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

Study Overview
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Brief Summary
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This phase II trial is studying how well giving bevacizumab together with cisplatin, radiation therapy, and fluorouracil works in treating patients with stage IIB, stage III, stage IVA, or stage IVB nasopharyngeal cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of nasopharyngeal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving bevacizumab together with chemotherapy and radiation therapy may kill more tumor cells.

Detailed Description
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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.

Official Title
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A Phase II Study of Concurrent Chemoradiotherapy Using Three-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT) + Bevacizumab (BV) for Locally or Regionally Advanced Nasopharyngeal Cancer

Conditions
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Stage II Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7, Stage III Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7, Stage III Nasopharyngeal Undifferentiated Carcinoma AJCC v7, Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7, Stage IV Nasopharyngeal Undifferentiated Carcinoma AJCC v7

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Biological: Bevacizumab
* Drug: Cisplatin
* Drug: Fluorouracil
* Radiation: Intensity-Modulated Radiation Therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bevacizumab, cisplatin, fluorouracil, IMRT, 3D-CRT)<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo 3D-CRT<br>* Other names: Radiation Conformal Therapy;Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With a Grade 4 Hemorrhage or Any Grade 5 Adverse Event Assessed to be Definitely, Probably, or Possibly Related to Protocol Treatment During the First Year. | Estimated using a binomial distribution along with the 95% confidence interval. Adverse events (AE) are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | From start of treatment to one year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Grade 4 Hemorrhage or Any Grade 5 Adverse Event Assessed to be Definitely, Probably, or Possibly Related to Protocol Treatment After the First Year. | Estimated using a binomial distribution along with the 95% confidence interval. Adverse events (AE) are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | Analysis occurs after all patients have been on study for at least 2 years. Patients are followed from day 366 to death or study termination whichever occurs first, up to 3.6 years. | 
| Patient Tolerability to Each Component (Concurrent and Adjuvant) of the Protocol Treatment Regimen | Evaluated in terms of protocol treatment delivery. For concurrent treatment, measured by the percentage of patients who received 2 or more cycles of cisplatin (CDDP) and bevacizumab (BV) during concurrent treatment with radiation therapy(RT) and who had RT scored by the study chair as no variation or minor variation. For adjuvant treatment, measured by the percentage of patients who received 2 or more cycles of CDDP and 5-FU and BV during the adjuvant treatment phase. Estimated using a binomial distribution along with their associated 95% confidence intervals. | From start of treatment to end of treatment (approximately day 109). | 
| Death During or Within 30 Days of Discontinuation of Protocol Treatment. | The percentage of patients dying during protocol treatment or within 30 days after the end of treatment. Estimated using a binomial distribution along with associated 95% confidence interval. | From start of treatment to 30 days after end of treatment (treatment ends approximately day 109). | 
| One- and Two-year Distant Metastases-free Rates | Distant metastasis is defined as clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where possible. Distant metastasis-free rate estimated by cumulative incidence method with death considered a competing risk. | From registration to two years | 
| One- and Two-year Loco-regional Progression-free Rates | Loco-regional progression is defined as an estimated increase in the size of the tumor (product of the perpendicular diameters of the two largest dimensions) of greater than 25%, taking as reference the smallest value of all previous measurements or appearance of new areas of malignant disease. Local-regional progression-free rate estimated by cumulative incidence with death considered a competing risk. | Analysis occurs after all patients have been on study for at least 2 years. Patients are followed from study registration to death or study termination whichever occurs first, up to 3.6 years. | 
| One- and Two-year Progression-free Survival Rates | Progression-free survival rate estimated by Kaplan-Meier method along with 95% confidence interval. An event is loco-regional or distant progression, or death due to any cause. Loco-regional progression is defined as an estimated increase in the size of the tumor (product of the perpendicular diameters of the two largest dimensions) of greater than 25%, taking as reference the smallest value of all previous measurements or appearance of new areas of malignant disease. Distant progression is defined as distant metastases. | Analysis occurs after all patients have been on study for at least 2 years. Patients are followed from study registration to death or study termination whichever occurs first, up to 3.6 years. | 
| One- and Two-year Overall Survival Rates | Overall survival rate estimated by Kaplan-Meier method along with 95% confidence interval. An event is death due to any cause. | Analysis occurs after all patients have been on study for at least 2 years. Patients are followed from study registration to death or study termination whichever occurs first, up to 3.6 years. | 
| Percentage of Patients With Other Grade 3-5 Adverse Events Assessed to be Definitely, Probably, or Possibly Related to Protocol Treatment | Estimated using a binomial distribution along with the 95% confidence interval. Adverse events (AE) are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | Analysis occurs after all patients have been on study for at least 2 years. Patients are followed from start of treatment to death or study termination whichever occurs first, up to 3.6 years. |