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

Study Overview
=================
Brief Summary
-----------------
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

Detailed Description
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Recurrent Lymphoepithelioma of the Oropharynx, Stage III Salivary Gland Cancer, Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma, Recurrent Adenoid Cystic Carcinoma of the Oral Cavity, Recurrent Basal Cell Carcinoma of the Lip, Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity, Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity, Recurrent Lymphoepithelioma of the Nasopharynx, Recurrent Metastatic Squamous Neck Cancer With Occult Primary, Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity, Recurrent Mucoepidermoid Carcinoma of the Oral Cavity, Recurrent Salivary Gland Cancer, Recurrent Squamous Cell Carcinoma of the Hypopharynx, Recurrent Squamous Cell Carcinoma of the Larynx, Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity, Recurrent Squamous Cell Carcinoma of the Nasopharynx, Recurrent Squamous Cell Carcinoma of the Oropharynx, Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Recurrent Verrucous Carcinoma of the Larynx, Recurrent Verrucous Carcinoma of the Oral Cavity, Stage III Adenoid Cystic Carcinoma of the Oral Cavity, Stage III Basal Cell Carcinoma of the Lip, Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity, Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity, Stage III Lymphoepithelioma of the Nasopharynx, Stage III Lymphoepithelioma of the Oropharynx, Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity, Stage III Mucoepidermoid Carcinoma of the Oral Cavity, Stage III Squamous Cell Carcinoma of the Hypopharynx, Stage III Squamous Cell Carcinoma of the Larynx, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage III Squamous Cell Carcinoma of the Nasopharynx, Stage III Squamous Cell Carcinoma of the Oropharynx, Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage III Verrucous Carcinoma of the Larynx, Stage III Verrucous Carcinoma of the Oral Cavity, Stage IV Adenoid Cystic Carcinoma of the Oral Cavity, Stage IV Basal Cell Carcinoma of the Lip, Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity, Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity, Stage IV Lymphoepithelioma of the Nasopharynx, Stage IV Lymphoepithelioma of the Oropharynx, Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity, Stage IV Mucoepidermoid Carcinoma of the Oral Cavity, Stage IV Salivary Gland Cancer, Stage IV Squamous Cell Carcinoma of the Hypopharynx, Stage IV Squamous Cell Carcinoma of the Larynx, Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IV Squamous Cell Carcinoma of the Nasopharynx, Stage IV Squamous Cell Carcinoma of the Oropharynx, Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IV Verrucous Carcinoma of the Larynx, Stage IV Verrucous Carcinoma of the Oral Cavity, Untreated Metastatic Squamous Neck Cancer With Occult Primary

Intervention / Treatment
-----------------
* Drug: hydroxyurea
* Drug: fluorouracil
* Biological: bevacizumab
* Radiation: radiation therapy
* Biological: filgrastim
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (hydroxyurea, fluorouracil, bevacizumab, radiation)<br>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 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. | Drug: hydroxyurea<br>* Given orally<br>* Other names: Hydurea;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;Biological: filgrastim<br>* Given subcutaneously<br>* Other names: Neupogen;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity assessed using NCI CTCAE version 3.0 |  | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (CR+PR) assessed using RECIST criteria | The associated 95% confidence interval will be determined. | Up to 9 years | 
| Pattern of failure, described as locoregional, distant, or both |  | Up to 9 years | 
| Duration of response |  | From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 9 years | 
| Progression free survival | Will be calculated using the Kaplan-Meier method, and median progression-free and overall survival times, along with their 95% confidence intervals, will be derived using the procedure described in Brookmeyer and Crowley. | From the date of registration to the date of progressive disease or death, assessed up to 9 years | 
| Overall survival | Will be calculated using the Kaplan-Meier method, and median progression-free and overall survival times, along with their 95% confidence intervals, will be derived using the procedure described in Brookmeyer and Crowley. | From the date of registration to the date of death, assessed up to 9 years |