Liver Cancer
Conditions
Keywords
Primary liver tumors, Bleomycin, Electrochemotherapy
Brief summary
The aim of the study is to evaluate toxicity and effectiveness of electrochemotherapy with bleomycin in treatment of primary liver tumors in clinical study phase I and II. The study will include 10 patients in phase I clinical study and additional 15 patients in phase II clinical study (or in the extension of the clinical study), which will fulfill inclusion criteria. Treatment effectiveness will be evaluated by DCE-US or CT perfusion, to detect early events in tumor perfusion after ECT compared to tumor perfusion before ECT. Long term effectiveness of the treatment will be evaluated by modified RECIST criteria, which will take into account difference in size and density, determined from images obtained by CT perfusion of the treated tumor nodules before and after ECT. Tumor volume will be calculated by following formula , where a will be shorter and b longer tumor diameter. The secondary objectives of the trial are to quantify the impact of the treatment on the patient's quality of life, tolerance to the therapy and suitability for larger study to be conducted.
Detailed description
The study will be conducted on patients with primary liver tumors. 10 patients will be included in phase I clinical study and additional 15 patients in phase II clinical study (or in the extension of the clinical study). Depending on the position of tumors, appropriate electrodes will be selected; hexagonal needle electrodes with fixed geometry for tumors not larger than 3 cm in diameter, where lower edge of the tumor is located up to 3 cm below the liver capsule or longer single needle electrodes. Individual electrodes, positioned according to the prepared treatment plan will be used for tumors up to 7 cm in diameter, or located near vena cava or large hepatic or portal veins. Electrochemotherapy will be performed within 8-28 min after intravenous in bolus administration of bleomycin (15 mg/m2). Triggering of electric pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. All patients will be treated after the procedure has been thoroughly described to them, and have signed informed consent.
Interventions
PROCEDUREElectrochemotherapy
Exploration, anesthesia, adhesiolysis, mobilization of liver, intra-operative US or CT, bleomycin administration, electroporation
DEVICECliniporator Vitae®
Positioning of electrodes, 8-28 min after administration of bleomycin application of electric pulses (8 pulses, duration 100 microseconds, frequency 8 Hz with amplitude adequate to cover the whole treated lesion with electric field necessary for reversible plasma membrane permeabilization), removal of electrodes. The maximum duration of procedure is 90 minutes, after liver mobilization.
Intravenous in bolus administration of bleomycin (15 mg/m2)
Sponsors
Institute of Oncology Ljubljana
University of Ljubljana
Masa Bosnjak
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with primary liver tumors; hepatocellular carcinoma, intrahepatic cholangiocarcinoma and other primary tumors not larger than 7 cm that are positioned in unresectable liver area, near blood vessels in operable patients. 2. Patients with the progression of the disease (confirmed by radiological imaging) after treatment with TACE, RFA or percutaneous alcohol ablation, which are not suitable for potentially curative treatment, but with relatively good performance status and Child-Pugh score \< 8. Patients from group 1. and 2. are patients, in whom standard treatment procedures are not eligible, so ECT will be the only therapeutic option. In patients with multiple liver tumors, unresectable tumors which are also unsuitable for RAF will be treated by ECT, whereas other tumors will be resected or treated by RAF. 3. Patients with tumors smaller tumors, not suitable for liver transplantation, but also unsuitable for RFA treatment or percutaneous alcohol ablation because of the position of the tumor. Electrochemotherapy will be as bridge therapy, till liver transplantation. 4. Patients with tumors\> 4 cm in diameter, in difficult to reach locations, and patients unsuitable for treatment with other treatment options. Patients from group 3. and 4. are patients, potentially curable with standard treatment. Electrochemotherapy in these patients will not affect the standard of care of these patients, recommended in guidelines for HCC. 5. Electrochemotherapy is offered to the patients also when they refuse standard treatments. 6. Histologically confirmed primary liver cancer and/or based on radiological imaging laboratory tests confirmed primary liver cancer by multidisciplinary team for liver tumors. 7. Age more than 18. 8. Life expectancy more than 3 month. 9. Performance status Karnofsky ≥ 70 or (World Health Organization) WHO \< or 2. 10. Treatment free interval 2-5 weeks, depending on the drugs used. 11. Patient must be mentally capable of understanding the information given. 12. Patient must give informed consent. 13. Patient must be discussed at the multidisciplinary team for liver tumors before entering the trial.
Exclusion criteria
1. Secondary primary tumor, except surgically treated noninvasive cancer of cervix, or surgically or irradiated basal cell carcinoma 2. Visceral, bone or diffuse metastases. 3. Life-threatening infection and/or heart failure and/or liver failure and/or other severe systemic pathologies. 4. Clinically significant ascites. 5. Significant reduction in respiratory function. 6. Age less than 18 years. 7. Coagulation disturbances (those who do not respond on standard treatment with vitamin-K or fresh frozen plasma). 8. Cumulative dose of 250 mg/m2 bleomycin received. 9. Allergic reaction to bleomycin. 10. Impaired kidney function (creatinin \> 150 µmol/l). 11. Patients with epilepsy. 12. Patients with arrhythmias. 13. Patients with heart failure or pace maker. 14. Pregnancy. 15. Patient incapable of understanding the aim of the study or disagree with the entering into the clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Toxicity Related to Electrochemotherapy | After operation on day 7 | Biochemistry, blood test and/or US |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response Evaluation According to RECIST v1.1 | After operation on days 1, 7, 30, 60, 90, 120 | Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI/CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
Countries
Slovenia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Electrochemotherapy Treatment Electrochemotherapy: Exploration, anesthesia, adhesiolysis, mobilization of liver, intra-operative US or CT, bleomycin administration, electroporation
Cliniporator Vitae®: Positioning of electrodes, 8-28 min after administration of bleomycin application of electric pulses (8 pulses, duration 100 microseconds, frequency 8 Hz with amplitude adequate to cover the whole treated lesion with electric field necessary for reversible plasma membrane permeabilization), removal of electrodes.
The maximum duration of procedure is 90 minutes, after liver mobilization.
Bleomycin PHC 15 e. (United States Pharmacopeia - USP): Intravenous in bolus administration of bleomycin (15 mg/m2) | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Electrochemotherapy Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 65.6 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 15 / 24 |
| serious Total, serious adverse events | 0 / 24 |
Outcome results
Primary
Number of Participants With Toxicity Related to Electrochemotherapy
Biochemistry, blood test and/or US
Time frame: After operation on day 7
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Electrochemotherapy Treatment | Number of Participants With Toxicity Related to Electrochemotherapy | ECT-related adverse events | 0 Participants |
| Electrochemotherapy Treatment | Number of Participants With Toxicity Related to Electrochemotherapy | Non-ECT-related within 24 h | 0 Participants |
| Electrochemotherapy Treatment | Number of Participants With Toxicity Related to Electrochemotherapy | Non-ECT-related after 24 h | 4 Participants |
| Electrochemotherapy Treatment | Number of Participants With Toxicity Related to Electrochemotherapy | No adverse events | 20 Participants |
Secondary
Clinical Response Evaluation According to RECIST v1.1
Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI/CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: After operation on days 1, 7, 30, 60, 90, 120
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Electrochemotherapy Treatment | Clinical Response Evaluation According to RECIST v1.1 | complete response (CR) | 19 Participants |
| Electrochemotherapy Treatment | Clinical Response Evaluation According to RECIST v1.1 | partial response (PR) | 4 Participants |
| Electrochemotherapy Treatment | Clinical Response Evaluation According to RECIST v1.1 | stable disease (SD) | 1 Participants |
| Electrochemotherapy Treatment | Clinical Response Evaluation According to RECIST v1.1 | progressive disease (PD) | 0 Participants |