Electroporation Potentiated Immunotherapy in Cancer

Study Overview
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Brief Summary
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The study is investigating the efficacy and safety of combined irreversible electroporation (IRE) and checkpoint inhibition in metastatic pancreatic cancer.

Detailed Description
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The aim of the study is to investigate whether checkpoint inhibition in conjunction with IRE of a single liver metastasis can elicit a systemic anticancer immune response in patients with pancreatic cancer. Adult patients, in WHO performance status 0-1, with liver metastatic pancreatic cancer, intolerant to or progressing on first or further lines of chemotherapy can enter the trial. Pembrolizumab infusion is given every six weeks for up to six months. IRE of a single liver metastasis is performed between the first and second pembrolizumab infusion. Response to the therapy is examined by CT (RECIST) on non-IRE-ablated lesions every 2 months. Assessments of changes in peripheral blood immune cell composition, tumor gene expression and tumor infiltrating lymphocytes is performed on serial biopsies and blood samples.

Official Title
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A Phase II Study of Electroporation Potentiated Immunotherapy in Liver Metastatic

Conditions
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Pancreas Cancer, Metastatic

Intervention / Treatment
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* Drug: Pembrolizumab
* Device: Irreversible electroporation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically verified pancreatic adenocarcinoma, based on either a biopsy of the primary tumor or a metastasis One liver metastasis treatable by IRE (as determined by MDT at Aalborg University Hospital) One tumor lesion suited for repeated biopsy by transcutaneous core needle (preferably another lesion than that used for IRE) At least one measurable lesion (RECIST version 1.1) other than the liver metastasis to be treated by IRE At least one course of chemotherapy for metastatic or inoperable disease discontinued due to treatment failure or intolerance Performance status 0-1 ASA ≤ 3 ≥ 18 years of age Written and orally informed consent Sufficient available histological tumor material stored in biobank or obtainable by new biopsy Patient acceptance of collection of blood samples for translational research and two additional biopsies during treatment Adequate bone marrow function, liver function, and renal function (within 7 days prior to enrollment): Neutrophils (ANC) ≥ 1.5 x 109/l Platelet count ≥ 100 x 109/l Hemoglobin ≥ 6 mmol/l Plasma bilirubin ≤ 1.5 x ULN Plasma alanine transaminase (ALAT) < 5 x ULN Plasma creatinine ≤ 1.5 x ULN INR ≤ 1.5 Exclusion Criteria: Underlying medical disease not adequately treated (e.g. poorly regulated diabetes and symptomatic cardiac disease) Prior or current autoimmune disorder with risk of serious toxicity during treatment with checkpoint inhibitor Acute myocardial infarction, cerebral vascular attack, transient ischemic attack or subarachnoid hemorrhage within 6 months from start of treatment Previous reception of allogeneic stem cells or solid organ donation Active infection requiring systemic therapy within 7 days prior to treatment initiation Positive HIV, HBV, and HCV test results (prior testing or new testing in patients at risk) Active psychiatric disease or history of drug or alcohol abuse affecting participation Allergy to active substance or any of the auxiliary agents, including known severe allergy to anesthetic agent, paralytic agent or any of the equipment used during treatment Expected need for systemic corticosteroid or other systemic immunosuppressive drug during the course of this clinical trial. A low dose of e.g. prednisone ≤ 10 mg/day is permitted for maximally 7 consecutive days Coexisting malignant disease, except non-melanoma skin cancer Symptomatic or untreated CNS metastases Liver cirrhosis Child Pugh >A Pregnant or breast-feeding patients. For women of childbearing potential, a negative pregnancy test (minimum sensitivity 25mIU(hCG)/ml) is mandatory prior to inclusion and every month during the trial Women of childbearing potential not willing to use effective methods of contraception during treatment and for 6 months after the end of treatment. Male patients with a fertile partner are also required to secure effective methods of contraception (definition available in protocol) Previous immunotherapy Patients referred from a hospital outside of Denmark Major dilation of veins or bowel obstructing the needle path Persistent atrial fibrillation Metal objects (e.g. biliary SEMS) within 5 cm of ablation target Cardiac pacemaker or ICD, that cannot be safely disconnected during IRE treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Day 1: Pembrolizumab 400mg Day 10: Irreversible electroporation Day 42/84/126/168: Pembrolizumab 400mg | Drug: Pembrolizumab<br>* 400mg every 6 weeks<br>* Other names: Irreversible electroporation (NanoKnife(tm), Angiodynamics);Device: Irreversible electroporation<br>* Percutaneous ablation of one liver metastasis<br>* Other names: NanoKnife(tm) (Angiodynamics);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) according to RECIST 1.1 | (in patients receiving at least one dose of pembrolizumab, IRE and an evaluable CT-scan) | 6 months after treatment start | 
| Serious adverse reaction (SAR) rate according to CTCAE v5 | (in patients receiving at least one dose of pembrolizumab) | cumulative after 12 months after treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median overall survival |  | Through study completion, an average of 1 year | 
| Median progression-free survival |  | Through study completion, an average of 1 year | 
| ORR | (in patients that have received at least one dose of pembrolizumab and an evaluable CT-scan) | 2 months, 4 months and 6 months after treatment start | 
| Clinical benefit ratio | (defined as objective response or stable disease for at least 8 weeks during treatment in patients receiving at least one dose of pembrolizumab, IRE and an evaluable CT-scan) | 8 weeks after treatment start | 
| Serum CA-19-9 response | (response defined as a decrease of at least 20 % observed during treatment in patients with elevated CA 19-9 at baseline) | 2 months, 4 months and 6 months after treatment start | 
| Survival rate |  | 6 months and 12 months after treatment start | 
| Progression-free survival rate |  | 6 months and 12 months after treatment start | 
| Mean difference in perceived quality of life measured by EORTC QLQ-C30 v3 | (for subscales: Global health status, Physical functioning, Fatigue, Nausea and vomiting, Pain, Appetite loss and Diarrhea) | 2 months, 4 months, 6 months, 8 months, 10 months and 12 months after treatment start | 
| Mean difference in nutrition status measured by PG-SGA-SF | (difference in total numerical score of the patient-generated subjective global assessment (short form) PG-SGA(c) SF (range 0-37, lower is better) | 2 months, 4 months, 6 months, 8 months, 10 months and 12 months after treatment start | 
| Difference in peripheral blood naïve T cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood effector memory T cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood central memory T cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood effector T cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood terminally differentiated effector T cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood exhausted T cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood regulatory T cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood conventional dendritic cell type 1 count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood conventional dendritic cell type 2 count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood plasmacytoid dendritic cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Difference in peripheral blood myeloid-derived suppressor cell count prior to IRE-treatment, 1 day after IRE-treatment and 6 weeks after IRE-treatment compared to baseline | (based on flow cytometry measures of naïve, EM, CM, EFF, TE, EX T cells, Tregs, cDC1, cDC2, pDC and MDSC concentrations) | 8 days, 11 days, 52 days after treatment start | 
| Histological tumor regression grade in tumor biopsies after pembrolizumab and after pembrolizumab + IRE compared to baseline | (based on the CAP regression grading system) | 10 days and 52 days after treatment start | 
| Difference in tumor RNA expression after pembrolizumab and after pembrolizumab + IRE compared to baseline | (based on NanoString RNA panCancer IO 360 gene panel. Analysis will explore the cancer-immunological mechanisms of the therapy in order to guide future studies. No specific outcomes are predetermined) | 10 days and 52 days after treatment start | 
| Difference in (histological) tumor infiltrating leukocyte (TIL) pattern after pembrolizumab and after pembrolizumab + IRE compared to baseline | (Based on analysis by immunohistochemistry. The relative concentration of leukocytes will be estimated and compared. The exact subpopulations of leukocytes will be based on the findings in outcomes 12 and 14, to validate the results) | 10 days and 52 days after treatment start | 
| Adverse event rate (CTCAEv5, all grades) | (all events registered during active treatment and follow-up) | cumulative after 12 months after treatment start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irreversible electroporation, Pembrolizumab, Immune checkpoint inhibitor