A Study of Gemcitabine, Capecitabine and Bevacizumab to Treat Cancer of the Gall Bladder or Bile Ducts

Study Overview
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Brief Summary
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To assess the proposed therapy for patients with advanced gallbladder or biliary cancers.

Detailed Description
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The primary objective of this study is to assess progression free survival with proposed therapy for patients with locally advanced or metastatic adenocarcinoma of the gallbladder or biliary ducts.

Official Title
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A Multicenter Phase II Study of Gemcitabine, Capecitabine and Bevacizumab for Locally Advanced or Metastatic Adenocarcinoma of the Gall Bladder or Biliary Ducts.

Conditions
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Cholangiocarcinoma

Intervention / Treatment
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* Drug: Gemcitabine, Capecitabine and Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed gallbladder or biliary tract adenocarcinoma that is unresectable or metastatic, or metastatic adenocarcinoma which is radiologically confirmed to be of gallbladder or biliary origin. No prior systemic therapy for metastatic disease. Prior adjuvant therapy is permitted if completed over 6months ago. Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of bevacizumab in combination with gemcitabine in patients over 18 years of age, children are excluded from this study, but will be eligible for future pediatric phase 1 combination trials. ECOG performance status 0 or 1. Life expectancy > 3 months. Patients must have normal organ and marrow function as defined below: leukocytes ≥ 3,000/microL absolute neutrophil count ≥ 1,500/microL platelets ≥ 1OO,OOO/microL total bilirubin ≤ 2 mg/dl AST or ALT ≤ 5 times upper limit of normal (UNL) for subjects with documented liver metastases; ≤ 2.5 times UNL for subjects without evidence of liver metastases. creatinine < 1.5 mg/dL or 24 hour urine creatinine clearance > 50 ml/min. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Signed, written informed consent document. Patient must have measurable disease Exclusion Criteria: Subjects meeting any of the following criteria are ineligible for study entry: Compromised renal or hepatic function. Screening clinical laboratory values INR ≥ 1.5 (except those subjects who are receiving full-dose warfarin) Hemoglobin < 9 gm/dL (may be transfused or receive epoetin alfa (e.g., Epogen@) to maintain or exceed this level). Bevacizumab risk factors: History of serious systemic disease, including uncontrolled hypertension (blood pressure of greater than 160/110 mmHg on medication), prior history of hypertensive crisis or hypertensive encephalopathy, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), or clinically significant peripheral vascular disease (Grade II or greater). Presence of central nervous system or brain metastases. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of the study; fine needle aspirations or core biopsies within 7 days prior to Day O. Pregnancy (positive pregnancy test) or lactation. 24 hour urine creatinine clearance < 50 ml/min or urine protein/creatinine ratio greater than or equal to 1.0 at screening. Serious, nonhealing wound, ulcer, or bone fracture. Evidence of bleeding diathesis or coagu1opathy. Recent (less than or equal to six months) arterial thromboembolic events, including transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina, or myocardial infarction (MI). Inability to comply with study and/or follow-up procedures. Patients with known duodenal or gastric wall involvement should be excluded. Patients with suspected involvement of stomach or duodenum should have screening endoscopies to exclude the same prior to therapy. Patients with esophageal or gastric varices. Patients with recent hemoptysis (within 1 week).

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: Gemcitabine, Capecitabine and Bevacizumab<br>Estimate the toxicity of the regimen, and estimate the quality of life (QOL). | Drug: Gemcitabine, Capecitabine and Bevacizumab<br>* Bevacizumab 15 mg/ kg every 3 weeks, starting day 1; Capecitabine 650 mg/m2 bid x 14 days starting day 1, Gemcitabine 1000 mg/m2 days 1 and 8, cycles to be repeated every 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Objective of This Study is to Assess Progression Free Survival (PFS) With Proposed Therapy for Patients With Locally Advanced or Metastatic Gallbladder and Biliary Cancers. | Progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.0). Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either measurable or non-measurable using the criteria provided below. The term evaluable in reference to measurability will not be used because it does not provide additional meaning or accuracy. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the Proportion of Patients With Clinical Response | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years | 
| Assess the Toxicity of the Regimen. | Number of patients with Serious Adverse Events. Please refer to the adverse event reporting for more detail. | up to 5 years | 
| Assess the Change in the Quality of Life Among Patients Using the FACT-Hep (Version 4) for Hepatobiliary Cancers. | We utilized the FACT-HEP TOTAL SCORE (version 4) quality-of-life scale, which is a 45 item scale ranging from 96-178. Higher scores of the reflect better quality of life. For a Detailed description see: Nancy Heffernan, David Cella, Kimberly Webster, Linda Odom, Mary Martone, Steven Passik, Marilyn Bookbinder, Yuman Fong, William Jarnagin, and Leslie Blumgart: Measuring Health-Related Quality of Life in Patients With Hepatobiliary Cancers: The Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire. Journal of Clinical Oncology, Vol 20, No 9 (May 1), 2002: pp 2229-2239. No subscales were analyzed. . | Baseline, Day 22 and Day 43 | 
| Assess Overall Survival (OS) |  | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years | 
| Circulating Tumor Cells (CTC) Will be Assessed at Baseline, Day 22 and Day 43 | Mean number of CTCs in 7.5 ml of whole blood | baseline, day 22 and day 43 | 
| Collect Samples at Baseline, Day 8 and Day 43 for Future Biomarker Studies and Development of Profiles of Responders to Anti-VEGF Therapy (Optional) | This was a tissue banking end point of sample collection for future studies. No analysis was completed. | Baseline, day 8 and day 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biliary Duct Cancer, Cancer of the Gallbladder, Adenocarcinoma of the Gall Bladder, Adenocarcinoma of the Biliary Ducts, Cholangiocarcinoma, Extrahepatic cholangiocarcinoma