Ph II of Capecitabine, Carboplatin & Bevacizumab for Gastroesophageal Junction & Gastric Carcinoma

Study Overview
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Brief Summary
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To investigate bevacizumab in combination with carboplatin and capecitabine for patients with unresectable or metastatic GEJ or gastric cancers. We hope that by adding bevacizumab to standard chemotherapy for this patient population we will improve Progression Free Survival by 90% over historical controls.

Detailed Description
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Primary Objectives: To investigate if the addition of Bevacizumab to standard chemotherapy for metastatic or unresectable GEJ and gastric adenocarcinoma will improve PFS by 90% over historical controls. Secondary Objectives: Assess toxicities using CTCAE v3.0 Evaluate overall survival (OS) using Kaplan-Meier analysis Evaluate objective response rate (RR) by RECIST criteria Explore biomarkers of tumor response: CEA, CA 19.9, and serum VEGF Bank serum and tissue for future correlative studies Evaluate CT Perfusion to predict early therapeutic response to combination chemotherapy and anti-angiogenic therapy (OPTIONAL).

Official Title
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A Phase II Study of Capecitabine, Carboplatin, and Bevacizumab for Metastatic or Unresectable Gastroesophageal Junction and Gastric Adenocarcinoma

Conditions
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Stomach Cancer, Gastric (Stomach) Cancer, Neoplasm of Cardioesophageal Junction, Gastrointestinal Stromal Tumor (GIST)

Intervention / Treatment
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* Drug: bevacizumab
* Drug: carboplatin
* Drug: capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be treated at Stanford University Medical Center for the entire length of study participation. Patients with histologically or cytologically confirmed adenocarcinoma of the GEJ or stomach. Patients must be deemed unresectable due to involvement of critical vasculature or adjacent organ invasion. If unresectable, patients must show evidence of disease progression prior to enrollment. Patients with prior surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of > 5 years has elapsed between the primary surgery and the development of metastatic disease. Clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease if there is substantial clinical ambiguity regarding the nature or source of apparent metastases. Prior carboplatin as neoadjuvant or adjuvant therapy will be allowed if >= 6 months from the time of study entry. If patients use aspirin (>325mg/day) or NSAIDS at the time of enrollment, they must have a 10 day washout period prior to beginning protocol treatment. Low molecular weight heparin (or its equivalent, excluding warfarin) will be allowed for treatment of venous thromboembolic events if patients have no evidence of bleeding on full-dose anticoagulation. Patients must have a primary or metastatic lesion measurable in at least one dimension by Modified RECIST criteria (see Section 11.2.3) within 4 weeks prior to entry of study Patients must have ECOG performance status of 0-1 Patients must be >= 18 years of age Laboratory values <= 2 weeks prior to randomization: Absolute Neutrophil Count (ANC) >= 1.5 x 109/L (>= 1500/mm3) Platelets (PLT) >= 100 x 109/L (>= 100,000/mm3) Hemoglobin (Hgb) >= 9 g/dL Serum creatinine <= 1.5 x ULN Serum bilirubin <= 1.5 x ULN (<= 3.0 x ULN if liver metastases present) Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) <= 3.0 x ULN (<= 5.0 x ULN if liver metastases present). Note: ERCP or percutaneous stenting may be used to normalize the liver function tests. Life expectancy >= 12 weeks Inclusion and exclusion criteria for DCE-MRI and DWI imaging will be determined by CT scan as part of routine post-chemotherapy imaging. Subjects will be eligible if one liver metastasis is greater than 1 cm in size. Participation in the DCE-MRI and DWI correlate is not required for eligibility. Ability to give written informed consent according to local guidelines Exclusion Criteria: Disease-Specific Exclusions Prior chemotherapy for metastatic disease Prior full field radiotherapy <= 4 weeks or limited field radiotherapy <= 2 weeks prior to enrollment. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease. Prior biologic or immunotherapy <= 2 weeks prior to registration. Patients must have recovered from all therapy-related toxicities Prior therapy with anti-VEGF agents If history of other primary cancer, subject eligible only if she or he has: Curatively resected non-melanomatous skin cancer Curatively treated cervical carcinoma in situ Other primary solid tumor curatively treated with no known active disease present and no treatment administered for the last 3 years Concurrent use of other investigational agents and patients who have received investigational drugs <= 4 weeks prior to enrollment. Hypersensitivity to capecitabine, fluorouracil, or any component of the formulation and or a known deficiency of dihydropyrimidine dehydrogenase. General Medical Exclusions Subjects known to have chronic or active hepatitis B or C infection History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with study participation or study drug administration or may interfere with the conduct of the study or interpretation of study results Male subject who is not willing to use adequate contraception upon enrollment into this study and for 6 months following the last dose of second-line treatment Female subject (of childbearing potential, post-menopausal for less than 6 months, not surgically sterilized, or not abstinent) who is not willing to use an oral, patch or implanted contraceptive, double-barrier birth control, or an IUD during the course of the study and for 6 months following the last dose of second-line treatment Female subject who is breast-feeding or who has positive serum pregnancy test 72 hours prior to randomization Pleural effusion or ascites that causes respiratory compromise (>= CTCAE grade 2 dyspnea) Any of the following concurrent severe and/or uncontrolled medical conditions within 24 weeks of enrollment which could compromise participation in the study: Unstable angina pectoris Symptomatic congestive heart failure Myocardial infarction <= 6 months prior to registration and/or randomization Serious uncontrolled cardiac arrhythmia Uncontrolled diabetes Active or uncontrolled infection Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung. Chronic renal disease Acute or chronic liver disease (e.g., hepatitis, cirrhosis) Patients unwilling to or unable to comply with the protocol 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 bevacizumab cancer study Bevacizumab-Specific Exclusions Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 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 A) 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, brain metastases. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy 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 Serious, non-healing wound, ulcer, or bone fracture Urine protein >= 2+ on urinalysis dipstick and >= 1.0 gram on 24-hour urine collection Known hypersensitivity to any component of bevacizumab History of hemoptysis (bright red blood of ½ teaspoon or more per episode) within 3 months prior to study enrollment. Current, ongoing treatment with full-dose warfarin.

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: bevacizumab+ carboplatin +capecitabine<br>Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break. | Drug: bevacizumab<br>* Intravenous 15 mg/kg<br>* Other names: Avastin;Drug: carboplatin<br>* AUC 6, Intravenously Day 1 every 21 days<br>* Other names: Paraplatin;Drug: capecitabine<br>* 850mg/m2, Orally twice daily days 1-14 every 21 days.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Tumor progression was assessed according to the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), presented below. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Objective Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria. Progression-Free Survival is assessed as the number of evaluable participants who were alive without disease progression at 1 year. Participants without out assessment at 12 months will not be included. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events ≥ Grade 3 and Related to Bevacizumab | Toxicity was assessed as the number of adverse events ≥ Grade 3 and also possibly, probably, or definitely related to bevacizumab. The outcome is reported as the total number of applicable events, and as the number of events that were a hematologic toxicity; a non-hematologic toxicity; which are numbers without dispersion. | 12 months | 
| Overall Survival (OS) | Overall survival (OS) will be assessed from time from the date of enrollment to the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of data cutoff for the final analysis. The outcome is presented as the median survival in days with standard deviation. | 7.5 years | 
| Objective (Overall) Therapeutic Response | Tumor response was assessed per the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions, and assessed by physical measurement; magnetic resonance imaging (MRI); computed tomography (CT), positron emission tomography (PET)-CT; and/or X-rays/radiologic scan. Response was determined based on the criteria below. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Objective Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome is provided as the number of participants who achieved each of the defined responses, with objective (overall) response defined as the sum of CR and PR. The outcome is reported as values without dispersion. | 12 months | 
| CEA and CA 19.9 Tumor Response Biomarkers | The detected blood levels for tumor biomarkers CEA and CA 19.9 were to be correlated to the results for progression-fee survival (PFS), with the outcome presented as the median with standard deviation. | 9 weeks | 
| Vascular Endothelial Growth Factor Tumor Response Biomarker | The detected blood levels for tumor biomarker vascular endothelial growth factor (VEGF) were to be correlated to the results for progression-fee survival (PFS), with the outcome presented as the median with standard deviation. | 9 weeks |