2nd-line, 3rd-line and Greater Metastatic Pancreatic Cancer
Conditions
Keywords
cancer, cancer vaccine, Listeria monocytogenes, Listeria-based vaccine, GVAX, cyclophosphamide, Cytoxan, immunotherapy, mesothelin
Brief summary
Test the safety, immune response and efficacy of GVAX pancreas vaccine (with cyclophosphamide) and CRS-207 compared to chemotherapy or CRS-207 alone in adults with previously treated metastatic pancreatic adenocarcinoma
Interventions
BIOLOGICALGVAX Pancreas Vaccine
BIOLOGICALCRS-207
DRUGChemotherapy
Investigator's choice of one of the following commercially available products: gemcitabine; capecitabine; fluorouracil with or without leucovorin; irinotecan; or erlotinib.
DRUGcyclophosphamide
Sponsors
Johns Hopkins University
Aduro Biotech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histologically proven malignant adenocarcinoma of the pancreas; measurable disease is not required, mixed histology is not allowed; subjects must have metastatic disease * 2nd line, 3rd line or greater * At least 18 years of age * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Anticipated life expectancy \>12 weeks * For women and men of childbearing potential, a medically acceptable method of highly effective contraception (oral hormonal contraceptive, condom plus spermicide, or hormone implants) must be used throughout the study period and for 28 days after their final vaccine administration. A barrier method of contraception must be employed by all subjects (male and female), regardless of other methods. * Have adequate organ function as defined by specified laboratory values
Exclusion criteria
* Allergy to both penicillin & sulfa or suspected hypersensitivity to granulocyte-macrophage colony stimulating factor (GM-CSF), dimethyl sulfoxide, fetal bovine serum, trypsin, yeast, glycerol or other component of the therapy options * Known history or evidence of brain metastases, immunodeficiency disease or immunocompromised state or history of autoimmune disease requiring systemic steroids or other immunosuppressive treatment * Have any evidence of hepatic cirrhosis or clinical or radiographic ascites * Have prosthetic heart valves, major implant or device placed in the last 12 months or history of infection with implant/device that cannot be easily removed * Rapidly progressing disease * Clinically significant and/or malignant pleural effusion * Received prior GVAX pancreas vaccine or CRS-207 * Major surgery or significant traumatic injury (or unhealed surgical wounds) occurring within 28 days prior to receiving study drug, or planned surgery requiring general anesthesia * Infection with HIV or hepatitis B or C at screening * Valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis * Pregnant or breastfeeding * Unable to avoid close contact with another individual known to be at high risk of listeriosis (e.g., newborn infant, pregnant woman, HIV-positive individual) during the course of CRS-207 treatment until completion of antibiotic regimen * Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Cohort: Overall Survival (OS) Censored at 138 Deaths (ITT Set) | Subjects were followed from date of randomization to the date of death by any cause, whichever came first, assessed up to 32 months. Analysis conducted when 138 deaths reached in the Primary Cohort in the FAS. | OS was estimated using Kaplan-Meier (KM) methods with 95% confidence intervals (CIs), with censoring at the date when 138 deaths were reached in the Primary Cohort in the FAS. Subjects without documentation of death at the time of final analysis were censored as of the date the subject was last known to be alive on/prior to the primary analysis data cut. |
| Primary Cohort: OS (All Data, FAS) | Subjects followed for survival from date of randomization until lost to follow-up, withdrawal of consent, or death, whichever came first, assessed up to 32 months. | For all treated subjects, OS was calculated using KM methods with 95% CIs. Subjects without documentation of death at the time of the analysis were censored as of the date the subject was last known to be alive on/prior to the final analysis data cut. |
| 2nd-line Cohort: OS (All Data, FAS) | Subjects followed for survival from date of randomization until lost to follow-up, withdrawal of consent, or death, whichever came first, assessed up to 32 months. | For all treated subjects, OS was calculated using KM methods with 70% CIs. Subjects without documentation of death at the time of the analysis were censored as of the date the subject was last known to be alive on/prior to the final analysis cut. 70% CIs were selected to provide an 80% probability to rule out differences in median survival less than -2.4 months between the 2nd-line Cohort: Chemotherapy arm and the 2nd-line Cohort: Cy/GVAX + CRS-207 and 2nd-line Cohort: CRS-207 arms, based upon the assumptions made in the statistical analysis plan (SAP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | From the start of the first study drug administration on Day 1, Week 1, through 28 days after the last study drug dose, assessed up to 32 months from the date of randomization. | Safety was assessed based upon the number of adverse events (AEs) that occurred in the FAS of each treatment arm, including serious AEs and total AEs. Total AEs included both serious and non-serious AEs. |
Countries
Canada, United States
Participant flow
Recruitment details
This study enrolled patients with previously treated metastatic pancreatic adenocarcinoma from 21 medical centers in the United States and Canada. The last patient completed the study in August 2016.
Pre-assignment details
Participants screened over a 21-day period.
Participants by arm
| Arm | Count |
|---|---|
| Primary Cohort: Cy/GVAX + CRS-207 | 68 |
| Primary Cohort: CRS-207 | 58 |
| Primary Cohort: Chemotherapy | 43 |
| 2nd-line Cohort: Cy/GVAX + CRS-207 | 26 |
| 2nd-line Cohort: CRS-207 | 29 |
| 2nd-line Cohort: Chemotherapy | 11 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 67 | 64 | 66 | 28 | 29 | 22 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 4 | 3 | 2 | 1 | 1 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 4 | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Primary Cohort: Cy/GVAX + CRS-207 | Primary Cohort: CRS-207 | Primary Cohort: Chemotherapy | 2nd-line Cohort: Cy/GVAX + CRS-207 | 2nd-line Cohort: CRS-207 | 2nd-line Cohort: Chemotherapy | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 7.96 | 63.2 years STANDARD_DEVIATION 8.92 | 64.0 years STANDARD_DEVIATION 10.85 | 63.9 years STANDARD_DEVIATION 11.83 | 64.1 years STANDARD_DEVIATION 9.43 | 66.6 years STANDARD_DEVIATION 10.86 | 63.7 years STANDARD_DEVIATION 9.48 |
| Sex: Female, Male Female | 31 Participants | 29 Participants | 26 Participants | 15 Participants | 10 Participants | 5 Participants | 116 Participants |
| Sex: Female, Male Male | 37 Participants | 29 Participants | 17 Participants | 11 Participants | 19 Participants | 6 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 88 / 94 | 82 / 87 | 51 / 54 |
| other Total, other adverse events | 94 / 94 | 87 / 87 | 51 / 54 |
| serious Total, serious adverse events | 44 / 94 | 32 / 87 | 15 / 54 |
Outcome results
Primary
2nd-line Cohort: OS (All Data, FAS)
For all treated subjects, OS was calculated using KM methods with 70% CIs. Subjects without documentation of death at the time of the analysis were censored as of the date the subject was last known to be alive on/prior to the final analysis cut. 70% CIs were selected to provide an 80% probability to rule out differences in median survival less than -2.4 months between the 2nd-line Cohort: Chemotherapy arm and the 2nd-line Cohort: Cy/GVAX + CRS-207 and 2nd-line Cohort: CRS-207 arms, based upon the assumptions made in the statistical analysis plan (SAP).
Time frame: Subjects followed for survival from date of randomization until lost to follow-up, withdrawal of consent, or death, whichever came first, assessed up to 32 months.
Population: Analysis based on subjects in the 2nd-line Cohort in the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary Cohort: Cy/GVAX + CRS-207 | 2nd-line Cohort: OS (All Data, FAS) | 4.6 months |
| Primary Cohort: CRS-207 | 2nd-line Cohort: OS (All Data, FAS) | 4.0 months |
| Primary Cohort: Chemotherapy | 2nd-line Cohort: OS (All Data, FAS) | 6.9 months |
Primary
Primary Cohort: OS (All Data, FAS)
For all treated subjects, OS was calculated using KM methods with 95% CIs. Subjects without documentation of death at the time of the analysis were censored as of the date the subject was last known to be alive on/prior to the final analysis data cut.
Time frame: Subjects followed for survival from date of randomization until lost to follow-up, withdrawal of consent, or death, whichever came first, assessed up to 32 months.
Population: Analysis based on subjects in the Primary Cohort in the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary Cohort: Cy/GVAX + CRS-207 | Primary Cohort: OS (All Data, FAS) | 4.2 months |
| Primary Cohort: CRS-207 | Primary Cohort: OS (All Data, FAS) | 5.2 months |
| Primary Cohort: Chemotherapy | Primary Cohort: OS (All Data, FAS) | 4.7 months |
Primary
Primary Cohort: Overall Survival (OS) Censored at 138 Deaths (ITT Set)
OS was estimated using Kaplan-Meier (KM) methods with 95% confidence intervals (CIs), with censoring at the date when 138 deaths were reached in the Primary Cohort in the FAS. Subjects without documentation of death at the time of final analysis were censored as of the date the subject was last known to be alive on/prior to the primary analysis data cut.
Time frame: Subjects were followed from date of randomization to the date of death by any cause, whichever came first, assessed up to 32 months. Analysis conducted when 138 deaths reached in the Primary Cohort in the FAS.
Population: Analysis based on subjects in the Primary Cohort in the intent-to-treat (ITT) set. The ITT set is the analysis population that included all randomized study subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary Cohort: Cy/GVAX + CRS-207 | Primary Cohort: Overall Survival (OS) Censored at 138 Deaths (ITT Set) | 3.8 months |
| Primary Cohort: CRS-207 | Primary Cohort: Overall Survival (OS) Censored at 138 Deaths (ITT Set) | 5.4 months |
| Primary Cohort: Chemotherapy | Primary Cohort: Overall Survival (OS) Censored at 138 Deaths (ITT Set) | 4.6 months |
Secondary
Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen
Safety was assessed based upon the number of adverse events (AEs) that occurred in the FAS of each treatment arm, including serious AEs and total AEs. Total AEs included both serious and non-serious AEs.
Time frame: From the start of the first study drug administration on Day 1, Week 1, through 28 days after the last study drug dose, assessed up to 32 months from the date of randomization.
Population: Analysis conducted for the FAS of each study arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Primary Cohort: Cy/GVAX + CRS-207 | Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | Serious AEs | 44 Participants |
| Primary Cohort: Cy/GVAX + CRS-207 | Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | Total AEs | 94 Participants |
| Primary Cohort: CRS-207 | Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | Serious AEs | 32 Participants |
| Primary Cohort: CRS-207 | Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | Total AEs | 87 Participants |
| Primary Cohort: Chemotherapy | Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | Serious AEs | 15 Participants |
| Primary Cohort: Chemotherapy | Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | Total AEs | 52 Participants |