Bevacizumab in Reducing CNS Side Effects in Patients Who Have Undergone Radiation Therapy to the Brain for Primary Brain Tumor, Meningioma, or Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
Bevacizumab may reduce CNS side effects caused by radiation therapy. This randomized phase II trial is studying how well bevacizumab works in reducing CNS side effects in patients who have undergone radiation therapy to the brain for primary brain tumor, meningioma, or head and neck cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. Determine to what extent bevacizumab can reduce active radiation toxicity to the CNS in patients who have undergone cranial irradiation for primary brain neoplasm, meningioma, or head and neck cancer. SECONDARY OBJECTIVES: I. Determine to what extent this drug can reduce dexamethasone dependence in these patients. II. Determine to what extent this drug can improve neurologic function in these patients. III. Determine to what extent this drug can improve quality of life of these patients. OUTLINE: This is a randomized, placebo-controlled, crossover, double-blind study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients in arm II who have failed to respond to treatment at 6 or 12 weeks may cross over to arm I and receive 2 courses of bevacizumab as in arm I. Patients in arm I (including crossover patients) who have responded to treatment may receive 2 additional courses of bevacizumab. Patients undergo MRI after courses 2 and 4. Quality of life and neurologic function are assessed at baseline, periodically during study treatment, and at 12 and 24 weeks after completion of study treatment. After completion of study treatment, patients are followed at 12 and 24 weeks.

Official Title
-----------------
A Randomized Phase II Trial of Bevacizumab to Control Brain Radiation Damage

Conditions
-----------------
Recurrent Mucoepidermoid Carcinoma of the Oral Cavity, Adult Ependymoma, Adult Anaplastic Astrocytoma, Adult Anaplastic Ependymoma, Adult Anaplastic Meningioma, Adult Anaplastic Oligodendroglioma, Adult Brain Stem Glioma, Adult Central Nervous System Germ Cell Tumor, Adult Choroid Plexus Tumor, Adult Diffuse Astrocytoma, Adult Grade II Meningioma, Adult Grade III Meningioma, Adult Malignant Hemangiopericytoma, Adult Mixed Glioma, Adult Oligodendroglioma, Adult Papillary Meningioma, Adult Pineocytoma, Malignant Neoplasm, Meningeal Melanocytoma, Radiation Toxicity, Recurrent Adenoid Cystic Carcinoma of the Oral Cavity, Recurrent Adult Brain Tumor, 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 Lymphoepithelioma of the Oropharynx, Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal 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 I Adenoid Cystic Carcinoma of the Oral Cavity, Stage I Basal Cell Carcinoma of the Lip, Stage I Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity, Stage I Inverted Papilloma of the Paranasal Sinus and Nasal Cavity, Stage I Lymphoepithelioma of the Nasopharynx, Stage I Lymphoepithelioma of the Oropharynx, Stage I Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity, Stage I Mucoepidermoid Carcinoma of the Oral Cavity, Stage I Salivary Gland Cancer, Stage I Squamous Cell Carcinoma of the Hypopharynx, Stage I Squamous Cell Carcinoma of the Larynx, Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage I Squamous Cell Carcinoma of the Nasopharynx, Stage I Squamous Cell Carcinoma of the Oropharynx, Stage I Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage I Verrucous Carcinoma of the Larynx, Stage I 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 Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity, Stage III Mucoepidermoid Carcinoma of the Oral Cavity, Stage III Salivary Gland Cancer, 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

Intervention / Treatment
-----------------
* Drug: bevacizumab
* Drug: placebo
* Procedure: magnetic resonance imaging
* Procedure: quality-of-life assessment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: No evidence of bleeding diathesis or coagulopathy Fertile patients must use effective contraception during and for >= 2 months after completion of study therapy No diarrhea >= grade 1 Histologically confirmed primary brain neoplasm, meningioma, or head and neck cancer [WHO grade 2 or 3 disease--no WHO grade 4 primary brain neoplasms (i.e., glioblastoma or gliosarcoma)] Patients with head and neck cancer must not have any of the following: Evidence of metastatic disease Evidence of tumor invasion to major vessels (e.g., the carotid) History of bleeding related to tumor or radiotherapy during or after completion of radiotherapy Must have undergone cranial irradiation Must have radiographic evidence to support the diagnosis of radiation necrosis and/or surgical biopsy evidence of necrosis without tumor within the past 2 months Must have evidence of progressive neurologic signs or symptoms appropriate to the location of the radiation necrosis No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No significant traumatic injury within the past 28 days No evidence of active CNS hemorrhage Karnofsky performance status 60-100% No clinically significant cardiovascular disease, including any of the following: Inadequately controlled hypertension (i.e., systolic BP > 140 mm Hg and/or diastolic BP > 90 mm Hg despite antihypertensive medication) Large vessel cerebrovascular accident within the past 6 months Myocardial infarction or unstable angina within the past 6 months No clinically significant cardiovascular disease, including any of the following: NYHA class II-IV congestive heart failure Serious or inadequately controlled cardiac arrhythmia Significant vascular disease (e.g., aortic aneurysm or history of aortic dissection) Clinically significant peripheral vascular disease At least 6 months since prior radiotherapy Platelet count > 75,000/mm^3 Granulocyte count > 1,500/mm^3 Creatinine < 1.0 times ULN AST < 2.5 times ULN Not pregnant or nursing Negative pregnancy test Prior chemotherapy for tumor allowed Prior tyrosine kinase inhibitors of VEGF receptor (VEGFR) allowed More than 28 days since prior and no concurrent major surgical procedure or open biopsy Concurrent dexamethasone allowed provided patient is on a stable dose for >= 1 week prior to study entry Concurrent full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 allowed provided the following criteria are met: In-range INR (usually between 2 and 3) and patient is on a stable dose of oral anticoagulant for 1 week or on a stable dose of low molecular weight heparin No active bleeding or pathological condition that carries a high risk of bleeding Concurrent full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 allowed provided the following criteria are met: No evidence of serious or nonhealing wound, ulcer, or bone fracture No concurrent chemotherapy or tyrosine kinase inhibitors of VEGFR No prior bevacizumab More than 7 days since prior core biopsy History of seizures allowed provided the patient is receiving anticonvulsant therapy Hemoglobin >= 9.0 g/dL Bilirubin =< 1.5 times upper limit of normal (ULN) No other concurrent investigational 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Procedure: magnetic resonance imaging<br> <br> * Other names: nuclear magnetic resonance imaging;Procedure: quality-of-life assessment<br> <br> * Other names: quality of life assessment;|
| Placebo Comparator: Arm II<br>Patients receive placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: placebo<br>* Given IV<br>* Other names: PLCB;Procedure: magnetic resonance imaging<br> <br> * Other names: nuclear magnetic resonance imaging;Procedure: quality-of-life assessment<br> <br> * Other names: quality of life assessment;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Response ( > 25% Reduction in T2 Flair) From Baseline to Evaluation at 6 Weeks Post Treatment | Change in magnetic resonance imaging (MRI) from baseline to evaluation at 6 weeks for participants where MRI changes are based on the size of edema (T2 FLAIR) and Gd-contrast enhancement (lesion diameter and perfusion/dynamic). A 25% reduction in T2 flair volume constitutes a response for study. | Baseline to 12 weeks |