Electroporation and Immunotherapy in Metastatic Colorectal Cancer

The trial is designed as an investigator initiated prospective phase 2 study in patients with metastatic pMMR colorectal cancer (CRC) to determine the safety and efficacy of calcium electroporation (CaEP) performed concurrently with irreversible electroporation (IRE) followed by a PD-1 inhibitor (pembrolizumab).

Inclusion Criteria:Signed informed consentAge ≥ 18 years of ageHistologically confirmed stage IV, non-resectable pMMR colorectal cancerThe 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 endoscopyAt 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 biopsyPrevious chemotherapy a), or b):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)Patients with favourable biological disease, characterized byi. Non-progressive disease ≥ 6 months after last administration of prior 1st line chemotherapy or ≥ 18 months since diagnosis of metastatic disease1. Patients in this category must have been exposed to an EGFR-inhibitor if RAS/RAF wild type8. Life expectancy greater than 3 months9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 110. Adequate bone marrow function:a. Hemoglobin ≥ 5.6 mmol/L or ≥ 9 g/dL, b. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L c. Platelet count ≥ 75 × 109/L11. Adequate kidney function:a. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min or creatinine ≤1.5 X upper limit of normal (ULN)12. Adequate liver function:a. Total bilirubin ≤ 1.5 × ULN b. Alanine aminotransferase (ALT): ≤2.5 X ULN or ≤5 X ULN for subjects with liver metastases c. Aspartate aminotransferase (AST): ≤2.5 X ULN or ≤5 X ULN for subjects with liver metastases d. Albumin: >25 g/L13. Adequate coagulation function:a. 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 b. 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 anticoagulants14. 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 doseParticipants 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 doseWomen 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 productRadiotherapy or major surgery within the last two weeks prior to entering the studyAny 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.gUncorrectable coagulation disorder.Highly inflamed gastrointestinal tissue which is ulcerated and bleedingKnown history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitisHas known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the studyPatients 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:i. History of allergy to study drug components ii. History of severe hypersensitivity reaction to any monoclonal antibodyPatients 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 administrationAbsolute contraindications for IRE:Implanted pacemaker or ICD unit.History of epilepsyHistory of cardiac (ventricular) arrhythmiaRecent myocardial infarctionCongestive heart failure (>NYHA class 2)Uncontrollable hypertensionRelative contraindications for IRE:Atrial fibrillationCombined severe stenosis of the common hepatic artery and main portal vein branch