This proof of concept trial aims to assess whether the combination of IRE with Nivolumab is safe and effective to treat metastatic pancreatic cancer, based on the available preliminary evidence that IRE is able to cause a systemic anti-tumor immune response (i.e. abscopal effect), which may enhance the effect of subsequent Nivolumab treatment. In addition, the trial aims to clarify the systemic effects of IRE over time and thereby to provide more insight in the mechanism of work of the technique.
The prognosis of patients newly diagnosed with pancreatic ductal adenocarcinoma (PDAC) is extremely poor with a 5-year overall survival rate of less than 5%. To improve this dismal outcome, new treatment approaches are urgently needed. So far, immune-checkpoint therapy was not successful in patients with PDAC. Given the poor response to conventional chemotherapy, there is an imperative need to make PDACs amenable to immune-checkpoint therapy. Irreversible electroporation (IRE) is a relatively novel and safe ablation technique that destroys tumors by using apoptosis-inducing electrical currents inducing local and systemic pro-inflammatory cytokine expression and enhances the presence of cytotoxic CD8+ T-cells, while the apoptotic cell material preserves neo-antigen properties detectable by dendritic cells. This effect might be further enhanced by immune-checkpoint therapy. The rationale of our study is to convert immunologically cold PDACs into hot PDACs by triggering an enhanced local and systemic immune response. We hypothesize that among patients with metastatic PDAC, the IRE of one liver metastasis followed by the administration of an immune-checkpoint inhibitor leads to a measurable radiological response in a selected non-treated liver metastasis. Furthermore, we hypothesize that the immune response is both local in the form of tumor infiltrating lymphocytes (TILS) and an immunologically activated tumor microenvironment in the IRE-treated metastasis, as well as systemic as evidenced by an abscopal response in the IRE-untreated metastatic and primary site. The objective of the trial is to examine whether for patients with metastatic PDAC the combination of IRE of one liver metastasis followed by the administration of five doses of nivolumab leads to a measurable radiological response in a selected non-treated liver metastasis. To demonstrate that the trial treatment leads to a measurable immune response, multiple translational research projects will assess the effect of IRE and nivolumab on the development of the local and peripheral tumor immune response over time.
Study Type
INTERVENTIONAL
The patients start treatment with nivolumab on day 1 after IRE and will be given nivolumab at a flat dose of 240 mg every 2 weeks (q2wk) for 5 cycles until Week 8.
Lindenhofspital
Bern, Canton of Bern, Switzerland
St. Claraspital
Basel, Switzerland
UniversitätsSpital Zürich
Zurich, Switzerland
The objective response rate (ORR) after the 5th dose of nivolumab of the reference liver metastasis that was not biopsied.
The objective response rate (ORR) according to RECIST v1.1 after the 5th dose of nivolumab of the reference liver metastasis that was not biopsied, assessed 2-4 weeks after the 5th dose of nivolumab, defined as proportion of patients achieving Complete Response (CR) or Partial Response (PR). The assessment will be based on re-staging the patients with a CT-scan 2-4 weeks after the 5th dose of nivolumab. Patients without tumor assessment 2-4 weeks after the 5th dose of nivolumab will be counted as non-responders.
Time frame: At 2-4 weeks after the 5th dose of nivolumab
Objective Response Rate (ORR) after the 5th dose of nivolumab of the primary tumor site (pancreas).
The ORR according to RECIST v1.1 after the 5th dose of nivolumab of the primary tumor site (pancreas), assessed 2-4 weeks after the 5th dose of nivolumab, defined as percentage of patients achieving Complete Response (CR) or Partial Response (PR). Patients without tumor assessment 2-4 weeks after the 5th dose of nivolumab will be counted as non-responders.
Time frame: At 2-4 weeks after the 5th dose of nivolumab
ORR after the 5th dose of nivolumab of the IRE-treated liver metastasis
The ORR according to RECIST v1.1 after the 5th dose of nivolumab of IRE-treated liver metastasis, assessed 2-4 weeks after the 5th dose of nivolumab, defined as percentage of patients achieving CR or PR. Patients without tumor assessment 2-4 weeks after the 5th dose of nivolumab will be counted as non-responders.
Time frame: At 2-4 weeks after the 5th dose of nivolumab
ORR based on best overall response
The ORR based on best overall response according to RECIST v1.1, assessed at any time between registration and disease progression by RECIST v1.1, death, or subsequent anticancer therapy, whichever occurs first, defined as percentage of patients achieving CR or PR.
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Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
8
Time frame: From the date of registration until the date of progressive disease according to RECIST v1.1 or death, whichever occurs first, assessed up to 4 years after registration
Immune ORR (iORR) based on best overall immune response
The immune ORR (iORR) based on best overall immune response according to iRECIST, assessed at any time between registration and disease progression by iRECIST, death, or subsequent anticancer therapy, whichever occurs first, defined as percentage of patients achieving CR, PR, iCR or iPR.
Time frame: From the date of registration until the date of progressive disease according to RECIST v1.1 or death, whichever occurs first, assessed up to 4 years after registration
Progression free survival (PFS)
Progression-free survival (PFS), defined as the time from registration until progression according to RECIST v1.1 or death from any cause, whichever occurs first.
Time frame: From the date of registration until the date of progressive disease according to RECIST v1.1 or death, whichever occurs first, assessed up to 4 years after registration
Immune PFS (iPFS)
Immune PFS (iPFS), defined as the time from registration until progression according to iRECIST (first iUPD without documented iSD, iPR or iCR thereafter) or death from any cause, whichever occurs first. Patients without event at the time of analysis and patients starting a new anticancer therapy in the absence of an event will be censored at the date of the last tumor assessment showing non-progression (before the start of the new therapy, if any).
Time frame: From the date of registration until the date of progressive disease according to RECIST v1.1 or death, whichever occurs first, assessed up to 4 years after registration
Overall survival (OS)
Overall survival (OS), defined as time form registration to death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known alive.
Time frame: From the date of registration until the date of death, assessed up to 4 years after registration
Adverse events
Adverse events, assessed according to NCI CTCAE v5.0 and Clavien-Dindo Classification for procedural complications
Time frame: From the date of registration to 100 days after last trial treatment