A Phase I Study Of Bevacizumab (Recombinant Humanized Monoclonal Antibody To Vascular Endothelial Growth Factor) In Addition To Flourouracil And Hydroxyurea As Initial Chemotherapy With Concomitant Radiotherapy (B-FHX) For Poor Prognosis Head And Neck Cancer
A Phase I Study Of Bevacizumab (Recombinant Humanized Monoclonal Antibody To Vascular Endothelial Growth Factor) In Addition To Flourouracil And Hydroxyurea As Initial Chemotherapy With Concomitant Radiotherapy (B-FHX) For Poor Prognosis Head And Neck Cancer
Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining monoclonal antibody therapy with chemotherapy and radiation therapy may be an effective treatment for head and neck cancer. This phase I trial is to see if combining bevacizumab, fluorouracil, and hydroxyurea with radiation therapy works in treating patients who have 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
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:
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