Phase Ib clinical trial using Autologous Dendritic Cell Vaccine Loaded with Personalized Peptides (PEP) in order to stimulate/induce both innate and adaptive immunity by activating T-cells and Natural Killer (NK) cells, combined with standard of care (SOC) adjuvant chemotherapy, followed by nivolumab, an antibody against Programmed Cell Death 1 (PD-1), to maintain and boost the vaccine's effect in patients with non-metastatic resectable pancreatic adenocarcinoma
This is a single center, single arm, phase Ib trial to evaluate the feasibility, safety, immunogenicity, and efficacy of subcutaneous dendritic cell (DC) vaccine loaded with personalized peptides \[PEP-DC vaccine\] in combination with standard of care adjuvant chemotherapy (subgroup 1: mFOLFIRINOX or subgroup 2: gemcitabine and capecitabine), followed by the antibody nivolumab in patients with non-metastatic surgically resected pancreatic adenocarcinoma. All patients will have previously undergone collection of resected advanced pancreatic tumor tissue under a different research protocol with a separate informed consent. After registration, all patients will receive standard of care chemotherapy: Subgroup 1: intravenous mFOLFIRINOX for twelve 2-week cycles. Subgroup 2: intravenous gemcitabine, and oral capecitabine for eight 21-day cycles. Additionally, all eligible patients will undergo apheresis during the cycle 5 of mFOLFIRINOX (subgroup 1) or the last week of cycle 3 of gemcitabine/ capecitabine (subgroup 2) to collect peripheral blood mononuclear cells (PBMCs) for dendritic cell vaccine production. All patients will receive at least six PEP-DC vaccinations starting concomitant with the 8th cycle (subgroup 1) or the 5th cycle (subgroup 2) of chemotherapy. Subgroup 1: Vaccine will be delivered subcutaneously every 4 weeks, on day 3(+1) of every second 14-day cycle, and thereafter every four weeks starting from the first nivolumab administration. Subgroup 2: Vaccine will be administered subcutaneously every 3 weeks, on day 9 (the day after last gemcitabine infusion) of each 21-day cycle, and thereafter every four weeks starting from the second nivolumab administration. Nivolumab will be administered intravenously over a period of 30 minutes to all patients, for a maximum duration of 2 years, as follows: Subgroup 1: Nivolumab treatment will start after the last cycle of chemotherapy (2 weeks after C12D1) and will be given as flat dose of 240 mg given every 2 weeks, during 14 weeks (2-week cycles). Then it will be administered as flat dose of 480 mg every 4 weeks (4-week-cycles), until the last vaccine dose. Subgroup 2: Nivolumab treatment will start after the last cycle of chemotherapy (3 weeks after C8D1) as flat dose of 240 mg given every 2 weeks, for 14 weeks. Then it will be administered as flat dose of 480 mg every 4 weeks, until the last vaccine dose. Nivolumab treatment should be maintained for at least for 8 weeks after end of the last chemotherapy cycle if vaccination stops earlier. Nivolumab maintenance for both subgroups: After the end of combined treatment period (vaccination plus nivolumab), nivolumab will be given at 480 mg (flat dose) every four weeks to all patients until appearance of new lesions, unacceptable toxicity or until the maximum time for nivolumab treatment (2 year) is reached. Regular physical examination, radiological evaluation and blood testing for safety parameters will be performed according to the schedule during treatment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
SOC: Subgroup1: intravenous mFOLFIRINOX for twelve 14-day cycles. Subgroup2: intravenous gemcitabine twice, on days 1 and 8, and oral capecitabine for 14 days of 21-day cycles, for eight cycles. PEP-DC vaccine: At least 5 subcutaneous vaccinations starting on cycle 8 (subgroup1) or cycle 5 (subgroup2) of chemotherapy: Subgroup1: every 4 weeks, on day 3 of every second 14-day cycle, and then every 4 weeks starting from the first nivolumab administration. Subgroup2: Every 3 weeks, on day 9 of each 21-day cycle, and then every 4 weeks starting from the second nivolumab administration. Nivolumab for a maximal duration of 2 years: intravenous, starting after the last chemotherapy cycle. Administered as flat dose of 240mg every 2 weeks during 14 weeks, then as flat dose of 480 mg every 4 weeks until the last vaccination. Then, as a maintenance therapy at 480 mg every 4 weeks until appearance of new lesions or unacceptable toxicity.
CHUV Oncology Department
Lausanne, Canton of Vaud, Switzerland
Number of cases for which vaccine is produced
Feasibility will be assessed measuring the number of cases, in which vaccine is produced successfully (defined as production and quality control release of at least 5 PEP-DC vaccines for a patient) among the enrolled patients and number of patients who receive at least one dose of vaccine
Time frame: 3 years after study activation
Assessment of adverse events
Collection of adverse events and serious adverse events, treatment limiting toxicities and assessment of immunogenicity
Time frame: 3 years after study activation
Relapse free survival
Time from enrolment (registration) date until one of the following events: a. patients disease-free at inclusion, until first date of documented progression, b. patients with non-measurable lesions at inclusion, until first date of documented progression, c. death
Time frame: 8 years
Overall survival
Time from enrolment (registration) date to date of death due to any cause, or last patient contact. For living patients, the date of most recent clinic visit or a phone or email contact will be employed to document the overall survival time.
Time frame: 8 years
Gene analysis of immunological response
The assessment of the interactions between tumor cells and the immune system within the tumor microenvironment will be performed by gene expression quantification using with multiplex gene expression profiling.
Time frame: 8 years
Cell analysis of immunological response
The assessment of the interactions between tumor cells and the immune system within the tumor microenvironment will be performed by cell quantification using with multi-parametric single-cell cytometry and single cell RNA sequencing analysis
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Time frame: 8 years
Evaluation of tumor marker carbohydrate antigene 19-9 (CA19-9) or carcinoembryonic antigen (CEA) kinetics
Measurement of tumoral markers by blood analysis
Time frame: 8 years
Correlation between immune-related adverse events and relapse-free survival
Number of immune-related adverse events using the CTCAE v.4.03 correlated with relapse-free survival (time in months)
Time frame: 8 years