Bevacizumab, Fluorouracil, and Hydroxyurea Plus Radiation Therapy in Treating Patients With Advanced Head and Neck Cancer

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and dose-limiting toxicity of bevacizumab when given in combination with fluorouracil, hydroxyurea, and radiotherapy in patients with advanced head and neck cancer.

II. Determine the time to progression, pattern of failure, local control, and distant failure rate in patients treated with this regimen.

III. Determine the local toxic effects of this regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of bevacizumab.

Patients receive oral hydroxyurea every 12 hours on days 1-6, fluorouracil IV continuously on days 1-5, and bevacizumab IV over 90 minutes on day 1. Patients also undergo radiotherapy once daily on days 1-5. Patients receive filgrastim (G-CSF) subcutaneously on days 6-12. Treatment repeats every 2 weeks for up to 7 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Additional patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 27-39 patients will be accrued for this study within 5.4-19.5 months.

Inclusion criteria

• Histologically or cytologically confirmed advanced head and neck cancer

• Requiring regional palliative radiotherapy
• Not amenable to standard therapy
• Previously untreated disease allowed only if prognosis is poor (i.e., estimated 2-year survival of less than 10% if treated with standard therapy alone)
• No obvious tumor involvement of major vessels on CT scan
• No known brain metastases
• Performance status - ECOG 0-2
• Performance status - Karnofsky 60-100%
• More than 12 weeks
• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• No history of bleeding diathesis
• Bilirubin normal
• AST/ALT no greater than 2.5 times upper limit of normal
• Creatinine normal
• Urine protein no greater than trace
• Urine protein less than 0.5 g/24 hours
• No significant renal impairment
• No symptomatic congestive heart failure
• No cardiac arrhythmia
• No deep venous thrombosis
• No uncontrolled hypertension
• No clinically significant peripheral artery disease
• No arterial thromboembolic event within the past 6 months, including any of the following:

• Transient ischemic attack
• Cerebrovascular accident
• Unstable angina
• Myocardial infarction
• No hemoptysis of at least 1 tablespoon
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab or other agents used in this study
• No non-healing wounds within the past 4 weeks
• No significant ongoing or active infection
• No other uncontrolled illness
• No other severe complicating medical illness that would preclude study participation
• No psychiatric illness or social situation that would preclude study compliance
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior fluorouracil and hydroxyurea with radiotherapy
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• See Disease Characteristics
• See Chemotherapy
• At least 4 months since prior radiotherapy and recovered
• At least 4 weeks since prior major surgery
• No prior or concurrent chronic use of aspirin or other nonsteroidal anti-inflammatory agents
• No other concurrent investigational agents
• No concurrent anticoagulation therapy
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer agents