Pancreatic Tumor Cell Vaccine (GVAX), Cyclophosphamide, SBRT, and FOLFIRINOX in Patients With Resected Adenocarcinoma of the Pancreas

Pilot Study Evaluating Allogeneic GM-CSF-Transduced Pancreatic Tumor Cell Vaccine (GVAX) and Low Dose Cyclophosphamide With Fractionated Stereotactic Body Radiation Therapy (SBRT) and FOLFIRINOX Chemotherapy in Patients With Resected Adenocarcinoma of the Pancreas

The purpose of this study is to estimate safety of GVAX Pancreas Vaccine (GVAX) with immune modulating doses of cyclophosphamide (Cy) followed by SBRT and FOLFIRINOX chemotherapy in pancreatic cancer patients after surgery.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Radiation: Stereotactic Body Radiation; Drug: FOLFIRINOX; Drug: Cyclophosphamide; Biological: GVAX Pancreas Vaccine

Detailed Description

This study enrolled patients with surgically resected adenocarcinoma of the pancreas who had titanium clips placed at the time of surgery in order to guide SBRT treatment.

Enrollment was based on traditional 3+3 design with grade 3-4 diarrhea and/or neutropenia defined as the dose limiting toxicity (DLT) within the first 2 cycles (8 weeks) of FOLFIRINOX. The first group of 3 patients (Cohort 1) received SBRT and full dose FOLFIRINOX. The second group of 4 patients (Cohort 2) received SBRT and modified FOLFIRINOX, and the third group of 12 patients (Cohort 3) received SBRT and modified FOLFIRINOX as well as Cy/GVAX vaccinations.

Cy/GVAX (patients 8-19): cyclophosphamide (Cy) at 200 mg/m^2 intravenously over 30 minutes the day before each vaccine. Each vaccination (GVAX) consists of six total intradermal injections of vaccine, two each in the upper right and left thighs, and two in the upper non-dominant arm. Each injection consists of approximately 2.5x10^8 cells of each cell line (PANC 6.03/PANC 10.05) for a total of 5x10^8 cells. The first dose of Cy/GVAX was given within 6-10 weeks from surgery.

Adjuvant SBRT was given 13-17 days after the first dose of Cy/GVAX. Patients receive 5 days of SBRT (6.6 gray (Gy) daily for 33 Gy total) to the tumor bed as delineated by surgical clips placed by the surgeon.

Six 28-day cycles of FOLFIRINOX, starting at least one week after completion of SBRT.

This was permitted to be given locally. Patients were evaluated for dose limiting toxicities (DLTs) within the first 2 cycles (8 weeks).

Cy/GVAX #2-5 was given every 28 days (+/- 3 days), starting 35 days (+/- 7 days) after completion of FOLFIRINOX. Patients without evidence of recurrence could then qualify for additional Cy/GVAX boosts every 6 months (every 12 months with Amendment #10) until disease recurrence, toxicity, withdrawal, or death.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (abbreviated):

1. Documented cancer of the pancreas (head, neck, and/or uncinate process), that has been completely resected
2. No prior Chemotherapy, radiation therapy or biologic therapy for pancreatic cancer
3. Must be within 10 weeks from surgical resection of cancer
4. Titanium clips (minimum 1) must be placed at the time of surgery to aid in SBRT treatment planning
5. ECOG Performance Status of 0 to 1
6. Adequate organ function as defined by study-specified laboratory tests
7. Must use acceptable form of birth control through the study and for 28 days after final dose of study drug
8. Signed informed consent form
9. Willing and able to comply with study procedures

Exclusion criteria (abbreviated):

1. Currently have or have history of certain study-specified heart, liver, kidney, lung, neurological, immune or other medical conditions
2. Presence of metastatic disease
3. Clinical metabolic or laboratory abnormalities defined as Grade 3 or 4 of the National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
4. Systemically active steroids
5. Chemotherapy, radiation therapy or biologic therapy within 28 days prior to receiving study drug
6. Inability to begin protocol treatment within 70 days (10 weeks) after surgery to remove cancer
7. History of HIV, hepatitis B or C infection
8. Pregnant or lactating
9. Conditions, including alcohol or drug dependence, or intercurrent illness that would affect the patient's ability to comply with study visits and procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: SBRT and FOLFIRINOX; The initial 3 patients were treated with SBRT and full dose FOLFIRINOX and observed for the first 2 cycles (8 weeks) for dose limiting toxicities (DLTs). If 2-3 patients are observed with uncontrolled grade 3-4 diarrhea, 2-3 patients are observed with grade 3-4 thrombocytopenia, or if 3 patients are observed with grade 3-4 neutropenia within the first 2 cycles of FOLFIRINOX administration (8 weeks) then the dose level will be deemed unacceptable.	Radiation: Stereotactic Body Radiation; Cohort 1 and 2: SBRT (6.6 Gy per day, 33 Gy total dose) will be administered over 5 days within 6-10 weeks of pancreas surgery (Whipple). Cohort 3: SBRT (6.6 Gy) will be administered over 5 days starting between 13-17 days after the first dose of CY/GVAX.; Other Names: SBRT; Drug: FOLFIRINOX; FOLFIRINOX is given over six 28-day cycles, starting at least 1 weeks after SBRT. FOLFIRINOX consists of the following drugs given IV on days 1 and 15 of each cycle: Oxaliplatin (85 mg/m^2), Irinotecan (180 mg/m^2), Leucovorin (400 mg/m^2), Fluorouracil (400 mg/m^2 bolus followed by 2,400 mg/m^2 continuous infusion over 46-48 hours); modified FOLFIRINOX consists of the same regimen described above but without the 400 mg/m^2 Fluorouracil bolus.
Experimental: Cohort 2: SBRT and modified FOLFIRINOX; The next 4 patients were treated with SBRT and modified FOLFIRINOX and observed for the first 2 cycles (8 weeks) for dose limiting toxicities (DLTs). If no patients are observed with grade 3-4 diarrhea, thrombocytopenia, or neutropenia, then the next cohort of patients will receive SBRT, modified FOLFIRINOX, and GVAX (with Cy).	Radiation: Stereotactic Body Radiation; Cohort 1 and 2: SBRT (6.6 Gy per day, 33 Gy total dose) will be administered over 5 days within 6-10 weeks of pancreas surgery (Whipple). Cohort 3: SBRT (6.6 Gy) will be administered over 5 days starting between 13-17 days after the first dose of CY/GVAX.; Other Names: SBRT; Drug: FOLFIRINOX; FOLFIRINOX is given over six 28-day cycles, starting at least 1 weeks after SBRT. FOLFIRINOX consists of the following drugs given IV on days 1 and 15 of each cycle: Oxaliplatin (85 mg/m^2), Irinotecan (180 mg/m^2), Leucovorin (400 mg/m^2), Fluorouracil (400 mg/m^2 bolus followed by 2,400 mg/m^2 continuous infusion over 46-48 hours); modified FOLFIRINOX consists of the same regimen described above but without the 400 mg/m^2 Fluorouracil bolus.
Experimental: Cohort 3: CY, GVAX, SBRT, and modified FOLFIRINOX; The last 12 patients will receive Cy, GVAX, SBRT, and modified FOLFIRINOX.	Radiation: Stereotactic Body Radiation; Cohort 1 and 2: SBRT (6.6 Gy per day, 33 Gy total dose) will be administered over 5 days within 6-10 weeks of pancreas surgery (Whipple). Cohort 3: SBRT (6.6 Gy) will be administered over 5 days starting between 13-17 days after the first dose of CY/GVAX.; Other Names: SBRT; Drug: FOLFIRINOX; FOLFIRINOX is given over six 28-day cycles, starting at least 1 weeks after SBRT. FOLFIRINOX consists of the following drugs given IV on days 1 and 15 of each cycle: Oxaliplatin (85 mg/m^2), Irinotecan (180 mg/m^2), Leucovorin (400 mg/m^2), Fluorouracil (400 mg/m^2 bolus followed by 2,400 mg/m^2 continuous infusion over 46-48 hours); modified FOLFIRINOX consists of the same regimen described above but without the 400 mg/m^2 Fluorouracil bolus.; Drug: Cyclophosphamide; Cyclophosphamide (Cy) 200 mg/m^2 administered one day prior to GVAX (day 0). One dose will be given prior to SBRT and FOLFIRINOX and four additional doses after FOLFIRINOX completion for a total of 5 doses. Additional CY/GVAX boosts may be given every 6 months thereafter until disease recurrence.; Other Names: Cytoxan; Cy; Biological: GVAX Pancreas Vaccine; GVAX administered one day after Cy (day 1). One dose will be given prior to SBRT and FOLFIRINOX and four additional doses after FOLFIRINOX completion for a total of 5 doses. Additional CY/GVAX boosts may be given every 6 months thereafter until disease recurrence.; Other Names: PANC 10.05 pcDNA-1/GM-Neo and PANC 6.03 pcDNA-1/GM-Neo vaccine; GVAX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicities	The number of participants experiencing grade 3-4 diarrhea, neutropenia, and thrombocytopenia within the first 2 cycles (8 weeks) of treatment, regardless of attribution. The rates of each of these toxicities were considered unacceptable if they were 40%, 60%, and 40%, respectively. A decision rule similar to the traditional 3+3 design was used to determine whether it was safe to continue on to the next cohort.	8 weeks
Grade 3 or Higher Cy/GVAX-related Adverse Events	Number of participants with grade 3 or above adverse event attributed to Cy or the GVAX pancreas vaccine. Each adverse event (as defined by NCI CTCAE v4.0) was counted only once for a given subject.	116 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was measured as the amount of time from date of surgery until death or end of follow-up. OS was 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.	96 months
Disease-free Survival (DFS)	DFS was measured as the time from date of surgery until pancreatic cancer recurrence or death. Disease status was monitored by radiologic scans done approximately every 12 weeks. DFS was censored on the date of last radiologic scan for subjects without documentation of cancer recurrence or death at the time of analysis. Estimation based on the Kaplan-Meier curve.	96 months
Distant Metastases Free Survival (DMFS)	DMFS was measured as the amount of time from date of surgery until metastatic disease progression or death. Metastatic disease progression is the appearance of one or more new lesions outside the primary tumor area (pancreas). Disease status was monitored by radiologic scans done approximately every 12 weeks. DMFS was censored on the date of last radiographic scans for subjects without documentation of metastatic disease progression or death at the time of analysis. Estimation based on the Kaplan-Meier curve.	96 months
Freedom From Local Progression (FFLP)	FFLP was measured as the time from date of surgery until disease recurrence in the pancreas or death. Disease status was monitored by radiologic scans done approximately every 12 weeks. FFLP was censored on the date of last radiographic scans for subjects without documentation of local disease recurrence or death at the time of analysis. Estimation based on the Kaplan-Meier curve.	96 months

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: The Skip Viragh Foundation
• Investigators: Principal Investigator: Daniel Laheru, M.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2012
• Primary Completion (Actual): October 18, 2023
• Study Completion (Actual): October 18, 2023

Study Registration Dates

• First Submitted: April 27, 2012
• First Submitted That Met QC Criteria: May 9, 2012
• First Posted (Estimated): May 10, 2012

Study Record Updates

• Last Update Posted (Actual): August 14, 2024
• Last Update Submitted That Met QC Criteria: July 22, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Cyclophosphamide; SBRT; Cytoxan; Pancreatic Vaccine; GVAX; FOLFIRINOX; Adjuvant therapy; Stereotactic radiation therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Vaccines; Pancrelipase; Folfirinox
• Other Study ID Numbers: J1179; NA_00050233 (Other Identifier: JHMIRB)