 days since prior biopsies

- More than 1 week since prior fine-needle aspirations or placement of percutaneous
gastrostomy tube

- More than 4 weeks since prior major surgical procedures

- No prior radiotherapy to the region of the study cancer that would result in overlap
of radiation therapy fields

- No prior bevacizumab or other vascular endothelial growth factor-targeting agents

- No prior systemic chemotherapy for the study cancer

- Prior chemotherapy for a different cancer allowed

- No concurrent hematologic growth factors (e.g. filgrastim [G-CSF], darbepoetin alfa,
epoetin alfa) during study chemoradiotherapy

- No concurrent prophylactic growth factors for neutropenia during study adjuvant
therapy

- No concurrent prophylactic amifostine or pilocarpine

- No other concurrent experimental therapeutic cancer treatments