Pancreatic Cancer
Conditions
Keywords
Adjuvant therapy, Immunotherapy, Cytoxan, Cyclophosphamide, Pancreatic Vaccine, Stereotactic radiation therapy, SBRT, FOLFIRINOX, GVAX
Brief summary
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.
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.
Interventions
DRUGCyclophosphamide
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.
BIOLOGICALGVAX 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.
RADIATIONStereotactic 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.
DRUGFOLFIRINOX
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.
Sponsors
The Skip Viragh Foundation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 76 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities | 8 weeks | 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. |
| Grade 3 or Higher Cy/GVAX-related Adverse Events | 116 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 96 months | 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. |
| Disease-free Survival (DFS) | 96 months | 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. |
| Distant Metastases Free Survival (DMFS) | 96 months | 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. |
| Freedom From Local Progression (FFLP) | 96 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: SBRT and FOLFIRINOX Stereotactic Body Radiation Therapy (SBRT, 33 Gy cumulative dose) was administered to the surgical bed over 5 days, starting 6-10 weeks after pancreas surgical resection (Whipple procedure).
Six 28-day cycles of FOLFIRINOX were given starting 7-28 days after completion of SBRT. Full dose 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). Dose reductions of FOLFIRINOX were permitted. | 3 |
| Cohort 2: SBRT and Modified FOLFIRINOX Stereotactic Body Radiation Therapy (SBRT, 33 Gy cumulative dose) was administered to the surgical bed over 5 days, starting 6-10 weeks after pancreas surgical resection (Whipple procedure).
Six 28-day cycles of modified FOLFIRINOX were given, starting 7-28 days after completion of SBRT. Modified 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 (2,400 mg/m\^2 continuous infusion over 46-48 hours). Dose reductions of FOLFIRINOX were permitted.
The difference between Cohort 1 and 2 is that the Fluorouracil bolus was dropped in Cohort 2. | 4 |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX Cyclophosphamide (Cy) 200 mg/m\^2 was administered on Day 0 of each vaccine cycle. GVAX Pancreas Vaccine (GVAX) was administered one day after Cy (Day 1 of each cycle). The first Cycle of Cy/GVAX was given 6-10 weeks after pancreas surgical resection (prior to SBRT and FOLFIRINOX). Four additional doses were given after FOLFIRINOX completion for a total of 5 priming doses. Additional Cy/GVAX boosts were given every 6 months thereafter until disease recurrence.
Stereotactic Body Radiation Therapy (SBRT), 33 Gy cumulative dose, was administered to the surgical bed over 5 days, starting about 2 weeks after the first dose of Cy/GVAX.
Six 28-day cycles of modified FOLFIRINOX were given, starting 7-28 days after completion of SBRT. Modified 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 (2,400 mg/m\^2 continuous infusion over 46-48 hours). Dose reductions were permitted. | 12 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Cohort 2: SBRT and Modified FOLFIRINOX | Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Cohort 1: SBRT and FOLFIRINOX | Total |
|---|---|---|---|---|
| Age, Continuous | 55 years | 58 years | 69 years | 58 years |
| Eastern Cooperative Oncology Group (ECOG) Classification ECOG 0 | 2 Participants | 7 Participants | 2 Participants | 11 Participants |
| Eastern Cooperative Oncology Group (ECOG) Classification ECOG 1 | 2 Participants | 5 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 12 Participants | 3 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 12 Participants | 2 Participants | 18 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 3 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 4 | 8 / 12 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 12 / 12 |
| serious Total, serious adverse events | 3 / 3 | 1 / 4 | 6 / 12 |
Outcome results
Primary
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.
Time frame: 8 weeks
Population: One patient in cohort 2 was not evaluable because they did not complete 2 cycles of FOLFIRINOX.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: SBRT and FOLFIRINOX | Dose Limiting Toxicities | Neutropenia | 3 Participants |
| Cohort 1: SBRT and FOLFIRINOX | Dose Limiting Toxicities | Diarrhea | 0 Participants |
| Cohort 1: SBRT and FOLFIRINOX | Dose Limiting Toxicities | Thrombocytopenia | 2 Participants |
| Cohort 2: SBRT and Modified FOLFIRINOX | Dose Limiting Toxicities | Neutropenia | 0 Participants |
| Cohort 2: SBRT and Modified FOLFIRINOX | Dose Limiting Toxicities | Diarrhea | 0 Participants |
| Cohort 2: SBRT and Modified FOLFIRINOX | Dose Limiting Toxicities | Thrombocytopenia | 0 Participants |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Dose Limiting Toxicities | Diarrhea | 1 Participants |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Dose Limiting Toxicities | Thrombocytopenia | 0 Participants |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Dose Limiting Toxicities | Neutropenia | 1 Participants |
Primary
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.
Time frame: 116 months
Population: Only Cohort 3 received Cy and GVAX and could be evaluated for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: SBRT and FOLFIRINOX | Grade 3 or Higher Cy/GVAX-related Adverse Events | 2 Participants |
Secondary
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.
Time frame: 96 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: SBRT and FOLFIRINOX | Disease-free Survival (DFS) | 10.5 months |
| Cohort 2: SBRT and Modified FOLFIRINOX | Disease-free Survival (DFS) | 14.5 months |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Disease-free Survival (DFS) | 24.1 months |
Secondary
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.
Time frame: 96 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: SBRT and FOLFIRINOX | Distant Metastases Free Survival (DMFS) | 10.5 months |
| Cohort 2: SBRT and Modified FOLFIRINOX | Distant Metastases Free Survival (DMFS) | 19.0 months |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Distant Metastases Free Survival (DMFS) | 42.0 months |
Secondary
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.
Time frame: 96 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: SBRT and FOLFIRINOX | Freedom From Local Progression (FFLP) | 17.3 months |
| Cohort 2: SBRT and Modified FOLFIRINOX | Freedom From Local Progression (FFLP) | 20.5 months |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Freedom From Local Progression (FFLP) | 34.0 months |
Secondary
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.
Time frame: 96 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: SBRT and FOLFIRINOX | Overall Survival (OS) | 22.2 months |
| Cohort 2: SBRT and Modified FOLFIRINOX | Overall Survival (OS) | 27.5 months |
| Cohort 3: CY, GVAX, SBRT, and Modified FOLFIRINOX | Overall Survival (OS) | 61.3 months |