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Trial registered on ANZCTR


Registration number
ACTRN12621000955819
Ethics application status
Approved
Date submitted
7/06/2021
Date registered
21/07/2021
Date last updated
21/07/2021
Date data sharing statement initially provided
21/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigation of the safety and effectiveness of irreversible electroporation (IRE) using the NanoKnife® System in patients with unresectable stage 3 pancreatic cancer who have received 3 months of chemotherapy.
Scientific title
Investigation of the safety and efficacy of irreversible electroporation (IRE) using the NanoKnife® System in patients with unresectable stage 3 pancreatic cancer who have received 3 months of chemotherapy (DIRECT/InspIRE Australia)
Secondary ID [1] 304142 0
NONE
Universal Trial Number (UTN)
Trial acronym
DIRECT/InspIRE Australia
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pancreatic Cancer 321840 0
Condition category
Condition code
Cancer 319900 319900 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open-label, prospective, multi-centre registry-based study evaluating the use of Irreversible Electroporation (IRE) with the NanoKnife system in unresectable stage 3 pancreatic cancer. Irreversible electroporation (IRE) is a technique using non-thermal energy to create permanent nanopores in the cell membrane in order to disrupt cellular homeostasis. After delivering a sufficient number of high voltage pulses, the cells within the electrical field will be irreversibly damaged. These damaged cells die by apoptosis and are removed by the body’s own lymphatic system.
Stage 3 pancreatic cancer patients must have received 3 months of FOLFIRINOX or gemcitabine-based chemotherapy for unresectable stage 3 pancreatic cancer prior to enrolment. These two chemotherapy regimens reflect current clinical practice and guideline recommendations. The study investigator will evaluate the risk to each participant on an individual basis and discuss the risks and benefits of study participation with the participant/legal representative. While the benefits of the NanoKnife procedure in pancreatic cancer have not been well characterised and doing so is the purpose of this trial, anecdotal reports of use in unresectable pancreatic carcinoma suggest that the procedure may improve survival and ameliorate pain due to the disease. Results from the use of IRE in prostate carcinoma support a low complication rate.
All study participants will undergo IRE with the NanoKnife System, and the IRE procedure should be undertaken 1 to 3 weeks from the completion of 3 months of chemotherapy. Only a surgeon qualified in the use of the NanoKnife System will perform the IRE, and the duration of the IRE procedure is approximately 2-3 hours. Information related to the NanoKnife device specifications, IRE procedure, adjunctive procedures (if any were performed), anaesthesia/surgical observations and adverse events (if any were experienced) will be captured for every participant.
In the setting of pancreatic cancer, due to the retroperitoneal position of the pancreas, irreversible electroporation by the NanoKnife System is undertaken using an open approach. A general anaesthetic will be required. A diagnostic laparoscopy is undertaken initially to rule out occult solid organ liver as well as peritoneal or mesenteric metastases. A midline abdominal lesion is then performed. Intra-operative ultrasound will be utilised to assess the tumour dimension and surrounding structures to determine the number and configuration of probes. Two to six probes (depending on the size and position of the tumour) will be inserted. Probe placement can be tracked with ultrasound throughout placement. Short, high voltage pulses are then delivered by the NanoKnife System. Involved lymph nodes may be treated if they are within the IRE field but probe placement is determined by the primary tumour and not the presence of involved nodes. The IRE procedure aims to treat the whole tumour and not just reduce the size of the tumour. The procedure will not include surgical resection (“debulking”) of the tumour. A tissue biopsy will be undertaken intra-operatively for exploratory/translational studies only if it is safe to do so. After recovery from anaesthesia, patients will remain hospitalised for up to 7 days and discharged home when they are well.
Participants will be follow-up for a minimum period of 24 months post-IRE. Following treatment with the NanoKnife system, any systemic chemotherapy should be administered as per standard institution guidelines. Dose modifications to chemotherapy in line with standard clinical care are acceptable at the treating oncologist’s discretion. Participants will be required to attend clinic visits for follow-up every 3 to 4 months for a minimum of 24 months after enrolment.
Intervention code [1] 320765 0
Treatment: Surgery
Intervention code [2] 321043 0
Treatment: Devices
Comparator / control treatment
There is no enrolment of patients into a control (no IRE) arm. The PURPLE registry (Pancreatic cancer: Understanding Routine Practice and Lifting End Results) (ACTRN12617001474347) will be used to provide prospectively collected data for a comparator arm of matched eligibility patients receiving chemotherapy alone. The PURPLE registry started in January 2016 and data collection is ongoing. The PURPLE registry will be used to capture information related to progression-free survival, recurrence treatment and overall survival.
Control group
Active

Outcomes
Primary outcome [1] 327772 0
Safety, defined as the type and frequency of grade 3 or higher (> G3) adverse events and serious adverse events associated with IRE with NanoKnife System. Assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Timepoint [1] 327772 0
Safety will be assessed on the day of IRE, and then at post-IRE surgery day 1, 7, 14, 30, 60 and 90, and then every three months post-enrolment until study discontinuation or until participant death.
Primary outcome [2] 328122 0
Efficacy, defined as the progression-free survival associated with IRE with the NanoKnife System. This is defined as the time (in months) from enrolment to the date of first observed disease progression (by predefined clinical and radiologic criteria), or death from any cause, if death occurs without documented disease progression. Progression assessed by the investigator based on RECIST (Response Evaluation Criteria in Solid Tumours). Data for patients without the occurrence of disease progression or death at the end of the study will be censored at the time of last tumour assessment.
Timepoint [2] 328122 0
Progression-free survival will be assessed at post-IRE surgery day 30, 60 and 90, and then every three months post-enrolment until study discontinuation or until participant death.
Secondary outcome [1] 396538 0
To examine overall survival associated with IRE use following standard of care chemotherapy. Overall survival will be assessed by accessing patient medical records and from use of the PURPLE registry (ACTRN12617001474347).
Timepoint [1] 396538 0
Overall survival is defined as the time (in months) from enrolment to the date of death for any reason. Participants lost to follow-up at the time of analysis will be censored at the last date they were known to be alive.
Secondary outcome [2] 396539 0
To examine procedure-related pain response to IRE. Procedure-related pain will be reported in participants undergoing IRE with the NanoKnife system using the Brief Pain Inventory (BPI) Short form.
Timepoint [2] 396539 0
Procedure-related pain will be assessed at enrolment (baseline) and then at post-IRE surgery days 1, 7, 14 and 30.
Secondary outcome [3] 396540 0
To examine cancer-related pain. Cancer-related pain will be reported in participants undergoing IRE with the NanoKnife system using the Brief Pain Inventory (BPI) Short form.
Timepoint [3] 396540 0
Cancer-related pain will be assessed at enrolment (baseline), at 3 and 6 months post-enrolment and then at 6-monthly intervals post-enrolment for the duration of the study.
Secondary outcome [4] 397722 0
Quality of Life (QOL) will be reported in participants undergoing IRE with the NanoKnife system using the EQ-5D QOL questionnaire.
Timepoint [4] 397722 0
Quality of Life (QOL) will be assessed at enrolment (baseline) and at 3 and 6 months post-enrolment, and then at 6 monthly post-enrolment intervals for the duration of the study.

Eligibility
Key inclusion criteria
1 Patient has a diagnosis of unresectable Stage 3 pancreatic ductal adenocarcinoma cancer cytologically or pathologically confirmed as per American Joint Committee on Cancer (AJCC) staging criteria.
2 Patient is newly diagnosed and has only received a single line of therapy for at least 3 months prior to enrolment. They must have received either modified FOLFIRINOX or gemcitabine-based chemotherapy.
3 Patient has a tumour evaluated as Stage 3 according to National Comprehensive Cancer Network (NCCN) guidelines, based on radiographic imaging or exploratory surgery.
4 Maximum axial tumour dimension of less than or equal to 3.5cm, after receiving at least three months of treatment with a modified FOLFIRINOX or gemcitabine-based regimen.
5 Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6 Patient has an American Society of Anaesthesiologists (ASA) classification of physical health status of 1 or 2.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1 Patients who at 3 months after induction chemotherapy have evidence of disease progression.
2 Patients who have undergone prior radiation therapy or surgical resection for treatment of pancreatic cancer.
3 Patients who have received IRE for margin accentuation.
4 Patients who are unable to tolerate general anaesthetic with full skeletal muscle blockade.
5 History of another primary cancer within the last 3 years, with the exception of non-melanomatous skin cancer and carcinoma in-situ.
6 Patients who are actively bleeding, anticoagulated, coagulopathy, or have any of the following haematology results:
a. Haemoglobin <100 g/L without the support of growth factors or transfusion
b. Absolute neutrophil count <1.5 x 109/L
c. Platelet count <100 x 109/L
7 Patients with the presence of implanted cardiac pacemakers, defibrillators, electronic devices or implanted devices with metal parts in the thoracic cavity at the time of IRE.
8 Patients with history of epilepsy or other neurological disease.
9 Patients with inadequate organ function:
a. Patients with Stage 3 (GFR 30 to 44ml/min), 4 (15 to 29ml/min), or 5 (<15ml/min) chronic kidney disease.
b. Aspartate aminotransferase/alanine aminotransferase >2.5 x upper limit of normal.
c. Clinically significant cardiovascular disease i.e. active or <12 months since e.g. cerebrovascular accident, myocardial infraction, unstable angina, New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmias requiring medications, uncontrolled hypertension.
10 Patients who are pregnant or breastfeeding. Women of childbearing potential (WOCBP) must undergo pregnancy testing.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This will be the first of its kind prospective registry-based IRE study in Australia investigating the utility of IRE after initial chemotherapy, filling an unmet need and gap in the treatment of locally advanced unresectable pancreatic cancer in Australia. The study will leverage off and utilise the PURPLE (Pancreatic cancer: Understanding Routine Practice and Lifting End results) registry (ACTRN12617001474347).
The PURPLE registry is an ethically approved registry that prospectively captures clinicopathologic, treatment and outcome data in patients with pancreatic cancer. This multi-site, multi-disciplinary translation pancreatic cancer registry aims to increase data sharing and collaboration across cancer centres and research laboratories. To date over 1600 patients have been registered since its commencement in 2016. Data is entered at the point of care onto a password-protected database, and is de-identified prior to analysis.
The PURPLE registry will be used to identify eligible study patients at participating sites allowing a more efficient and thorough patient identification process. Longitudinal patient data such as subsequent therapies and data of death will be recorded in the PURPLE registry as part of the usual process of cataloging a patient on this registry.
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
No formal hypothesis testing is planned. Descriptive statistics will be used to summarise the safety, tolerability, and clinical activity of IRE by the NanoKnife System.
The sample size will be 20 participants. This sample size is determined by available resources and drug and no sample size calculation or power calculation was done.
All analyses will be based on the safety-evaluable population, defined as all participants who commenced protocol treatment.
Descriptive statistics of baseline characteristics of all patients will be summarised. Continuous variables will be summarised using means, standard deviations, median and ranges; categorical variables will be presented using counts and percentages. All summaries will be presented by cohort.
Time to event endpoints (PFS and overall survival and time to death or onset of grade 4 AE) will be described using Kaplan-Meier methods to calculate the median survival with 95% confidence intervals. The time to PFS will be calculated as the time between enrolment into the study and the first of death due to any cause or disease progression. Patients who do not experience these events will be censored if lost to follow-up, withdrawn or at study end. Data for patients without the occurrence of disease progression or death at the end of study will be censored at the time of last tumour assessment. The time to overall survival will be calculated as the time between enrolment into the study and death. Patients who do not die will be censored at the time they are lost to follow-up, withdrawn or at study end. Data for patients who are alive at the time of the analysis data cut-off will be censored at the last date they were known to be alive. Time to death or new onset grade 4 AE will be analysed in a similar manner.
Procedure-related pain will be summarised descriptively for participants undergoing IRE with the NanoKnife System. Pain Severity Score and average Pain Interference Score will be derived for each participant from BPI-Short Form questionnaire. Both Pain Severity Scores and average Pain Interference Score will be summarised by treatment arm and by visit.
The PURPLE (Pancreatic cancer: Understanding Routine Practice and Lifting End results) registry (ACTRN12617001474347) will also be used to provide prospectively collected data for a comparator arm of matched eligibility patients receiving chemotherapy alone for the final analysis report.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 19636 0
The Alfred - Melbourne
Recruitment hospital [2] 19641 0
Epworth Freemasons (Clarendon Street) - East Melbourne
Recruitment postcode(s) [1] 34269 0
3004 - Melbourne
Recruitment postcode(s) [2] 34274 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 308518 0
Commercial sector/Industry
Name [1] 308518 0
AngioDynamics
Address [1] 308518 0
14 Plaza Drive
Latham NY 12110
Country [1] 308518 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Walter & Eliza Hall Institute of Medical Research (WEHI)
Address
1G Royal Parade
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 309371 0
None
Name [1] 309371 0
Address [1] 309371 0
Country [1] 309371 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308475 0
Melbourne Health HREC
Ethics committee address [1] 308475 0
Office for Research
Level 2
South West
300 Grattan Street
Parkville VIC 3052
Ethics committee country [1] 308475 0
Australia
Date submitted for ethics approval [1] 308475 0
Approval date [1] 308475 0
01/04/2021
Ethics approval number [1] 308475 0
HREC/62088/MH-2020

Summary
Brief summary
The aim of this study is to investigate whether addition of a new therapy using the NanoKnife system improves survival in patients with unresectable stage 3 pancreatic cancer. The Nanoknife system is a type of irreversible electroporation (IRE) device. “Electroporation” is a cellular destruction technology that can be used to treat cancer. It uses electrical pulses to make small holes in cells that cause cell death. This destroys the targeted tissue in the body and the treated tissue is then removed by the body’s natural processes in a matter of weeks, mimicking natural cell death.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, have a diagnosis of unresectable stage 3 pancreatic ductal adenocarcinoma, and have received (or will receive) at least 3 months of a single line of chemotherapy prior to enrolment.

Study details
Within 1 to 3 weeks after completing their 3 months of chemotherapy, all participants will undergo the IRE procedure. The IRE procedure will only be performed by a surgeon qualified in the use of the NanoKnife System. The procedure will require a general anaesthetic and will take approximately 2-3 hours to complete. As part of the procedure, a diagnostic laparoscopy (a procedure where a camera is inserted into the abdomen through small incisions) will be used to rule out the presence of metastases. Following this, the abdomen will be opened to perform IRE. A tissue biopsy will be taken during the procedure if safe to do so. After recovery from anaesthesia, participants will stay in hospital for up to 7 days before being discharged home when they are well. Participants will be asked to complete a number of questionnaires at 3, 6, 12, 18, and 24 months following the procedure, and will also be asked to report any side-effects that they experience for the duration of follow-up. Following treatment with the NanoKnife, you may continue to receive other standard of care treatment such as further chemotherapy or radiotherapy. This will be decided by your treating oncologist.

It is hoped that this study may demonstrate that use of the NanoKnife system in patients with unresectable stage 3 pancreatic cancer who have already received chemotherapy is safe to use, improves survival, reduces pain, and increases quality of life compared to patients receiving chemotherapy alone.
Trial website
Trial related presentations / publications
Public notes
Patients may be referred as potential candidates for the study by their oncologist from any hospital in Victoria, however, the IRE surgical procedure will be undertaken at The Alfred hospital, Melbourne or Epworth Freemasons Hospital, East Melbourne as these are the only participating hospitals in Victoria that have the NanoKnife Device.

Contacts
Principal investigator
Name 110822 0
Dr Belinda Lee
Address 110822 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Country 110822 0
Australia
Phone 110822 0
+61 3 9345 2893
Fax 110822 0
Email 110822 0
belinda.lee@mh.org.au
Contact person for public queries
Name 110823 0
Dr Roslynn Murphy
Address 110823 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Country 110823 0
Australia
Phone 110823 0
+61 3 9345 2748
Fax 110823 0
Email 110823 0
roslynn.murphy@mh.org.au
Contact person for scientific queries
Name 110824 0
Dr Richard To
Address 110824 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Country 110824 0
Australia
Phone 110824 0
+61 9345 2748
Fax 110824 0
Email 110824 0
Richard.To@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD is not required for data analysis, and any published findings will not contain any reference to patient names or patient identifiers.
What supporting documents are/will be available?
No other documents available
Summary results
No Results