Irreversible Electroporation + Nivolumab for Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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The trial investigates the safety and efficacy of irreversible electroporation in combination with checkpoint inhibition in patients with metastatic pancreatic cancer.

Detailed Description
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The trial is designed as an investigator initiated prospective phase 2 study in patients with metastatic pancreatic cancer (PC) to determine the efficacy and safety of checkpoint inhibition administered concurrently with irreversible electroporation. A recently published preclinical study by Zhao et al. (2019) showed that the combination of IRE and PD-1-inhibitor suppressed the tumour growth and increased the survival of mice bearing pancreatic cancer. The aim of the trial is to initiate an abscopal response, leveraging the patient's immune system in eliciting a sufficient immune response.

Official Title
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Irreversible Electroporation in Combination With Immune Checkpoint Inhibition, in Patients With Metastatic Pancreatic Cancer - A Prospective, Phase 2 Study

Conditions
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Pancreas Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Device: Irreversible electroporation (IRE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent. Histopathological confirmation of pancreatic adenocarcinoma. At least one measurable primary in-situ (or locally-recurrent) or metastatic tumor must be present and, in the opinion of the investigators be amenable to IRE, and at least one additional metastatic tumor that will not undergo IRE. Both lesions must be accessible for image-guided percutaneous biopsy. Age > 18 years Life expectancy greater than 3 months ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) 0-1 Patients must have normal organ and marrow function as defined below: White blood cell count (WBC) ≥ 2 x 10⁹/L Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L Hemoglobin ≥ 5,6 mmol/l Platelet count ≥ 100 x 10⁹/L Serum bilirubin ≤1.5 x upper limit of normal (ULN) (patients with Gilbert's Syndrome must have a total bilirubin ≤ 50 mmol/L ) ASAT/ALAT ≤3 x ULN ( < 5 x ULN if known liver metastasis) PP ≥ 40 or INR ≤ 1.5 Serum creatinine ≤ 1.5 x ULN or eGFR ≥ 40 mL/min Women of childbearing potential (WOCBP) must use method(s) of contraception as indicated per protocol. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab. Women must not be breastfeeding Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Exclusion Criteria: Malignant ascites that is clinically detectable by physical examination or is symptomatic. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways Radiotherapy, or major surgery within the last 2 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. Patients should be excluded if they have an active, known or suspected autoimmune disease. Patients should be excluded if they are positive test for hepatitis B virus surface anti-gen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immuno-suppressive 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. PD-1 inhibitors may cause hepatic toxicity which may lead to caution regarding other potentially hepatotoxic drugs. 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 4 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 2 weeks prior to study drug administration Contraindications for IRE: Implanted pacemaker or ICD (Implantable cardioverter defibrillator) unit. History of epilepsy History of cardiac arrhythmia Recent myocardial infarction

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IRE + Nivolumab<br>IRE on Day 1, followed by Nivolumab on Day 2/3 and then every 2 weeks (q2w) for a maximum of 24 weeks. | Drug: Nivolumab<br>* Every 2 weeks (3 mg/kg, maximum of 240 mg) for up to 24 weeks Nivolumab is an immune checkpoint inhibitor (PD-1-inhibitor).<br>* Other names: Opdivo;Device: Irreversible electroporation (IRE)<br>* Percutaneous ablation of a primary in-situ (or locally-recurrent) or metastatic lesion. Irreversible electroporation is delivered through the NanoKnife system (AngioDynamics, New York, USA). The system is FDA-approved for medical use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment related adverse events [Safety and Tolerability] | Determined by the incidence and severity of treatment related adverse events according to CTCAE version 4.0 | 6 months after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response by CT | Based on CT chest/abdomen scans according to RECIST version 1.1 | Baseline compared to 3 and 6 months after start of treatment | 
| Tumor response by ultrasound | Based on contrast enhanced ultrasound (CEUS) utilizing the standardized and quantitative method Dynamic CEUS (DCEUS) | Baseline compared to 3 and 6 months after start of treatment | 
| Progression free survival | In terms of months | From start of treatment until unequivocal disease progression, assessed up to 5 years | 
| Overall survival | In terms of months | From start of treatment until unequivocal disease progression, assessed up to 5 years | 
| Quality of life using EORTC QLQ-C30 | EORTC QLQ-C30 | Baseline compared to 14 days, 3 and 6 months after start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irreversible electroporation, Immunotherapy, Nivolumab, Abscopal effect