Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Undergoing Chemotherapy and Radiation Therapy for Stage I or Stage II Pancreatic Cancer That Can Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Vaccines made from gene-modified tumor cells may help the body build an effective immune response to kill pancreatic cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vaccine therapy together with cyclophosphamide may kill more tumor cells. It is not yet known whether vaccine therapy is more effective with or without cyclophosphamide in treating patients with pancreatic cancer. PURPOSE: This randomized clinical trial is studying the side effects of vaccine therapy and to see how well it works when given with or without cyclophosphamide in treating patients undergoing chemotherapy and radiation therapy for stage I or stage II pancreatic cancer that can be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To evaluate the safety and feasibility of a GVAX pancreatic cancer vaccine (GM-CSF gene-transfected allogeneic pancreatic cancer vaccine) when administered alone or in combination with a single intravenous dose or daily metronomic oral doses of cyclophosphamide as neoadjuvant and adjuvant treatment in patients with resectable stage I or II adenocarcinoma of the head, neck, or uncinate process of the pancreas. To assess the immune cell infiltrates, particularly T-regulatory cells (Tregs) and CD4+ and CD8+ effector T cells, after neoadjuvant GVAX pancreatic cancer vaccination. To assess the changes in the number and function of peripheral mesothelin-specific CD8+ T cells and CD4+, FoxP3+, and GITR+ Tregs after each GVAX pancreatic cancer vaccination when administered alone or in combination with a single dose or metronomic doses of cyclophosphamide. Secondary To estimate disease-free and overall survival of patients treated with these regimens. To estimate the effect of immune parameters on disease-free and overall survival of these patients. OUTLINE: Patients are randomized to 1 of 3 treatment arms. Arm A: Patients receive GVAX pancreatic cancer vaccine intradermally (ID) on day 1 and undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive an additional dose of the vaccine. Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy comprising gemcitabine, fluorouracil or capecitabine, and radiotherapy over 26-28 weeks. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive the vaccine on day 1. Treatment with the vaccine repeats every 28 days for 4 courses. Arm B: Patients receive low-dose cyclophosphamide IV on day 0 and GVAX pancreatic cancer vaccine ID on day 1. Patients undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive low-dose cyclophosphamide IV on day 0 and the vaccine on day 1. Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy comprising gemcitabine, fluorouracil or capecitabine, and radiotherapy over 26-28 weeks. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive low-dose cyclophosphamide IV on day 0 and the vaccine on day 1. Treatment with cyclophosphamide and the vaccine repeats every 28 days for 4 courses. Arm C: Patients receive GVAX pancreatic cancer vaccine ID on day 1 and low-dose oral cyclophosphamide twice daily on days 1-7. Patients undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive the vaccine on day 1 and low-dose oral cyclophosphamide twice daily on days 1-7 and 15-21. Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy comprising gemcitabine, fluorouracil or capecitabine, and radiotherapy over 26-28 weeks. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive the vaccine on day 1 and low-dose oral cyclophosphamide twice daily on days 1-7 and 15-21. Treatment with the vaccine and cyclophosphamide repeats every 28 days for 4 courses. Patients undergo blood sample collection periodically for correlative laboratory studies, including immune cell analysis. Immune cell analysis includes monitoring the quantitative change of peripheral blood lymphocytes, including regulatory T cells (Tregs), and functional analysis of T-cell immune response. Tumor tissue samples collected at the time of surgery are analyzed for tumor antigens and infiltrating immune cells by immunohistochemistry and quantitative real-time PCR. After completion of study treatment, patients are followed periodically.

Official Title
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A Randomized Three-arm Neoadjuvant and Adjuvant Feasibility and Toxicity Study of a GM-CSF Secreting Allogeneic Pancreatic Cancer Vaccine Administered Either Alone or in Combination With Either a Single Intravenous Dose or Daily Metronomic Oral Doses of Cyclophosphamide for the Treatment of Patients With Surgically Resected Adenocarcinoma of the Pancreas

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Biological: GVAX pancreatic cancer vaccine
* Drug: cyclophosphamide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Newly diagnosed adenocarcinoma of the head, neck, or uncinate process of the pancreas Stage I or II disease Surgically resectable disease (R0 or R1) by spiral CT scan No distant metastases A clear fat plane is present around the celiac and superior mesenteric arteries Patent superior mesenteric and portal veins Candidate for a pancreaticoduodenectomy PATIENT CHARACTERISTICS: ECOG performance status 0-1 Hemoglobin ≥ 9 g/dL ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Serum creatinine ≤ 2 mg/dL AST and ALT ≤ 2 times upper limit of normal (ULN) Amylase ≤ 2 times ULN Alkaline phosphatase ≤ 5 times ULN Hyperbilirubinemia secondary to tumor-associated extrahepatic biliary obstruction allowed Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 4 weeks after the completion of study treatment No history of autoimmune disease, including systemic lupus erythematosus, sarcoidosis, rheumatoid arthritis, glomerulonephritis, or vasculitis No uncontrolled medical problems No active infections No other cancer within the past 5 years except for superficial bladder cancer, nonmelanoma skin cancer, or low-grade prostate cancer not requiring therapy PRIOR CONCURRENT THERAPY: More than 28 days since prior anticancer therapy No prior cancer immunotherapy, including the same pancreatic cancer vaccine used in this study More than 28 days since prior systemic steroid therapy or immunosuppressive therapy No systemic steroid therapy or immunosuppressive therapy during and within 28 days after vaccine administration No other concurrent immunotherapy, chemotherapy, radiotherapy, gene therapy, biologic therapy, or investigational therapy for the treatment of pancreatic cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Patients receive GVAX pancreatic cancer vaccine intradermally (ID) on day 1 of Cycle 1 and undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive an additional dose of the vaccine (Cycle 2). Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy comprising gemcitabine, fluorouracil or capecitabine, and radiotherapy over 26-28 weeks. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive the vaccine on day 1. Treatment with the vaccine repeats every 28 days for 4 additional cycles. | Biological: GVAX pancreatic cancer vaccine<br>* Given intradermally<br>|
| Experimental: Arm B<br>Patients receive low-dose cyclophosphamide IV on day 0 and GVAX pancreatic cancer vaccine ID on day 1 of Cycle 1. Patients undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive low-dose cyclophosphamide IV on day 0 and the vaccine (Cycle 2). Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy comprising gemcitabine, fluorouracil or capecitabine, and radiotherapy over 26-28 weeks. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive low-dose cyclophosphamide IV on day 0 and the vaccine on day 1. Treatment with cyclophosphamide and the vaccine repeats every 28 days for 4 additional cycles.. | Biological: GVAX pancreatic cancer vaccine<br>* Given intradermally<br>Drug: cyclophosphamide<br>* Given IV (Arm B), given orally (Arm C)<br>|
| Experimental: Arm C<br>Patients receive GVAX pancreatic cancer vaccine ID on day 1 of Cycle 1 and low-dose oral cyclophosphamide twice daily on days 1-7. Patients undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive the vaccine on day 1 and low-dose oral cyclophosphamide twice daily on days 1-7 and 15-21 (Cycle 2). Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy comprising gemcitabine, fluorouracil or capecitabine, and radiotherapy over 26-28 weeks. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive the vaccine on day 1 and low-dose oral cyclophosphamide twice daily on days 1-7 and 15-21. Treatment with the vaccine and cyclophosphamide repeats every 28 days for 4 additional cycles. | Biological: GVAX pancreatic cancer vaccine<br>* Given intradermally<br>Drug: cyclophosphamide<br>* Given IV (Arm B), given orally (Arm C)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Measured by Number of Participants With Treatment-related Grade 3 or 4 Local and Systemic Toxicity as Defined by NCI CTCAE v3.0 |  | 7 years | 
| Amount of T-regulatory Cells (Tregs) and CD4+ and CD8+ Effector T Cells, After Neoadjuvant GVAX Pancreatic Cancer Vaccination. |  | up to 8 years | 
| Change in the Number and Function of Peripheral Mesothelin-specific CD8+ T Cells and CD4+, FoxP3+, and GITR+ Tregs | Change in the number and function of peripheral mesothelin-specific CD8+ T cells and CD4+, FoxP3+, and GITR+ Tregs after each GVAX pancreatic cancer vaccination when administered alone or in combination with a single dose or metronomic doses of cyclophosphamide. | up to 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | OS will be measured from date of randomization until death or end of follow-up (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve. | 10 years and 7 months | 
| Disease Free Survival | Disease free survival is defined as the time interval from the date of randomization to the date of radiographic evidence of disease recurrence. Estimation based on the Kaplan-Meier curve. | 10 years and 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the pancreas, stage I pancreatic cancer, stage II pancreatic cancer