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

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

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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Biological: GVAX pancreatic cancer vaccine; Drug: cyclophosphamide

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.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm A; 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; Given intradermally
EXPERIMENTAL: Arm B; 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; Given intradermally; Drug: cyclophosphamide; Given IV (Arm B), given orally (Arm C)
EXPERIMENTAL: Arm C; 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; Given intradermally; Drug: cyclophosphamide; Given IV (Arm B), given orally (Arm C)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 2, 2008
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): February 1, 2019

Study Registration Dates

• First Submitted: August 1, 2008
• First Submitted That Met QC Criteria: August 1, 2008
• First Posted (ESTIMATE): August 4, 2008

Study Record Updates

• Last Update Posted (ACTUAL): February 25, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: adenocarcinoma of the pancreas; stage I pancreatic cancer; stage II pancreatic cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: J0810; P30CA006973 (U.S. NIH Grant/Contract); CDR0000600355; NA_00015858 (OTHER: JHM IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No