Pancreatic Cancer
Conditions
Keywords
adenocarcinoma of the pancreas, stage I pancreatic cancer, stage II pancreatic cancer
Brief summary
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
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.
Interventions
BIOLOGICALGVAX pancreatic cancer vaccine
Given intradermally
DRUGcyclophosphamide
Given IV (Arm B), given orally (Arm C)
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | up to 8 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 10 years and 7 months | 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. |
| Disease Free Survival | 10 years and 7 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A - GVAX Vaccine Without Cyclophosphamide 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.
GVAX pancreatic cancer vaccine: Given intradermally | 29 |
| Arm B - GVAX Vaccine With IV Cyclophosphamide 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..
GVAX pancreatic cancer vaccine: Given intradermally
cyclophosphamide: Given IV (Arm B), given orally (Arm C) | 28 |
| Arm C - GVAX Vaccine With PO Cyclophosphamide Patients receive GVAX pancreatic cancer vaccine ID on day 1 of Cycle 1 and low-dose oral (PO) 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.
GVAX pancreatic cancer vaccine: Given intradermally
cyclophosphamide: Given IV (Arm B), given orally (Arm C) | 30 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Disease Progression | 11 | 14 | 17 |
| Overall Study | Eligibility | 7 | 5 | 7 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A - GVAX Vaccine Without Cyclophosphamide | Arm B - GVAX Vaccine With IV Cyclophosphamide | Arm C - GVAX Vaccine With PO Cyclophosphamide | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 13 Participants | 18 Participants | 43 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 15 Participants | 12 Participants | 44 Participants |
| Age, Continuous | 62.79 years STANDARD_DEVIATION 10.83 | 64.96 years STANDARD_DEVIATION 11.73 | 67.97 years STANDARD_DEVIATION 9.96 | 65.28 years STANDARD_DEVIATION 10.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 24 Participants | 30 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 25 Participants | 26 Participants | 28 Participants | 79 Participants |
| Sex: Female, Male Female | 9 Participants | 12 Participants | 16 Participants | 37 Participants |
| Sex: Female, Male Male | 20 Participants | 16 Participants | 14 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 1 / 28 | 1 / 30 |
| other Total, other adverse events | 29 / 29 | 28 / 28 | 30 / 30 |
| serious Total, serious adverse events | 0 / 29 | 0 / 28 | 0 / 30 |
Outcome results
Primary
Amount of T-regulatory Cells (Tregs) and CD4+ and CD8+ Effector T Cells, After Neoadjuvant GVAX Pancreatic Cancer Vaccination.
Time frame: up to 8 years
Population: Data was not collected for this outcome measure.
Primary
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.
Time frame: up to 8 years
Population: Data was not collected for this outcome measure.
Primary
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
Time frame: 7 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - GVAX Vaccine Without Cyclophosphamide | 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 | 3 Participants |
| Arm B - GVAX Vaccine With IV Cyclophosphamide | 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 | 2 Participants |
| Arm C - GVAX Vaccine With PO Cyclophosphamide | 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 | 4 Participants |
Secondary
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.
Time frame: 10 years and 7 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - GVAX Vaccine Without Cyclophosphamide | Disease Free Survival | 18.92 months |
| Arm B - GVAX Vaccine With IV Cyclophosphamide | Disease Free Survival | 8.54 months |
| Arm C - GVAX Vaccine With PO Cyclophosphamide | Disease Free Survival | 5.56 months |
Secondary
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.
Time frame: 10 years and 7 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - GVAX Vaccine Without Cyclophosphamide | Overall Survival | 34.2 months |
| Arm B - GVAX Vaccine With IV Cyclophosphamide | Overall Survival | 15.4 months |
| Arm C - GVAX Vaccine With PO Cyclophosphamide | Overall Survival | 16.5 months |