Calcium electroporation in combination with irreversible electroporation and immunotherapy in patients with pMMR metastatic colorectal cancer - A prospective, phase 2 study
- Trial ID
- 2022-500045-25-00
- Protocol
- 010222
- Sponsor
- Zealand University Hospital
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and safety of calcium electroporation (Ca-EP) performed concurrently with irreversible electroporation (IRE), followed by administration of a PD-1 inhibitor, pembrolizumab, in patients with pMMR metastatic colorectal cancer. This objective is clinically relevant as it aims to assess a novel combination treatment approach that could potentially improve therapeutic outcomes in a challenging patient population with limited treatment options.
Secondary objectives include demonstrating how the treatment affects the local and systemic **immune response**, as measured by both blood samples and tumor biopsies. Understanding these effects is crucial for elucidating the immunomodulatory potential of the treatment regimen and its impact on tumor microenvironment and systemic immunity.
Participants
The clinical trial involves participants diagnosed with **colorectal cancer**, specifically those with histologically confirmed stage IV, non-resectable pMMR colorectal cancer. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have a life expectancy greater than three months and have at least two metastatic tumors, with one amenable to irreversible electroporation (IRE) and another accessible for biopsy. The sponsor has not provided the total number of participants. The selection criteria include previous exposure to chemotherapy, with specific conditions regarding the type and response to treatment. Lifestyle considerations such as diet and physical activity are not specified. The trial does not focus on any particular lifestyle habits beyond the medical and treatment history of the participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **calcium electroporation** (Ca-EP) in combination with irreversible electroporation (IRE) and the **PD-1 inhibitor pembrolizumab** in patients with stage IV, non-resectable pMMR metastatic colorectal cancer. This is a prospective, phase II study that employs a randomized, double-blind, controlled trial design. The trial is expected to last until June 2026, with recruitment having commenced in June 2022. Participants will be involved in the study for a maximum treatment period of 12 months, with the possibility of early termination if they do not meet the inclusion criteria or if adverse events occur.
The sequence of study visits begins with an inclusion (screening) visit, where eligibility is assessed based on criteria such as adequate bone marrow, kidney, liver, and coagulation function, as well as a confirmed diagnosis of colorectal cancer. Following the screening, participants will undergo a series of follow-up visits to monitor the safety and tolerability of the treatment, as well as to evaluate systemic and tumor responses. The primary endpoint is to assess the safety and tolerability of the combination therapy, while secondary endpoints include evaluating systemic response, tumor response per RECIST version 1.1, progression-free survival, overall survival, and quality of life.
The end-of-study visit will conclude the trial for each participant, where final assessments will be conducted to gather comprehensive data on the treatment's efficacy and safety. Participants are expected to adhere to the study protocol, including the use of contraception if of reproductive potential, and to attend all scheduled visits. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial aims to provide valuable insights into the potential benefits of combining Ca-EP, IRE, and pembrolizumab for treating metastatic colorectal cancer.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via **intravenous use**. The maximum daily dose is 200 mg, with a total maximum dose of 3600 mg over a treatment period of up to 12 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01XC18, and is produced by Merck Sharp & Dohme BV. The administration schedule and participant compliance are closely monitored to ensure adherence to the dosing regimen.
In addition to pembrolizumab, the trial utilizes **calcium chloride hexahydrate** as a non-experimental treatment. This compound is administered as a **solution for injection**. The maximum daily and total dose is 3 mmol, with a treatment period limited to one day. Calcium chloride hexahydrate serves as an auxiliary treatment in the study, and its administration is conducted through injection. The role of this compound is to support the primary treatment regimen, and its use is carefully documented to maintain the integrity of the trial data.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on evaluating the safety and tolerability of calcium electroporation (Ca-EP) and irreversible electroporation (IRE) in combination with the **PD-1 inhibitor pembrolizumab**. Secondary endpoints include the evaluation of systemic response through biopsy data from a metastasis not treated with IRE, the efficacy of Ca-EP and IRE in combination with pembrolizumab, and tumor response as per the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional secondary endpoints involve assessing tumor response via dynamic contrast-enhanced ultrasound (DCE-US), phenotypic changes of tumor-infiltrating lymphocytes (TILs) from the primary tumor using flow cytometry, progression-free survival, overall survival, and quality of life measured by the EORTC QLQ-C30 questionnaire.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent
- Age ≥ 18 years of age
- Histologically confirmed stage IV, non-resectable pMMR colorectal cancer
- The primary malignant tumor is left sided (cancer of the splenic flexure and cancer in regions distal to the splenic flexure, including the rectum)
- The primary tumor is described as reachable at index endoscopy
- At least two metastatic tumors must be present. One metastatic tumor, that in the opinion of the investigators is amenable to IRE, and at least one additional metastatic tumor that will not undergo IRE. Both lesions must be accessible for biopsy
- Previous chemotherapy a), or b): a) Patients refractory to, intolerable of, or refusing standard chemotherapy options including 5-FU, irinotecan, oxaliplatin, bevacizumab and EGFR-inhibitors e.g. panitumumab/cetuximab (if RAS/RAF wild type) b) Patients with favourable biological disease, characterized by • Non-progressive disease ≥ 6 months after last administration of prior 1st line chemotherapy or ≥ 18 months since diagnosis of metastatic disease o Patients in this category must have been exposed to an EGFR-inhibitor if RAS/RAF wild type
- Life expectancy greater than 3 months
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Adequate bone marrow function: • Hemoglobin ≥ 5.6 mmol/L or ≥ 9 g/dL, • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L • Platelet count ≥ 75 × 109/L
- Adequate kidney function: • Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min or creatinine ≤1.5 X upper limit of normal (ULN)
- Adequate liver function: • Total bilirubin ≤ 1.5 × ULN • Alanine aminotransferase (ALT): ≤2.5 X ULN or ≤5 X ULN for subjects with liver metastases • Aspartate aminotransferase (AST): ≤2.5 X ULN or ≤5 X ULN for subjects with liver metastases • Albumin: >25 g/L
- Adequate coagulation function: • International Normalized Ratio (INR) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as prothrombin Time (PT) or partial prothrombin time (PTT) is within therapeutic range of intended use of anticoagulants • Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- Follow the conditions regarding fertility, pregnancy, or lactation: • Female and male participants of reproductive potential (for definition refer to appendix 16.1) must agree to avoid becoming pregnant or impregnating a partner, respectively, while receiving pembrolizumab and for 120 days after the last dose • Participants of reproductive potential must use (or have their partner use) an acceptable method of contraception, as outlined in appendix 16.1, during heterosexual activity, while receiving pembrolizumab and for 120 days after the last dose • Women of reproductive potential (WORP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to receiving the first dose of pembrolizumab. • Women must not be breastfeeding.
Exclusion Criteria
- Prior treatment with an immune checkpoint inhibitor (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or anti-CTLA-4 agent)
- Concurrent treatment with an investigational medicinal product
- Radiotherapy or major surgery within the last two weeks prior to entering the study
- Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results E.g • Uncorrectable coagulation disorder. • Highly inflamed gastrointestinal tissue which is ulcerated and bleeding • Known history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitis • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
- Patients should be excluded if they have an active, known or suspected autoimmune disease (except thyroiditis with replacement therapy and type I diabetes mellitus).
- Patients should be excluded if they have a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies), active chronic, acute hepatitis B (e.g., HBsAg reactive), or hepatitis C (e.g., HCV RNA is detected).
- Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- Allergies and Adverse Drug Reaction: • History of allergy to study drug components • History of severe hypersensitivity reaction to any monoclonal antibody
- Patients are excluded if they have active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for [lowest minimum is four weeks or more] after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least two weeks prior to study drug administration
- Absolute contraindications for IRE: • Implanted pacemaker or ICD unit. • History of epilepsy • History of cardiac (ventricular) arrhythmia • Recent myocardial infarction • Congestive heart failure (>NYHA class 2) • Uncontrollable hypertension
- Relative contraindications for IRE: • Atrial fibrillation • Combined severe stenosis of the common hepatic artery and main portal vein branch
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 01 Jun 2022 | 12 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 200 | 12 | PRD4323105 |
CALCIUM CHLORIDE HEXAHYDRATE | Other | — | INJECTION | 3 | 1 | SUB13169MIG |