Clinical trial NCT04835402: Electroporation Potentiated Immunotherapy in Cancer
Official title: A Phase II Study of Electroporation Potentiated Immunotherapy in Liver Metastatic
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Pancreas Cancer, Metastatic
Keywords: Irreversible electroporation
Pembrolizumab
Immune checkpoint inhibitor
Lead sponsor: Aalborg University Hospital
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Aalborg University
name: Danish Cancer Society
First posted: 2021-04-08
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective response rate (ORR) according to RECIST 1.1
timeFrame: 6 months after treatment start
measure: Serious adverse reaction (SAR) rate according to CTCAE v5
timeFrame: cumulative after 12 months after treatment start
Secondary outcomes:
measure: Median overall survival
timeFrame: Through study completion, an average of 1 year
measure: Median progression-free survival
timeFrame: Through study completion, an average of 1 year
measure: ORR
timeFrame: 2 months, 4 months and 6 months after treatment start
measure: Clinical benefit ratio
timeFrame: 8 weeks after treatment start
measure: Serum CA-19-9 response
timeFrame: 2 months, 4 months and 6 months after treatment start
measure: Survival rate
timeFrame: 6 months and 12 months after treatment start
measure: Progression-free survival rate
timeFrame: 6 months and 12 months after treatment start
measure: Mean difference in perceived quality of life measured by EORTC QLQ-C30 v3
timeFrame: 2 months, 4 months, 6 months, 8 months, 10 months and 12 months after treatment start
measure: Mean difference in nutrition status measured by PG-SGA-SF
timeFrame: 2 months, 4 months, 6 months, 8 months, 10 months and 12 months after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: 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
timeFrame: 8 days, 11 days, 52 days after treatment start
measure: Histological tumor regression grade in tumor biopsies after pembrolizumab and after pembrolizumab + IRE compared to baseline
timeFrame: 10 days and 52 days after treatment start
measure: Difference in tumor RNA expression after pembrolizumab and after pembrolizumab + IRE compared to baseline
timeFrame: 10 days and 52 days after treatment start
measure: Difference in (histological) tumor infiltrating leukocyte (TIL) pattern after pembrolizumab and after pembrolizumab + IRE compared to baseline
timeFrame: 10 days and 52 days after treatment start
measure: Adverse event rate (CTCAEv5, all grades)
timeFrame: cumulative after 12 months after treatment start
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Department of Oncology
state: North Denmark Region
Study officials:
affiliation: Department of Oncology
name: Morten Ladekarl, DMSc
role: PRINCIPAL_INVESTIGATOR
References: