Preoperative Folfirinox, Radiation Therapy for Resectable Adenocarcinoma of the Pancreas

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if a chemotherapy combination called modified Folfirinox (or mFolfirinox), followed by a combination of gemcitabine and radiation therapy, followed by surgery, can help to control pancreatic cancer. The safety of this treatment will also be studied. mFolfirinox consists of 5-FU, oxaliplatin, and irinotecan. These 3 drugs, along with gemcitabine, are each designed to block the growth of cancer cells, which may lead to cancer cell death.

Detailed Description
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Study Drug Administration: You will receive up to 3 phases of study therapy: the systemic chemotherapy phase, the chemoradiation phase, and surgery, if possible. During the systemic chemotherapy phase, you will receive mFolfirinox 1 time every 2 weeks (Weeks 1, 3, 5, 7, 9 and 11) for 12 weeks. You will receive oxaliplatin by vein over a 2-hour period. After receiving oxaliplatin, you will receive irinotecan by vein over a 90-minute period. After receiving irinotecan, you will then receive 5-FU through a portable pump for the next 46 hours. You will take the portable pump home with you and will receive instructions on how to use it. You will begin receiving chemoradiation within 6 weeks after you have finished receiving the Week 11 dose of mFolfirinox. However, you will not begin receiving it until you have recovered from side effects of the chemotherapy. During the chemoradiation phase, you will receive gemcitabine over about 35 minutes 1 time each week for 5 weeks. You will also receive radiation therapy 5 days a week (Monday through Friday) for 5 1/2 weeks (a total of 28 treatments). If you miss any of the days of radiation, they will be made up at the end of treatment so that you will receive the full amount of radiation. You will be given a separate consent form that explains the radiation procedure and the risks it may present. After the chemoradiation phase, you will not receive any treatment for 4-6 weeks so your body can recover. If after this time the disease has not gotten worse or spread to other parts of the body, you will have surgery to try to remove the tumor. You will be given a separate consent form for the surgery that describes how it is performed and its risks. If the disease has gotten worse or spread to other parts of the body, you will not be able to have surgery. The study doctor will discuss other therapy options with you. Study Visits: At Weeks 1, 3, 5, 7, 9, and 11 of the systemic chemotherapy phase: You will have a physical exam, including measurement of your weight and vital signs (blood pressure and heart rate). Blood (about 3 tablespoons) will be drawn for routine tests. Within 4 weeks before beginning the chemoradiation phase: You will have CT or MRI scans to check the status of the disease. Blood (about 1 tablespoon) will be drawn for tumor marker testing. At Weeks 1, 2, 3, 4, 5, and 6 of the chemoradiation phase: You will have a physical exam, including measurement of your weight and vital signs. Blood (about 2-3 tablespoons) will be collected for routine tests. At Week 6, an additional 2 teaspoons of blood will be drawn for CTC testing. About 4 to 6 weeks after you complete the chemoradiation phase: Blood (about 1 tablespoon) will be drawn for tumor marker testing. You will have CT or MRI scans to check the status of the disease. If you are eligible to have surgery after the chemoradiation phase, the following tests and procedures will also be performed: Blood (about 4 teaspoons total) will be drawn within 2 weeks before surgery for CTC testing. Blood will also be collected during surgery, if the surgeon thinks it is safe and feasible. Tumor tissue collected during a previous procedure will be used for biomarker testing. An additional sample of tumor tissue will be collected from the tissue removed during surgery and used for biomarker testing. Biomarkers are found in the blood/tissue and may be related to your reaction to the study drug. Length of Study: You will receive study treatment over the course of up to 30 weeks. You will be taken off study if the disease gets worse, the study doctor thinks it is in your best interest, or if you do not follow the study directions. You may choose to stop receiving the study treatment at any time. If you choose to stop, you should tell the study doctor or a member of the staff right away. They will make sure that proper procedures are followed and a final visit will be scheduled for your safety. Follow-up: Blood (about 2 teaspoons) will be collected for CTC testing 2-3 months after your surgery, if you were one of the first 30 participants enrolled in the study. You will have a CT or MRI scan of the abdomen and pelvis every 4 months for 2 years to check the status of the disease. This is an investigational study. 5-FU, oxaliplatin, irinotecan, and gemcitabine are each FDA approved and commercially available to treat different types of cancer: 5-FU: pancreatic, gastric, breast, colon/rectum, and skin cancer (basal cell carcinoma) Oxaliplatin: colon and rectal cancer Irinotecan: colorectal cancer Gemcitabine: pancreatic, lung, ovarian, and breast cancer. The use of these 4 drugs together and in combination with radiation therapy for the treatment of pancreatic cancer is investigational. Up to 33 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Official Title
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A Phase II Study of Preoperative Systemic Chemotherapy (Modified FOLFIRINOX) Followed by Radiation Therapy for Patients With High Risk Resectable and Borderline Resectable Adenocarcinoma of the Pancreas

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: 5-FU
* Drug: Gemcitabine
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytologic or histologic proof of adenocarcinoma of the pancreas is required prior to treatment. Patients with Islet cell tumors are not eligible. Only untreated patients with high risk pancreatic adenocarcinomas will be eligible for the study. For this study, such patients are defined as those who meet one or more of the following radiographic or serologic criteria: a)Primary tumor that involves the superior mesenteric vein causing a vein deformity or segmental venous occlusion with a patent vessel above and below suitable for reconstruction. b)Primary tumor that involves </= 180 degrees of the superior mesenteric artery (SMA), celiac axis or any of its branches on CT or MRI. c) Primary tumor that abuts or encases (>/= 50% of the vessel circumference) a short segment of the common hepatic artery (typically at the gastroduodenal artery origin) (continuation of #2). d) Patients with a high CA19-9 (=/>500mg/dl) in the presence of a bilirubin =/< 2.0 mg/dL. e) Radiographic findings consistent with malignant peripancreatic lymphadenopathy outside the planned field on CT or MRI f) Radiographic findings of indeterminate liver or peritoneal lesions on CT or MRI concerning but not diagnostic of metastatic disease. Patients cannot have known hepatic or peritoneal metastases detected by ultrasound (US), CT scan, MRI or laparotomy. There will be no upper age restriction; patients with Eastern Cooperative Oncology Group (ECOG) 0-1 are eligible. Adequate renal, and bone marrow function: a) Leukocytes >/= 3,000/uL. b) Absolute neutrophil count >/=1,500/uL.c) Platelets >/=100,000/Ul. d) Serum creatinine </= 2.0 mg/dL. Hepatic function (endoscopic or percutaneous drainage as needed). a)Total bilirubin </= 2 X institutional upper limits of normal (ULN). b) AST (SGOT)/ALT (SGPT) </= 5 X institutional ULN. Patients must have no fever or evidence of infection or other coexisting medical condition that would preclude protocol therapy. Women of childbearing potential (defined as those who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months) must agree to practice adequate contraception and to refrain from breast feeding. Patients must sign a study-specific consent form. Exclusion Criteria: Patients whose tumors are defined as locally advanced cancer or metastatic cancer are not eligible. Unstable angina or New York Heart Association (NYHA) Grade II or greater congestive heart failure; multiple comorbidity that preclude a major abdominal surgery. Known presence of metastases. Inability to comply with study and/or follow-up procedures. Patients < 18 years of age. Pregnant women with a positive (blood B-HCG) pregnancy test are excluded from this study. Patients with an active second malignancy with the exception of non-melanoma skin cancer.

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: Chemotherapy + Radiation<br>SYSTEMIC PHASE: Chemotherapy with Oxaliplatin followed by Irinotecan followed by 5-FU. m FOLFIRINOX - oxaliplatin 75 mg/m2 d1 + irinotecan 150 mg/m2 d1 + 5-FUl 2,000 mg/m2 46h continuous infusion, every other week for 6 cycles (12 weeks). CHEMORADIATION PHASE: This phase will start at least 2 weeks, but no more than 6 weeks after completion of the last cycle of mFOLFIRINOX. Chemoradiation with Gemcitabine: 350 mg/m2 IV over 35 minutes every week for 5 doses beginning day 1 (days 1, 8, 15, 22, 29) Radiation: External beam radiation therapy will be delivered 5 days/week +/- 2 days over 5.5 weeks with 18-MeV photons. 3D conformal RT, a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions) to the GTV + 1.5 cm margin. SURGERY- At least 4-6 weeks after last dose of Gemcitabine, if no local progression or distant metastasis. Patients whose scans show unequivocal local or distant progression are not candidates for surgery. | Drug: Oxaliplatin<br>* 75 mg/m2 by vein on Day 1 of weeks 1, 3, 5, 7, 9 and 11 for 12 weeks.<br>* Other names: Eloxatin;Drug: Irinotecan<br>* 150 mg/m2 by vein on Day 1 of weeks 1, 3, 5, 7, 9 and 11 for 12 weeks.<br>* Other names: Camptosar;Drug: 5-FU<br>* 2000 mg/m2 by vein over 46 hour continuous infusion, on Days 1 - 2 during weeks 1, 3, 5, 7, 9 and 11 for 12 weeks.<br>* Other names: Efudex;Drug: Gemcitabine<br>* 350 mg/m2 by vein every week for 5 doses beginning Day 1 (days 1, 8, 15, 22, 29).<br>* Other names: Gemzar;Radiation: Radiation Therapy<br>* External beam radiation therapy delivered 5 days/week +/- 2 days over 5.5 weeks with 18-MeV photons. 3D conformal RT, a total dose of 50.4 Gy 1.8 Gy/fraction (28 fractions).<br>* Other names: RT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Resectability Rate | Patients with borderline resectable treated with preoperative modified FOLFIRINOX chemotherapy, followed by gemcitabine-based chemoradiation therapy. At least 4- 6 weeks after the last dose of gemcitabine if there is no local progression or distant metastasis, patients were scheduled for surgery. | 43 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With R0 Margin Resection | The specimen was designated R0 if no tumor cells were identified at any of the resection margins. | 43 months | 
| Disease Free Survival (DFS) | Disease free survival (DFS) was defined as the time interval from the date of surgery to the date of disease recurrence or death or the date of a participant was last known to be alive without disease recurrence. | 54 months | 
| Number of Participants That Were SMAD4 Positive Before and After Surgery | Tumor tissue collected pre-therapy and post-therapy for surgically resected patients was assessed for SMAD4 status and classified as either present or absent based on immunohistochemistry evaluation. | 43 months | 
| Overall Survival | Overall survival (OS) was defined as the time interval from the date of diagnosis to the date of death due to any cause or the date a patient was last known to be alive. Estimated by using the Kaplan-Meier method. | 54 months | 
| Number of Participants With Local and Distant Failure |  | 43 months | 
| Number of Participants Correlative Studies Including DPC4 (SMAD4) Staining and Circulating Tumor Cells (CTC) Pre-Surgery | Tumor tissue collected pre-therapy and post-therapy for surgically resected patients was assessed for SMAD4 status and classified as either present or absent based on immunohistochemistry evaluation. | 43 months | 
| Number of Participants Correlative Studies Including DPC4 (SMAD4) Staining and Circulating Tumor Cells (CTC) Post-Surgery | Tumor tissue collected pre-therapy and post-therapy for surgically resected patients was assessed for SMAD4 status and classified as either present or absent based on immunohistochemistry evaluation. | 43 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic Cancer, Adenocarcinoma of the Pancreas, High Risk Resectable, Borderline Resectable, Chemotherapy, Chemoradiation therapy, Oxaliplatin, Eloxatin, Irinotecan, CPT-11, Camptosar, 5-FU, 5-Fluorouracil, Adrucil, Efudex, Gemcitabine, Gemcitabine Hydrochloride, Gemzar, Radiation Therapy, XRT, RT, External Beam Radiation Therapy