Trial of Vascular Endothelial Growth Factor (VEGF), Bevacizumab, in Combination With Cytotoxic Chemotherapy for Endometrial Cancer

Study Overview
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Brief Summary
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The purpose of this study is to find out whether the addition of a drug called Avastin (avastin) to the two-drug combination of carboplatin and paclitaxel shrinks tumors better than the two-drug combination alone in the treatment of endometrial cancer. Avastin is a humanized monoclonal antibody (a type of protein that is normally made by the immune system to help defend the body from infection and cancer) produced by Genentech, Inc. Avastin is an antibody directed against vascular endothelial growth factor, or VEGF. VEGF is a potent, specific growth factor with a well defined role in normal and abnormal blood vessel formation. It is present in a wide variety of normal tissues, but is produced in excess by most solid cancers (tumors). In the setting of cancer, VEGF promotes the growth of blood vessels that feed the tumor cells.

Detailed Description
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Exclusion Criteria Disease-Specific Exclusions Patients with a concomitant malignancy other than non-melanoma skin cancer. Patients with a prior malignancy who have been disease-free for greater than 5 years or who received prior chemotherapy for that malignancy. Patients in whom pathological confirmation of the tumor is not obtainable. General Medical Exclusions Patients with concomitant medical illness such as serious uncontrolled infection, uncontrolled angina, or serious peripheral neuropathy, which, in the opinion of the treating physician, make the treatments prescribed on this study unreasonably hazardous for the patient. Patients with third degree or complete heart block are not eligible unless a pacemaker is in place. Patients on medications which alter cardiac conduction, such as digitalis, beta-blockers, or calcium channel blockers, or who have other conduction abnormalities or cardiac dysfunction may be placed on study at the discretion of the investigator. Patients whose circumstances will not permit study completion or adequate follow-up. Patients who are sensitive to E. Coli-derived drug preparations. Life expectancy of less than 12 weeks. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored avastin cancer study. Inadequately controlled hypertension (defined as systolic blood pressure greater than 150 and/or diastolic blood pressure greater than 100 mmHg on antihypertensive medications). Any prior history of hypertensive crisis or hypertensive encephalopathy. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix C). History of myocardial infarction or unstable angina within 6 months prior to study enrollment. History of stroke or transient ischemic attack within 6 months prior to study enrollment. Known CNS disease. Significant vascular disease (e.g., aortic aneurysm, aortic dissection). Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy. Blood coagulation parameters: PT such that international normalized ratio (INR) is less than 1.5 (or an in range INR, between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a PTT less than 1.5 times the institutional upper limit of normal. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment. -History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 6 months prior to study enrollment. Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration and/or nutrition. Serious, non-healing wound, ulcer, or bone fracture. Proteinuria at screening as demonstrated by: Urine protein:creatinine (UPC) ratio greater than or equal to 1.0 at screening Known hypersensitivity to any component of avastin. Pregnant (positive pregnancy test) or lactating. Refusal to use of effective means of contraception (men and women) in subjects of child-bearing potential.

Official Title
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A Phase II Trial of a Vascular Endothelial Growth Factor (VEGF) Monoclonal Antibody, AVASTIN, in Combination With Cytotoxic Chemotherapy CARBOPLATIN and PACLITAXEL for Recurrent/Advanced Endometrial Cancer

Conditions
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Endometrial Carcinoma

Intervention / Treatment
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* Drug: carboplatin, paclitaxel, and bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed primary Stage III or Stage IV (see FIGO staging-Appendix I) or recurrent endometrial carcinoma with MEASURABLE disease whose potential for cure by radiation therapy or surgery alone or in combination is very poor. Recurrent disease must be biopsy confirmed. Patients may have received prior cytotoxic chemotherapy (1 therapy) excluding a platinum/taxane. Patients may have received prior hormonal therapy or therapy with biologic agents, but such therapies must be discontinued 4 weeks prior to entry on this study. Patients in whom both radiation and chemotherapy is planned may receive radiation prior to entry on this study (order not specified). At least four weeks should have elapsed since completion of RT involving the whole pelvis or over 50% of the spine. Patients must be 18 years of age or older. Exclusion Criteria: Patients with a concomitant malignancy other than Genentech, Inc Page 27 of 62 Bevacizumab Protocol 03-10-08 Page 27 non-melanoma skin cancer. Patients with a prior malignancy who have been disease-free for < 5 years or who received prior chemotherapy for that malignancy. Patients in whom pathological confirmation of the tumor is not obtainable. Patients with concomitant medical illness such as serious uncontrolled infection, uncontrolled angina, or serious peripheral neuropathy, which, in the opinion of the treating physician, make the treatments prescribed on this study unreasonably hazardous for the patient. Patients with third degree or complete heart block are not eligible unless a pacemaker is in place. Patients on medications which alter cardiac conduction, such as digitalis, beta-blockers, or calcium channel blockers, or who have other conduction abnormalities or cardiac dysfunction may be placed on study at the discretion of the investigator. Life expectancy of less than 12 weeks. Patients who are sensitive to E. Coli-derived drug preparations. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: I<br> | Drug: carboplatin, paclitaxel, and bevacizumab<br>* All patients enrolled will receive carboplatin AUC 5 plus paclitaxel 175 mg/m2 (135 mg/m2 if prior radiation to greater than 25% of bone marrow) plus bevacizumab 15 mg/kg every 3 weeks.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression Free Survival (PFS=Date of Progression of Disease or Death) at 6 Months Using Bevacizumab, Carboplatin, and Paclitaxel in Patients With Measurable Disease for Advanced/Recurrent Endometrial Cancer | Number of patients with progression free survival measured at 6 months. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST version 1.0), as a 20% increased in the sum of the longest diameter of target lesions, or a measure increase in a non-target lesion, or the appearance of new lesions. | 58 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival of This Treatment Regimen in Patients With Advanced/Recurrent Endometrial Cancer. | Median progression free survival measured in months. Progression of disease is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST version 1.0), as a 20% increased in the sum of the longest diameter of the target lesions, or a measurable increased in a non-target lesion, or the appearance of a new lesion. | 58 months | 
| Number of Participants With Adverse Events Grades 1-5 | Toxicity and safety was monitored before every treatment cycle, during, and after treatment. Bevacizumab was discontinued if the following criteria was met: grade 4 hypertension, reversible posterior leukoencephalopathy syndrome or hypertensive encephalopathy, grade 4 nephritic syndrome, arterial thrombosis, symptomatic grade 4 or recurrent/worsening venous thromboembolic events after resumption of bevacizumab treatment, grade 3 hemorrhage, bowel perforation or fistula and any complete wound disruption. | 58 months |