Bevacizumab, Radiation Therapy, and Cisplatin in Treating Patients With Previously Untreated Locally Advanced Cervical Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying how well giving bevacizumab together with radiation therapy and cisplatin works in treating patients with previously untreated locally advanced cervical 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 cervical cancer by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with radiation therapy and cisplatin may kill more tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine treatment-related serious adverse-event rates and adverse-event rates within the first 90 days from treatment start in patients with previously untreated locally advanced carcinoma of the cervix treated with bevacizumab, cisplatin, and concurrent pelvic radiotherapy. SECONDARY OBJECTIVES: I. Evaluate treatment-related serious adverse events and adverse events at any time. II. Evaluate disease-free survival (local, regional, or distant failure, or death due to any cause). III. Evaluate overall survival (death due to any cause). IV. Implement the image-based brachytherapy guidelines proposed by the Transatlantic Image-Guided Brachytherapy Working Group. V. Collect CT scan or MRI-based dosimetry of brachytherapy applications used during the course of treatment for later analysis of feasibility and consistency as well as dose/volume assessments of tumor control and complications. OUTLINE: This is a multicenter study. Patients undergo pelvic external-beam radiotherapy (EBRT) once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35. After completion of study treatment, patients are followed periodically.

Official Title
-----------------
A PHASE II STUDY OF BEVACIZUMAB IN COMBINATION WITH DEFINITIVE RADIOTHERAPY AND CISPLATIN CHEMOTHERAPY IN UNTREATED PATIENTS WITH LOCALLY ADVANCED CERVICAL CARCINOMA

Conditions
-----------------
Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Not Otherwise Specified, Stage IB Cervical Cancer AJCC v6 and v7, Stage IIA Cervical Cancer AJCC v7, Stage IIB Cervical Cancer AJCC v6 and v7, Stage III Cervical Cancer AJCC v6 and v7

Intervention / Treatment
-----------------
* Biological: Bevacizumab
* Drug: Cisplatin
* Radiation: External Beam Radiation Therapy
* Radiation: Internal Radiation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed squamous cell, adenocarcinoma, or adenosquamous cell carcinoma of the uterine cervix, meeting 1 of the following stage criteria: Stage IIB-IIIB lymph nodes Stage IB-IIA disease with biopsy-proven pelvic node metastases and/or tumor size >= 5 cm No positive para-aortic lymph nodes Zubrod performance status 0-2 WBC >= 3,000/mm^3 Absolute granulocyte count >= 1,500/mm^3 Platelet count >= 100,000/mm^3 INR < 1.5 Total bilirubin =< 1.5 mg/dL Serum creatinine =< 1.5 mg/dL AST and ALT =< 2.5 times upper limit of normal (ULN) Serum calcium =< 1.3 times ULN Hemoglobin >= 10 g/dL (transfusion allowed) Urine protein:creatinine ratio ? 0.5 OR urine protein < 1,000 mg by 24-hour urine collection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception None of the following illnesses or conditions: Medical illness preventing the use of full-dose chemotherapy Evidence of bleeding diathesis or coagulopathy Prior medical or psychiatric illness that would prevent informed consent or limit survival to < 6 months History of aneurysms, cerebrovascular accident, or arteriovenous malformations Active gastrointestinal (GI) ulcers, GI bleeding, or active inflammatory bowel disease Serious, nonhealing wound, ulcer, or current healing fracture History of any type of fistula or GI perforation Intra-abdominal abscess within the past 6 months No prior invasive malignancy (except nonmelanomatous skin cancer) unless disease free for >= 3 years No significant traumatic injury within the past 28 days No clinically significant cardiovascular disease, such as the following: Uncontrolled hypertension (blood pressure > 160/90 mm Hg on medication) Myocardial infarction within the past 12 months Unstable angina within the past 12 months New York Heart Association class II-IV congestive heart failure Unstable symptomatic arrhythmia requiring medication (i.e., chronic atrial arrhythmia, atrial fibrillation, or paroxysmal supraventricular tachycardia) Arterial thromboembolic events, including transient ischemic attack or clinically significant peripheral artery disease, within the past 6 months Arterial thromboembolic events, including transient ischemic attack or clinically significant peripheral artery disease, within the past 6 months No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No known HIV No prior organ transplant No prior surgery for carcinoma of the cervix other than biopsy No prior surgical debulking of pelvic or para-aortic nodes No prior pelvic radiotherapy, including transvaginal irradiation to control bleeding No prior systemic chemotherapy No major surgical procedure or open biopsy within the past 28 days or anticipation of need for major surgical procedure during the course of the study No fine needle aspirations or core biopsies within the past 7 days No concurrent major surgical procedure No concurrent epoetin alfa or Hypericum perforatum (St. John's wort) No concurrent intensity-modulated radiotherapy No concurrent transvaginal irradiation to control bleeding
Sexes Eligible for Study
-----------------
Female

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 (radiation therapy, bevacizumab, cisplatin)<br>Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: external-beam radiation;Radiation: Internal Radiation Therapy<br>* Undergo brachytherapy<br>* Other names: Radiation Brachytherapy;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-related Serious Adverse Events (SAEs) and Adverse Events (AEs) as Assessed by CTCAE v. 3.0 Criteria Within the First 90 Days From Treatment Start. | Adverse events (AEs) graded using CTCAE v3.0. Grade (Gr) refers to the severity of the AE and assigns Gr 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: 1= Mild AE, 2= Moderate AE, 3= Severe AE, 4= Life-threatening or disabling AE, 5= Death related to AE. Treatment-related SAEs defined as Grade (Gr) >= 4 vaginal bleeding, Gr >=4 thrombotic event, Gr >=3 arterial event, gastrointestinal (GI) bleeding , or bowel/bladder perforation, and any Gr 5 treatment-related AE. Treatment-related AEs defined as all SAEs, Gr 3-4 nausea, vomiting, or diarrhea persisting for >2 weeks despite medical intervention, Gr 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia defined as a temperature >38.5 degree Celsius and granulocytes < 1000/mm3, Grade 3-4 hematologic toxicity with the exception of neutropenia and leukopenia, and Grade 3-4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs. | From start of treatment to 90 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-related SAEs and AEs as Assessed by CTCAE v. 3.0 Criteria at Any Time. | Adverse events (AEs) graded using CTCAE v3.0. Grade (Gr) refers to the severity of the AE and assigns Gr 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: 1= Mild AE, 2= Moderate AE, 3= Severe AE, 4= Life-threatening or disabling AE, 5= Death related to AE. Treatment-related SAEs defined as Gr >= 4 vaginal bleeding, Gr >=4 thrombotic event, Gr >=3 arterial event, gastrointestinal (GI) bleeding , or bowel/bladder perforation, and any Gr 5 treatment-related AE. Treatment-related AEs defined as all SAEs, Gr 3-4 nausea, vomiting, or diarrhea persisting for >2 weeks despite medical intervention, Gr 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia defined as a temperature >38.5 degree Celsius and granulocytes < 1000/mm3, Grade 3-4 hematologic toxicity with the exception of neutropenia and leukopenia, and Grade 3-4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs. | From start of treatment to last follow-up, up to 6.0 years. Analysis occurred after all patients had been on study for at least 2 years. | 
| Disease-free Survival (Three-year Rate Reported) | Failure is defined as local, regional, or distant disease, or death due to any cause. Disease-free survival time is defined as time from registration to the date of failure and disease-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive and disease-free are censored at the date of last contact. | From registration to 3 years | 
| Overall Survival (Three-year Rate Reported) | Overall survival time is defined as time from registration to the date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | From registration to 3 years |