Electroporation Potentiated Immunotherapy in Cancer

Ole Thorlacius-Ussing, MD, DMSc, Professor of Surgery8 enrolled

Overview

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

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pancreas Cancer, Metastatic

Interventions

PembrolizumabDRUG

400mg every 6 weeks

Irreversible electroporationDEVICE

Percutaneous ablation of one liver metastasis

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (1)

Department of Oncology

Aalborg, North Denmark, Denmark

Outcomes

Primary Outcomes

Objective response rate (ORR) according to RECIST 1.1

(in patients receiving at least one dose of pembrolizumab, IRE and an evaluable CT-scan)

Time frame: 6 months after treatment start

Serious adverse reaction (SAR) rate according to CTCAE v5

(in patients receiving at least one dose of pembrolizumab)

Time frame: cumulative after 12 months after treatment start

Secondary Outcomes

Median overall survival

Time frame: Through study completion, an average of 1 year

Median progression-free survival

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 2 months, 4 months and 6 months after treatment start

Survival rate

Time frame: 6 months and 12 months after treatment start

Data from ClinicalTrials.gov

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Progression-free survival rate

Time frame: 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)

Time frame: 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)

Time frame: 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