Electroporation Potentiated Immunotherapy in Cancer (EPIC-1)

A Phase II Study of Electroporation Potentiated Immunotherapy in Liver Metastatic

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

Study Overview

• Status: Active, not recruiting
• Conditions: Pancreas Cancer, Metastatic
• Intervention / Treatment: Drug: Pembrolizumab; Device: Irreversible electroporation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • North Denmark Region
    • Aalborg, North Denmark Region, Denmark, DK-9000
      • Department of Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically verified pancreatic adenocarcinoma, based on either a biopsy of the primary tumor or a metastasis
2. One liver metastasis treatable by IRE (as determined by MDT at Aalborg University Hospital)
3. One tumor lesion suited for repeated biopsy by transcutaneous core needle (preferably another lesion than that used for IRE)
4. At least one measurable lesion (RECIST version 1.1) other than the liver metastasis to be treated by IRE
5. At least one course of chemotherapy for metastatic or inoperable disease discontinued due to treatment failure or intolerance
6. Performance status 0-1
7. ASA ≤ 3
8. ≥ 18 years of age
9. Written and orally informed consent
10. Sufficient available histological tumor material stored in biobank or obtainable by new biopsy
11. Patient acceptance of collection of blood samples for translational research and two additional biopsies during treatment

12. Adequate bone marrow function, liver function, and renal function (within 7 days prior to enrollment):

    1. Neutrophils (ANC) ≥ 1.5 x 109/l
    2. Platelet count ≥ 100 x 109/l
    3. Hemoglobin ≥ 6 mmol/l
    4. Plasma bilirubin ≤ 1.5 x ULN
    5. Plasma alanine transaminase (ALAT) < 5 x ULN
    6. Plasma creatinine ≤ 1.5 x ULN
    7. INR ≤ 1.5

Exclusion Criteria:

1. Underlying medical disease not adequately treated (e.g. poorly regulated diabetes and symptomatic cardiac disease)
2. Prior or current autoimmune disorder with risk of serious toxicity during treatment with checkpoint inhibitor
3. Acute myocardial infarction, cerebral vascular attack, transient ischemic attack or subarachnoid hemorrhage within 6 months from start of treatment
4. Previous reception of allogeneic stem cells or solid organ donation
5. Active infection requiring systemic therapy within 7 days prior to treatment initiation
6. Positive HIV, HBV, and HCV test results (prior testing or new testing in patients at risk)
7. Active psychiatric disease or history of drug or alcohol abuse affecting participation
8. 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
9. 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
10. Coexisting malignant disease, except non-melanoma skin cancer
11. Symptomatic or untreated CNS metastases
12. Liver cirrhosis Child Pugh >A
13. 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
14. 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)
15. Previous immunotherapy
16. Patients referred from a hospital outside of Denmark
17. Major dilation of veins or bowel obstructing the needle path
18. Persistent atrial fibrillation
19. Metal objects (e.g. biliary SEMS) within 5 cm of ablation target
20. Cardiac pacemaker or ICD, that cannot be safely disconnected during IRE treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ole Thorlacius-Ussing, MD, DMSc, Professor of Surgery
• Collaborators: Odense University Hospital; Danish Cancer Society; Aalborg University
• Investigators: Principal Investigator: Morten Ladekarl, DMSc, Department of Oncology

Study record dates

Study Major Dates

• Study Start (Actual): May 26, 2021
• Primary Completion (Actual): March 7, 2022
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: March 24, 2021
• First Submitted That Met QC Criteria: April 6, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): March 9, 2022
• Last Update Submitted That Met QC Criteria: March 8, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Pembrolizumab; Irreversible electroporation; Immune checkpoint inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: EPIC-1; 2020-004536-22 (EudraCT Number); N-20200085 (Other Identifier: The North Denmark Region Committee on Health Research Ethics)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes