Efficacy of Neoadjuvant Chemoradiation for Potentially Resectable Pancreas Cancer

Study Overview
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Brief Summary
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This study is to determine the efficacy of bevacizumab and gemcitabine in combination with radiation therapy in the preoperative treatment of potentially-resectable subjects with pancreatic cancer.

Detailed Description
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This is a 2 stage phase II study of bevacizumab (10 mg/kg) and fixed dose rate (FDR) gemcitabine (1500 mg/m2 at 10 mg/kg/min) in combination with sequential rapid fractionation radiotherapy (30 Gy total) in the preoperative treatment of potentially-resectable subjects with adenocarcinoma of the pancreas. The purpose of this study is to determine the rate of margin negative surgical resection (R0 resection rate) and the rate of complete pathological response in patients with resected pancreas cancer. The overall goal of this study is to determine the merit of this novel regimen for further study in a Phase III trial examining time to progression and overall survival. Based on the need for 48 evaluable subjects to evaluate the primary endpoints, the study will be opened with a target accrual of 60 subjects given an expected 20% rate of attrition observed in prior studies of subjects with pancreas cancer at UPCI.

Official Title
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Phase II Study of the Anti-Vascular Endothelial Growth Factor (α-VEGF) Monoclonal Antibody Bevacizumab in Combination With Fixed Dose Rate (FDR) Gemcitabine and Rapid-Fractionation Radiotherapy in the Pre-operative Treatment of Potentially- Resectable Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Avastin (bevacizumab)
* Drug: Gemzar (Gemcitabine)
* Radiation: external beam radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic proof of pancreatic adenocarcinoma. Subjects with biopsy-proven adenocarcinoma of the pancreas which is potentially resectable by preoperative imaging. Subjects will be considered potentially resectable using criteria defined by Pisters (Pisters et al., 2001): if imaging detects no evidence of extrapancreatic disease; no evidence of tumor extension to the superior mesenteric artery (SMA) or celiac axis (intact fat plane between the tumor and the adjacent visceral artery), patent superior mesenteric-portal vein confluence no encasement of portal or superior mesenteric vein. Karnofsky performance status ≥ 80. No active second malignancy except for basal cell carcinoma of the skin Normal renal, hepatic, and hematologic function at the time of enrollment as evidenced by: Serum creatinine level ≤1.6 mg/dl ( Calculated Creat clearance >50) Serum total bilirubin level ≤1.5 X ULN Urine protein excretion ≤ 1+ by urine dipstick White blood cell count ≥ 3.5x109/ml per ml and platelet count ≥ 100x109 per ml Age >18 years. Children are excluded because of toxic effects of bevacizumab and gemcitabine on growth and development during preclinical studies. For subjects with obstructive jaundice, the biliary tract must be drained with a temporary plastic or a short permanent metallic biliary stent. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Disease-Specific Exclusions Subjects who have received chemotherapy within 12 months prior to study entry. Prior use of radiotherapy or investigational agents for pancreatic cancer. Subjects who have undergone laparotomy for pancreas cancer within 6 weeks Any evidence of metastasis to distant organs (liver, lung, peritoneum). Symptomatic or endoscopic evidence of gastric outlet obstruction • Endoscopic findings suggesting tumor erosion into the gastrointestinal mucosa. Concurrent malignancies with evidence of active or measurable disease except basal cell carcinoma of the skin. General Medical Exclusions Inability to adhere to study and/or follow-up procedures History of allergic reactions or hypersensitivity to the study drugs (bevacizumab, gemcitabine, and proton pump inhibitors). Other concurrent experimental therapy. Because subjects with immune deficiency are at increased risk for lethal infections when treated with marrow-suppressive therapy, HIV-positive subjects receiving combination anti-retroviral therapy are excluded from the study. Bevacizumab-Specific Exclusions Subjects who have had recent surgery (prior 6 weeks) Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment Subjects with the following co-morbid medical conditions: History of myocardial infarction or unstable angina within 12 months prior to study enrollment. Ascites Pregnancy/lactation - The effects of the study drugs on the developing human fetus are unknown. For this reason and because bevacizumab, gemcitabine, and radiation therapy used in this trial are known to be teratogenic in animal studies, women and men of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of study entry until 6 months after the completion 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. A serum pregnancy test for those females of childbearing potential must be done prior to their receiving study drugs. Due to the combined effects of chemotherapy and radiation, breastfeeding is not allowed for 6 months after the completion of study participation. Regular aspirin use > 325 mg per day Regular NSAID use Bleeding diathesis, coagulopathy, need for full-dose anticoagulation or INR > 1.5 Known central nervous system metastasis Previous cerebrovascular accident, transient ischemic attack, or seizure (within 6 months) Serious non-healing wound, ulcer, or bone fracture History of abdominal fistula, gastrointestinal perforation, diverticulitis, or intra-abdominal abscess within 6 months prior to study enrollment. Recent hemoptysis, Uncontrolled 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 2 or greater congestive heart failure (see Appendix I) Prior deep venous thrombosis or pulmonary embolism Urine protein excretion 2+ or ≥ 1 g per 24 hours Peripheral vascular disease such as lower extremity claudication and rest pain or prior lower extremity vascular surgery for arterial insufficiency Dyspnea requiring supplemental oxygen

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Single Arm<br>Intervention: Drug: Avastin (bevacizumab) 10 mg/kg, days 1, 15, 29 and 43 Intervention: Drug: Gemzar (Gemcitabine) On days 1, 15, and 29, subjects will receive gemcitabine 1500 mg/m2 IV over 150 minutes at the fixed-dose rate (10 mg/m2/min). Intervention:Radiation: external beam radiotherapy 3 Gy/fraction utilizing a 95% isodose field over 10 consecutive weekdays, Monday to Friday, for a total of 30 Gy | Drug: Avastin (bevacizumab)<br>* 10 mg/kg, days 1, 15, 29 and 43<br>Drug: Gemzar (Gemcitabine)<br>* On days 1, 15, and 29, subjects will receive gemcitabine 1500 mg/m2 IV over 150 minutes at the fixed-dose rate (10 mg/m2/min).<br>Radiation: external beam radiotherapy<br>* 3 Gy/fraction utilizing a 95% isodose field over 10 consecutive weekdays, Monday to Friday, for a total of 30 Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Margin Negative Surgical Resection (R0 Resection Rate) | Number of participants who underwent laparoscopy and pancreatic resections that were margin negative/total number of participants who underwent laparoscopy and pancreatic resections. | Up to 48 months | 
| Rate of Pathologic Complete Response (pCR) | Rate of pathologic complete response (pCR) is no residual invasive tumor, in situ carcinoma can be present, and no residual lymph node metastasis. Rate of pCR is the number of participants who underwent laparoscopy and pancreatic resections that experienced complete pathologic response/total number of participants who underwent laparoscopy and pancreatic resections. | Up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Up to 48 months | 
| Progression-free Survival (PFS) |  | Up to 48 months | 
| Rate of Surgical Resection | Number of participants that underwent resection / per the total number of evaluable participants | Up to 48 months | 
| Radiographic Tumor Response | CT scans evaluated for response using Response Evaluation Criteria in Solid Tumors (RECIST) | Up to 48 months | 
| Ca 19-9 Level (in Serum) - Biomarker Response | Percentage decrease in Ca 19-9 level (in serum) | Baseline and up to 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreas, pancreatic, cancer, resectable