Back to resultsIrreversible Electroporation (NanoKnife ®) and Immunotherapy for the Treatment of Stage IV Colorectal Cancer
Primary Purpose
Liver Metastasis Colon Cancer
Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
IRE plus checkpoint inhibitor
IRE plus Checkpoint Inhibitor plus CpG-ODN
Sponsored by
About this trial
This is an interventional treatment trial for Liver Metastasis Colon Cancer
Eligibility Criteria
Inclusion Criteria: Biopsy-proven colorectal liver metastases with at least one measuring < 3.5 cm in diameter and accessible to percutaneous IRE such that a complete ablation of the lesion is possible. Prior resection of the colorectal cancer primary. The imaging has been reviewed in multi-disciplinary Rounds and the colorectal liver metastases have been deemed unresectable. Patient has undergone chemotherapy and has not converted to resectable disease. Radiologic evidence of stable disease for at least two months on systemic therapy for colorectal cancer (may have had prior partial response or disease progression) Microsattelite instability (MSI)-stable or mismatch-proficient tumors Patient has HLA phenotype of Human Leukocyte Antigen (HLA) A1 or HLA A2. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Size of the metastasis being treated with IRE > 3.2 cm or < 2 cm. Size of any non-IRE-treated liver metastasis > 4 cm Pregnancy Major comorbid disease Active autoimmune disease Bone or brain or peritoneal metastases. MSI High disease Patients with cardiac arrhythmia other than rate controlled atrial fibrillation. Metal implant that cannot be removed within 10 cm of the area to be treated. Peritoneal disease. Poor performance status Cirrhosis
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
IRE plus Checkpoint Inhibitor
IRE plus Checkpoint Inhibitor plus CpG Oligodeoxynucleotides (CpG-ODN)
Arm Description
Nivolumab: Patients will receive 240 mg nivolumab (dissolved in 250 mL NaCl 0.9%) administered intravenously over 30 minutes. The first dose will take place one or two days before the IRE treatment. The second and third doses will be given 2 and 4 weeks post-IRE. Bloodwork will be done just prior to each treatment. IRE is performed in the CT scanner. Patients will receive a general anesthetic, and an ultrasound will be performed to locate the designated metastasis. Ultrasound-guided electrode placement (3 or 4 depending on cancer size, shape, and location) will be performed by interventional radiologist Dr. Chris Wall and the IRE device will be activated and used as per the technique of Martin et al.
Patients will receive 240 mg nivolumab as above and also receive 8 mg of CpG-ODN dissolved in 1 mL normal saline administered peritumorally just before the IRE treatment. Three or four electrodes will be placed using a combination of ultrasound and CT guidance in preparation for treatment. Then using the electrodes as landmarks, injection of ¼ or 1/3 cc of the CpG-ODN solution will be performed near each of the 3 or 4 electrodes to achieve a peritumoral administration of the drug. IRE is performed in the CT scanner. Patients will receive a general anesthetic and an ultrasound will be performed to locate the designated metastasis. Ultrasound-guided electrode placement (3 or 4 depending on cancer size, shape, and location) will be performed by interventional radiologist Dr. Chris Wall and the IRE device will be activated and used as per the technique of Martin et al.
Outcomes
Primary Outcome Measures
Complications
Complications (Clavien-Dindo classification of complications) at 30 days. The Clavien-Dindo Classification of Complications involves assigning a numbered classification to each complication, from 1-5, with 1 being a complication without need for any intervention required to 5 which is death of the patient. (a higher number indicates a higher severity). This is a validated measure in use for over 25 years.
Complications
Complications (Clavien-Dindo classification of complications) at 90 days. The Clavien-Dindo Classification of Complications involves assigning a numbered classification to each complication, from 1-5, with 1 being a complication without need for any intervention required to 5 which is death of the patient. (a higher number indicates a higher severity). This is a validated measure in use for over 25 years.
Abscopal effect: percent change in non-treated colorectal liver metastasis.
Two radiologists (one diagnostic and the other interventional) will examine the scans of all patients. They will select a colorectal metastasis from the scan just before the intervention that is between 2-3.2 cm in maximal diameter, accessible to percutaneous ablation, and treatable according to the interventional radiologist's opinion. Another metastasis, with a maximal diameter of less than 4 cm, will be selected to monitor for the abscopal effect (reduction in size of a colorectal liver metastasis that was not treated with IRE).
After 3 months, the radiologists will review the imaging again. They will assess the treatment mass area for any contrast uptake indicating incomplete ablation. The second metastasis will be measured in the same dimensions as before treatment. The difference in maximal diameter of the second metastasis will be calculated as (diameter before IRE - diameter after IRE) / diameter before IRE and expressed as a percentage.
Secondary Outcome Measures
Tumor-specific immune response: distribution on flow-cytometry plot
Distribution of Carcinoembryonic (CEA)-specific CD8+ T cells, CD4+ T cells, type-1 and 2 macrophages (M1 and M2), regulatory T (Treg) cells on the flow-cytometry plot.
Tumor-specific immune response: serum cytokine concentrations
Interleukin(IL)-2, Interferon (IFN)-α, IFN-γ, IL-10 and Transforming Growth Factor (TGF)-β.
Tumor-specific immune response: distribution on flow-cytometry plot.
Distribution of Carcinoembryonic (CEA)-specific CD8+ T cells, CD4+ T cells, type-1 and 2 macrophages (M1 and M2), regulatory T (Treg) cells on the flow-cytometry plot.
Tumor-specific immune response: serum cytokin concentrations
Interleukin(IL)-2, Interferon (IFN)-α, IFN-γ, IL-10 and Transforming Growth Factor (TGF)-β.
Tumor-specific immune response: distribution on flow-cytometry plot.
Distribution of Carcinoembryonic (CEA)-specific CD8+ T cells, CD4+ T cells, type-1 and 2
Tumor-specific immune response
Interleukin(IL)-2, Interferon (IFN)-α, IFN-γ, IL-10 and Transforming Growth Factor (TGF)-β.
Progression-free survival
Progression-free survival will be determined based on the CT scan conducted after one year. To prove the absence of progression, there should be no contrast uptake in the area that was treated with IRE one year prior, AND the maximal diameter of the second lesion (not treated with IRE) should have increased by less than 10%.
Progression-free survival
Progression-free survival will be determined based on the CT scan conducted after two years. To prove the absence of progression, there should be no contrast uptake in the area that was treated with IRE two years prior, AND the maximal diameter of the second lesion (not treated with IRE) should have increased by less than 10%
Quality of life questionnaire
Quality of life using FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire, a 27-item questionnaire, each item to be rated 1-5. The scores are totalled and total scores range from 0-108, with higher scores indicating a higher quality of life.
Quality of life questionnaire
Quality of life using FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire, a 27-item questionnaire, each item to be rated 1-5. The scores are totalled and total scores range from 0-108, with higher scores indicating a higher quality of life.
Quality of life questionnaire
Quality of life using FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire, a 27-item questionnaire, each item to be rated 1-5. The scores are totalled and total scores range from 0-108, with higher scores indicating a higher quality of life.
Full Information
NCT ID
NCT06047015
First Posted
February 21, 2023
Last Updated
September 13, 2023
Sponsor
University of Saskatchewan
1. Study Identification
Unique Protocol Identification Number
NCT06047015
Brief Title
Irreversible Electroporation (NanoKnife ®) and Immunotherapy for the Treatment of Stage IV Colorectal Cancer
Official Title
Immune Response to Irreversible Electroporation (NanoKnife ®) and a Checkpoint Inhibitor With or Without CpG Oligodeoxynucleotides for the Treatment of Stage IV Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
January 2024 (Anticipated)
Primary Completion Date
December 2026 (Anticipated)
Study Completion Date
December 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Saskatchewan
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The goal of this pilot clinical trial is to learn about the combination of immune boosting drugs and irreversible electroporation (IRE) in patients with colon cancer that has spread to the liver (metastasis). The main questions it aims to answer are:
to document the rate of complications associated with combining IRE with immune boosting drugs.
After one liver metastasis is treated with IRE and immune boosting drugs, what is the change in the size of the non-IRE-treated liver metastases?
What is the immune response (measured in a blood sample) when IRE is combined with one or two types of immune boosting drugs?
Detailed Description
Single-centre pilot study of the use of IRE for the treatment of 12 patients with unresectable colorectal liver metastases to assess feasibility and gain preliminary data to inform the design of a larger study.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Metastasis Colon Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This will be a pilot study examining 6 patients treated with IRE and checkpoint inhibitor (first 6, non-randomized) and 6 patients treated with IRE and checkpoint inhibitor and CpG
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
IRE plus Checkpoint Inhibitor
Arm Type
Experimental
Arm Description
Nivolumab: Patients will receive 240 mg nivolumab (dissolved in 250 mL NaCl 0.9%) administered intravenously over 30 minutes. The first dose will take place one or two days before the IRE treatment. The second and third doses will be given 2 and 4 weeks post-IRE. Bloodwork will be done just prior to each treatment.
IRE is performed in the CT scanner. Patients will receive a general anesthetic, and an ultrasound will be performed to locate the designated metastasis. Ultrasound-guided electrode placement (3 or 4 depending on cancer size, shape, and location) will be performed by interventional radiologist Dr. Chris Wall and the IRE device will be activated and used as per the technique of Martin et al.
Arm Title
IRE plus Checkpoint Inhibitor plus CpG Oligodeoxynucleotides (CpG-ODN)
Arm Type
Experimental
Arm Description
Patients will receive 240 mg nivolumab as above and also receive 8 mg of CpG-ODN dissolved in 1 mL normal saline administered peritumorally just before the IRE treatment. Three or four electrodes will be placed using a combination of ultrasound and CT guidance in preparation for treatment. Then using the electrodes as landmarks, injection of ¼ or 1/3 cc of the CpG-ODN solution will be performed near each of the 3 or 4 electrodes to achieve a peritumoral administration of the drug.
IRE is performed in the CT scanner. Patients will receive a general anesthetic and an ultrasound will be performed to locate the designated metastasis. Ultrasound-guided electrode placement (3 or 4 depending on cancer size, shape, and location) will be performed by interventional radiologist Dr. Chris Wall and the IRE device will be activated and used as per the technique of Martin et al.
Intervention Type
Combination Product
Intervention Name(s)
IRE plus checkpoint inhibitor
Intervention Description
Nivolumab: Patients will receive 240 mg nivolumab (dissolved in 250 mL NaCl 0.9%) administered intravenously over 30 minutes. The first dose will take place one or two days before the IRE treatment. The second and third doses will be given 2 and 4 weeks post-IRE. Bloodwork will be done just prior to each treatment.
Intervention Type
Combination Product
Intervention Name(s)
IRE plus Checkpoint Inhibitor plus CpG-ODN
Intervention Description
Patients will receive 240 mg nivolumab as above and also receive 8 mg of CpG-ODN dissolved in 1 mL normal saline administered peritumorally just before the IRE treatment. Three or four electrodes will be placed using a combination of ultrasound and CT guidance in preparation for treatment. Then using the electrodes as landmarks, injection of ¼ or 1/3 cc of the CpG solution will be performed near each of the 3 or 4 electrodes to achieve a peritumoral administration of the drug.
IRE is performed in the CT scanner. Patients will receive a general anesthetic and an ultrasound will be performed to locate the designated metastasis. Ultrasound-guided electrode placement (3 or 4 depending on cancer size, shape, and location) will be performed by interventional radiologist Dr. Chris Wall and the IRE device will be activated and used as per the technique of Martin et al.
Primary Outcome Measure Information:
Title
Complications
Description
Complications (Clavien-Dindo classification of complications) at 30 days. The Clavien-Dindo Classification of Complications involves assigning a numbered classification to each complication, from 1-5, with 1 being a complication without need for any intervention required to 5 which is death of the patient. (a higher number indicates a higher severity). This is a validated measure in use for over 25 years.
Time Frame
30 days
Title
Complications
Description
Complications (Clavien-Dindo classification of complications) at 90 days. The Clavien-Dindo Classification of Complications involves assigning a numbered classification to each complication, from 1-5, with 1 being a complication without need for any intervention required to 5 which is death of the patient. (a higher number indicates a higher severity). This is a validated measure in use for over 25 years.
Time Frame
90 days
Title
Abscopal effect: percent change in non-treated colorectal liver metastasis.
Description
Two radiologists (one diagnostic and the other interventional) will examine the scans of all patients. They will select a colorectal metastasis from the scan just before the intervention that is between 2-3.2 cm in maximal diameter, accessible to percutaneous ablation, and treatable according to the interventional radiologist's opinion. Another metastasis, with a maximal diameter of less than 4 cm, will be selected to monitor for the abscopal effect (reduction in size of a colorectal liver metastasis that was not treated with IRE).
After 3 months, the radiologists will review the imaging again. They will assess the treatment mass area for any contrast uptake indicating incomplete ablation. The second metastasis will be measured in the same dimensions as before treatment. The difference in maximal diameter of the second metastasis will be calculated as (diameter before IRE - diameter after IRE) / diameter before IRE and expressed as a percentage.
Time Frame
3 months from the time of IRE
Secondary Outcome Measure Information:
Title
Tumor-specific immune response: distribution on flow-cytometry plot
Description
Distribution of Carcinoembryonic (CEA)-specific CD8+ T cells, CD4+ T cells, type-1 and 2 macrophages (M1 and M2), regulatory T (Treg) cells on the flow-cytometry plot.
Time Frame
Day 8
Title
Tumor-specific immune response: serum cytokine concentrations
Description
Interleukin(IL)-2, Interferon (IFN)-α, IFN-γ, IL-10 and Transforming Growth Factor (TGF)-β.
Time Frame
Day 8
Title
Tumor-specific immune response: distribution on flow-cytometry plot.
Description
Distribution of Carcinoembryonic (CEA)-specific CD8+ T cells, CD4+ T cells, type-1 and 2 macrophages (M1 and M2), regulatory T (Treg) cells on the flow-cytometry plot.
Time Frame
Day 14
Title
Tumor-specific immune response: serum cytokin concentrations
Description
Interleukin(IL)-2, Interferon (IFN)-α, IFN-γ, IL-10 and Transforming Growth Factor (TGF)-β.
Time Frame
Day 14
Title
Tumor-specific immune response: distribution on flow-cytometry plot.
Description
Distribution of Carcinoembryonic (CEA)-specific CD8+ T cells, CD4+ T cells, type-1 and 2
Time Frame
Day 30
Title
Tumor-specific immune response
Description
Interleukin(IL)-2, Interferon (IFN)-α, IFN-γ, IL-10 and Transforming Growth Factor (TGF)-β.
Time Frame
Day 30
Title
Progression-free survival
Description
Progression-free survival will be determined based on the CT scan conducted after one year. To prove the absence of progression, there should be no contrast uptake in the area that was treated with IRE one year prior, AND the maximal diameter of the second lesion (not treated with IRE) should have increased by less than 10%.
Time Frame
1 year
Title
Progression-free survival
Description
Progression-free survival will be determined based on the CT scan conducted after two years. To prove the absence of progression, there should be no contrast uptake in the area that was treated with IRE two years prior, AND the maximal diameter of the second lesion (not treated with IRE) should have increased by less than 10%
Time Frame
2 years
Title
Quality of life questionnaire
Description
Quality of life using FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire, a 27-item questionnaire, each item to be rated 1-5. The scores are totalled and total scores range from 0-108, with higher scores indicating a higher quality of life.
Time Frame
baseline
Title
Quality of life questionnaire
Description
Quality of life using FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire, a 27-item questionnaire, each item to be rated 1-5. The scores are totalled and total scores range from 0-108, with higher scores indicating a higher quality of life.
Time Frame
12 weeks
Title
Quality of life questionnaire
Description
Quality of life using FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire, a 27-item questionnaire, each item to be rated 1-5. The scores are totalled and total scores range from 0-108, with higher scores indicating a higher quality of life.
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Biopsy-proven colorectal liver metastases with at least one measuring < 3.5 cm in diameter and accessible to percutaneous IRE such that a complete ablation of the lesion is possible.
Prior resection of the colorectal cancer primary.
The imaging has been reviewed in multi-disciplinary Rounds and the colorectal liver metastases have been deemed unresectable.
Patient has undergone chemotherapy and has not converted to resectable disease.
Radiologic evidence of stable disease for at least two months on systemic therapy for colorectal cancer (may have had prior partial response or disease progression)
Microsattelite instability (MSI)-stable or mismatch-proficient tumors
Patient has HLA phenotype of Human Leukocyte Antigen (HLA) A1 or HLA A2.
Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
Size of the metastasis being treated with IRE > 3.2 cm or < 2 cm.
Size of any non-IRE-treated liver metastasis > 4 cm
Pregnancy
Major comorbid disease
Active autoimmune disease
Bone or brain or peritoneal metastases.
MSI High disease
Patients with cardiac arrhythmia other than rate controlled atrial fibrillation.
Metal implant that cannot be removed within 10 cm of the area to be treated.
Peritoneal disease.
Poor performance status
Cirrhosis
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mike AJ Moser, MD, MSc
Phone
306-655-5319
Email
mike.moser@usask.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Shahid Ahmed, MD
Phone
306-655-2630
Email
shahid.ahmed@saskcancer.ca
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Irreversible Electroporation (NanoKnife ®) and Immunotherapy for the Treatment of Stage IV Colorectal Cancer
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