Cancer of the Pancreas, Pancreas Cancer, Pancreatic Cancer
Conditions
Brief summary
This is a phase 1 open-label study to evaluate the safety and immunogenicity of a neoantigen peptide vaccine strategy in pancreatic cancer patients following surgical resection and adjuvant chemotherapy. The neoantigen peptide vaccines will incorporate prioritized neoantigens and personalized mesothelin epitopes and will be co-administered with poly-ICLC. The hypothesis of this study is that neoantigen peptide vaccines will be safe and capable of generating measurable neoantigen-specific CD4 and CD8 T cell responses.
Interventions
BIOLOGICALNeoantigen Peptide Vaccine
• Each pool of vaccine study drug + poly IC:LC will be administered to one of the four limbs (A - Right Arm, B - Left Arm, C - Right Leg, D - Left Leg) by subcutaneous (SC) injection.
DRUGPoly ICLC
• Each pool of vaccine study drug + poly IC:LC will be administered to one of the four limbs (A - Right Arm, B - Left Arm, C - Right Leg, D - Left Leg) by subcutaneous (SC) injection.
PROCEDUREBlood for immune monitoring
-Baseline, day 1, day 22, day 50, day 78, week 25, and week 73
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma; mixed histology will be included as long as the predominant histology is adenocarcinoma. * Completed an R0 or R1 surgical resection as determined by pathology * Pathology review demonstrates tumor cellularity no less than 30% in quantities sufficient to obtain 6-8 1mm biopsies from the original FFPE blocks. * At least 18 years of age. * Life expectancy of \> 12 months. * ECOG performance status ≤ 2 * Normal bone marrow and organ function as defined below: * WBC\>=3,000/μL * absolute neutrophil count\>=1,500/μL * platelets\>=100,000/μL * total bilirubin≤1.5 X institutional upper limit of normal (subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level \>1.5 mg/dL if their conjugated bilirubin is \<1.5 x ULN) * AST≤ X institutional upper limit of normal * creatinine≤1.5 X institutional upper limit of normal * International Normalized Ratio (INR) and activated partial thromboplastin time (PTT) \< 1.5 x ULN provided the patient is not on anticoagulation therapy. 9-Patients who have had a stent placed for biliary obstruction can be included in the study provided serum bilirubin at time of enrollment is within protocol limits. * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Able to understand and willing to sign an IRB approved written informed consent document.
Exclusion criteria
* Evidence of neuroendocrine tumor, duodenal adenocarcinoma, or ampullary adenocarcinoma. * Received neoadjuvant chemotherapy for their pancreatic adenocarcinoma * Evidence of disease recurrence or metastasis following surgical resection at any time prior to the first vaccination administration. Most patients will undergo restaging midway through adjuvant chemotherapy and at the completion of therapy; however, timing of imaging is at the discretion of the patient's medical oncologist. * History of other malignancy ≤ 3 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only, carcinoma in situ of the cervix, or LCIS/DCIS of the breast * Known allergy, or history of serious adverse reaction to vaccines or TLR agonists such as anaphylaxis, hives, or respiratory difficulty. * Acute or chronic, clinically significant hematologic, pulmonary, cardiovascular, hepatic renal, and/or other functional abnormality that would jeopardize the health and safety of the participant as determined by the investigator based on medical history, physical examination, laboratory values, and/or diagnostic studies. * A psychiatric illness/social situations that would limit compliance with study requirements as determined by the investigator from the medical history, physical exam, and/or medical record * Prior or currently active autoimmune disease requiring management with immunosuppression. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication (e.g., corticosteroids) which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. In the case of asthma or chronic obstructive pulmonary disease taking inhaled corticosteroids that does not require daily systemic corticosteroids is acceptable. Additionally, local acting steroids (topical, inhaled, or intraarticular) will be allowed. Patients on intermittent or short course steroids will be allow if the dose does not exceed 4 mg of dexamethasone (or equivalent) per day for \> 7 consecutive days. Any patients receiving steroids should be discussed with the PI to determine if eligible. * Pregnant and/or breastfeeding. * Known HIV-positive status. These patients are ineligible because of the potential inability to generate an immune response to vaccines.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Neoantigen Peptide Vaccine as Measured by the Number of Serious Adverse Events | Through 30 days following completion of treatment (median follow-up of 107 days, full range of 88-157 days) | -Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Immune Response as Measured by ELISPOT Analysis | Baseline through week 52 | The ELISpot assay was performed after in vitro culture of patient PBMC with neoantigen peptide for \ 12 days. The number of spot-forming T cells, a surrogate for the number of neoantigen-specific T cells, was determined after neoantigen peptide re-stimulation for the duration of the assay (48 hours) and compared to that of control cells that were not re-stimulated with neoantigen during the assay. Independent t tests between pre- and post-vaccination PBMCs were performed. |
| Number of Participants With Immune Response as Measured by Multiparametric Flow Cytometry (CD4) | Baseline through week 52 | Multiparametric flow cytometry was performed as a second readout to characterize the neoantigen-specific T cell response. Markers included CD4, CD8, IFNγ, and a viability marker. After culture, as described above, T cells were stimulated overnight with/without neoantigen and stained with fluorescent antibodies specific for the various markers. Data were analyzed by comparing, between pre- and post-vaccination PBMCs, the percent ratio of IFNγ+ CD4/CD8 cells with neoantigen stimulation over those without stimulation; a \>2-fold increase in response after vaccination was considered positive. |
| Number of Participants With Immune Response as Measured by Multiparametric Flow Cytometry (CD8) | Baseline through week 52 | Multiparametric flow cytometry was performed as a second readout to characterize the neoantigen-specific T cell response. Markers included CD4, CD8, IFNγ, and a viability marker. After culture, as described above, T cells were stimulated overnight with/without neoantigen and stained with fluorescent antibodies specific for the various markers. Data were analyzed by comparing, between pre- and post-vaccination PBMCs, the percent ratio of IFNγ+ CD4/CD8 cells with neoantigen stimulation over those without stimulation; a \>2-fold increase in response after vaccination was considered positive. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neoantigen Peptide Vaccine The schedule for vaccination will be Days 1, 4, 8, 15, and 22 (delays of up to 96 hours are allowed for each dose based on the adverse events experienced). Additional vaccinations will be given on Days 50 and 78 (+/- 2 weeks). The first vaccine dose may be administered following confirmation of disease-free status and within 90 days following date of repeat imaging. All study injections will be given subcutaneously and co-administered with poly-ICLC by a trained healthcare provider. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Cannot make vaccine due to lack of tissue variants | 2 |
| Overall Study | Lack of Efficacy | 1 |
Baseline characteristics
| Characteristic | Neoantigen Peptide Vaccine |
|---|---|
| Age, Continuous | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
Primary
Safety of Neoantigen Peptide Vaccine as Measured by the Number of Serious Adverse Events
-Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.
Time frame: Through 30 days following completion of treatment (median follow-up of 107 days, full range of 88-157 days)
Population: 2 participants were not evaluable for this outcome measure as they did not start vaccine treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neoantigen Peptide Vaccine | Safety of Neoantigen Peptide Vaccine as Measured by the Number of Serious Adverse Events | Grade 3 ascites | 1 participants |
| Neoantigen Peptide Vaccine | Safety of Neoantigen Peptide Vaccine as Measured by the Number of Serious Adverse Events | Grade 3 anemia | 1 participants |
Secondary
Number of Participants With Immune Response as Measured by ELISPOT Analysis
The ELISpot assay was performed after in vitro culture of patient PBMC with neoantigen peptide for \ 12 days. The number of spot-forming T cells, a surrogate for the number of neoantigen-specific T cells, was determined after neoantigen peptide re-stimulation for the duration of the assay (48 hours) and compared to that of control cells that were not re-stimulated with neoantigen during the assay. Independent t tests between pre- and post-vaccination PBMCs were performed.
Time frame: Baseline through week 52
Population: 3 participants were not evaluable for this outcome measure. 2 participants were not enrolled but vaccine wasn't able to be made due to lack of tissue variants. 1 participant did not complete treatment due to disease progression.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neoantigen Peptide Vaccine | Number of Participants With Immune Response as Measured by ELISPOT Analysis | 9 Participants |
Secondary
Number of Participants With Immune Response as Measured by Multiparametric Flow Cytometry (CD4)
Multiparametric flow cytometry was performed as a second readout to characterize the neoantigen-specific T cell response. Markers included CD4, CD8, IFNγ, and a viability marker. After culture, as described above, T cells were stimulated overnight with/without neoantigen and stained with fluorescent antibodies specific for the various markers. Data were analyzed by comparing, between pre- and post-vaccination PBMCs, the percent ratio of IFNγ+ CD4/CD8 cells with neoantigen stimulation over those without stimulation; a \>2-fold increase in response after vaccination was considered positive.
Time frame: Baseline through week 52
Population: 3 participants were not evaluable for this outcome measure. 2 participants were not enrolled but vaccine wasn't able to be made due to lack of tissue variants. 1 participant did not complete treatment due to disease progression.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neoantigen Peptide Vaccine | Number of Participants With Immune Response as Measured by Multiparametric Flow Cytometry (CD4) | 5 Participants |
Secondary
Number of Participants With Immune Response as Measured by Multiparametric Flow Cytometry (CD8)
Multiparametric flow cytometry was performed as a second readout to characterize the neoantigen-specific T cell response. Markers included CD4, CD8, IFNγ, and a viability marker. After culture, as described above, T cells were stimulated overnight with/without neoantigen and stained with fluorescent antibodies specific for the various markers. Data were analyzed by comparing, between pre- and post-vaccination PBMCs, the percent ratio of IFNγ+ CD4/CD8 cells with neoantigen stimulation over those without stimulation; a \>2-fold increase in response after vaccination was considered positive.
Time frame: Baseline through week 52
Population: 3 participants were not evaluable for this outcome measure. 2 participants were not enrolled but vaccine wasn't able to be made due to lack of tissue variants. 1 participant did not complete treatment due to disease progression.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neoantigen Peptide Vaccine | Number of Participants With Immune Response as Measured by Multiparametric Flow Cytometry (CD8) | 7 Participants |