PANFIRE-3 Trial: Assessing Safety and Efficacy of Irreversible Electroporation (IRE) + Nivolumab + CpG for Metastatic Pancreatic Cancer

Phase 1

Recruiting

• Conditions: Metastatic Pancreatic Cancer; Pancreatic Cancer
• Interventions: Device: Irreversible Electroporation (IRE); Drug: Nivolumab; Drug: Toll-Like Receptor 9

• Registration Number: NCT04612530
• Lead Sponsor: Amsterdam UMC, location VUmc

Brief Summary

Irreversible electroporation is a local ablative technique used in the treatment of pancreatic cancer. In addition to its cytoreductive ability, IRE also induces a systemic immune response. However, this immune response is not potent enough to establish durable regression of the tumor. The immune response can be leveraged by combining IRE with immunotherapy. The primary aim of this study is to determine the safety of IRE + Nivolumab (arm B) and IRE + Nivolumab + CpG (arm C). The secondary aim is to assess efficacy of the experimental arms (B, C) and control arm A (Nivolumab monotherapy), based on overall and progression-free survival as well as locoregional and systemic immune modulation.

Detailed Description

Pancreatic carcinoma is one of the deadliest types of cancer. In contrast to other cancers, new treatment options have demonstrated only moderate improvements for pancreatic cancer in terms of overall survival. Patients with metastasized disease (stage IV, AJCC) that are treated with chemotherapy in the Netherlands currently present a median overall survival of 6.4 months. Previous research has shown promising results for patients with locally advanced pancreatic cancer (LAPC, stage III, AJCC) with regards to combination treatment with chemotherapy and irreversible electroporation (IRE), a local ablation technique that utilizes electrical pulses to destroy cancerous tissue. In addition to an increase in overall survival, IRE induced a systemic immune response. However, the immune response was not potent enough to generate a lasting anti-tumor effect. Leveraging the body's own immune response by using local and systemic immunotherapy may create a synergistic effect, potentially inducing a durable anti-tumor response. The PANFIRE-III is a prospective randomised phase 1 trial with the primary aim to determine safety of the combination therapies IRE + Nivolumab (arm B) and CpG + IRE + Nivolumab (arm C) in patients with oligo-metastasized pancreatic cancer. The secondary goal is to determine efficacy of the experimental arms (arm B, C) compared to the control arm A (Nivolumab monotherapy). This will be assessed by looking at the overall and progression-free survival as well as the locoregional and systemic immune response. The treatment combination of IRE with immunotherapy has the potential to generate systemic protection by in vivo vaccination against pancreatic cancer cells, hereby inhibiting both local and distant tumor growth.

Study Timeline

• Study Start: 2020-09-01
• Study First Submitted: 2020-09-09
• Study First Submitted QC: 2020-10-27
• Study First Posted: 2020-11-03
• Status Verified: 2022-12
• Last Update Submitted: 2022-12-18
• Last Update Posted: 2022-12-20
• Primary Completion: 2023-04-01
• Study Completion: 2023-06-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

• Radiological and histopathologically proven stage IV pancreatic cancer (according to the AJCC staging system for pancreatic cancer);
• Primary oligometastatic disease, defined as at least 1 hepatic metastasis but occurrence of other metastases is not necessarily restricted to the liver, maximum of metastases is to be determined on a case by case basis by the multidisciplinary tumor board.
• Primary tumor is in situ.
• A minimum of 4 cycles of FOLFIRINOX chemotherapy is required but with the explicit aim to strive for completion of 8 cycles of FOLFIRINOX before study inclusion, with at least stable disease on CTscan.
• Age ≥ 18 years.
• World Health Organisation scale (WHO) performance status 0 - 2;
• Adequate bile drainage in case of biliary obstruction.

Exclusion Criteria

• Trans-mucosal tumor invasion into surrounding duodenum or stomach;

• Active epilepsy (last convulsion < 5 years);

• History of cardiac disease:

  • Congestive heart failure > NYHA Class 2
  • Active coronary artery disease (defined as myocardial infarction within 6 months prior to screening);
  • Ventricular cardiac arrhythmias requiring anti-arrhythmic therapy or pacemaker (beta blockers for antihypertensive regimen are permitted; atrial fibrillation is not contra-indicated);

• Known hypersensitivity to any oligodeoxynucleotides.

• Compromised liver function defined as warning signs of portal hypertension, INR > 1,5 without use of anticoagulants, bilirubin > x 1.5 Upper limit of normal range (ULN) ASAT >3.0 x ULN, ALAT >3.0 x ULN.

• Compromised kidney function defined as eGFR <30 ml/min (using the Cockcroft Gault formula);

• Active autoimmune disease requiring disease-modifying therapy at the time of screening: i.e. > 10 mg prednisolone per day or equivalent to this regimen.

• Uncontrolled hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen;

• Uncontrolled infections (> grade 2 NCI-CTC version 3.0); requiring antibiotics

• Pregnant or breast-feeding subjects; Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment;

• Immunotherapy prior to the procedure for the treatment of cancer;

• Previous surgical therapy for pancreatic cancer;

• Second primary malignancy with median 5 year OS < 90%, this excludes adequately treated cancers like: non-melanoma skin cancer, in situ carcinoma of the cervix uteri, superficial bladder cancer or other malignancies treated previously without signs of recurrence.

• Allergy to contrast agent.

• Allergy to PET tracers 18F-FDG and 18F-BMS-986192 Zr-89-Nivolumab

• Any implanted stimulation device;

• Portal vein or VMS stenosis > 70% (relative contra-indication)

• Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: IRE + Nivolumab	Irreversible Electroporation (IRE)	4 weeks after pre-treatment with FOLFIRINOX (4-8 cycles), the patient will first receive (an incomplete) IRE of the primary pancreatic tumor. 2 weeks thereafter, they will start the Nivolumab scheme. The first month, a biweekly dose of 240 mg will be administered, followed by a monthly dose of 480 mg. This treatment will continue until disease progression.
Arm C: CpG + IRE + Nivolumab	Irreversible Electroporation (IRE)	4 weeks after pre-treatment with FOLFIRINOX (4-8 cycles), a toll-like receptor ligand (CpG) will be administered into the primary pancreatic tumor. A week later, the patient will receive (an incomplete) IRE of the primary tumor. 2 weeks thereafter, they will start the Nivolumab scheme. The first month, a biweekly dose of 240 mg will be administered, followed by a monthly dose of 480 mg. This treatment will continue until disease progression.
Arm C: CpG + IRE + Nivolumab	Toll-Like Receptor 9	4 weeks after pre-treatment with FOLFIRINOX (4-8 cycles), a toll-like receptor ligand (CpG) will be administered into the primary pancreatic tumor. A week later, the patient will receive (an incomplete) IRE of the primary tumor. 2 weeks thereafter, they will start the Nivolumab scheme. The first month, a biweekly dose of 240 mg will be administered, followed by a monthly dose of 480 mg. This treatment will continue until disease progression.
Arm A: Nivolumab	Nivolumab	4 weeks after pre-treatment with FOLFIRINOX (4-8 cycles), the patient will start with the Nivolumab scheme. The first month, a biweekly dose of 240 mg will be administered, followed by a monthly dose of 480 mg. This treatment will continue until disease progression.
Arm B: IRE + Nivolumab	Nivolumab	4 weeks after pre-treatment with FOLFIRINOX (4-8 cycles), the patient will first receive (an incomplete) IRE of the primary pancreatic tumor. 2 weeks thereafter, they will start the Nivolumab scheme. The first month, a biweekly dose of 240 mg will be administered, followed by a monthly dose of 480 mg. This treatment will continue until disease progression.
Arm C: CpG + IRE + Nivolumab	Nivolumab	4 weeks after pre-treatment with FOLFIRINOX (4-8 cycles), a toll-like receptor ligand (CpG) will be administered into the primary pancreatic tumor. A week later, the patient will receive (an incomplete) IRE of the primary tumor. 2 weeks thereafter, they will start the Nivolumab scheme. The first month, a biweekly dose of 240 mg will be administered, followed by a monthly dose of 480 mg. This treatment will continue until disease progression.

Primary Outcome Measures

Name	Time	Method
Safety of the combination treatment IRE + immunotherapy based on adverse events	From randomization until 1 year later	Determined by the treatment related (serious) adverse events

Secondary Outcome Measures

Name	Time	Method
Overall Survival	From date of randomization until death, assessed up to 5 years	Overall survival in terms of months
Progression-Free Survival	From date of randomization until unequivocal disease progression, assessed up to 5 years	Progression-free survival in terms of months
Immunomodulation (local)	Biopsies taken at T=0 (prior to treatment), T=2 weeks and T=6 weeks	The local immune response will be assessed using flow cytometry and immunohistochemistry of 2 biopsies (1x primary, 1x metastasis). Markers include those of T-cells, dendritic cells and others.
Immunomodulation (systemic)	Blood taken at T=0 (prior to treatment), T=2 weeks and T=6 weeks	The systemic immune response will be assessed using flow cytometry of peripheral blood. Markers include those of T-cells, dendritic cells, MDSCs, NK cells.
Tumor Response on Imaging	PET scans at T= 0 (prior to treatment), T= 6 weeks and T=3months. CT scans will be made at T= 0 (prior to treatment), T= 6 weeks, T=3months, followed by a scan every subsequent 3 months (T=6m,9m,12m etc) until unequivocal disease progression.	Tumor response will be assessed using PET-CT scans: tracer uptake of FDG and PD-L1. CT scans will be employed to determine tumor response based on the RECIST criteria.
Quality of Life throughout treatment based on overall health	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following EORTC questionnaire: EQ-5D-L5. Question types include: scale 1-5
Quality of Life throughout treatment based on specific health questions	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following EORTC questionnaire: QLQ-C30 Question types include: scale 1-5, scale 1-7
Quality of Life throughout treatment based on Chemotherapy-Induced Peripheral Neuropathy	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following EORTC questionnaire: QLQ-CIPN20 Question types include: scale 1-4
Quality of Life throughout treatment specifically in patients with pancreatic cancer	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following EORTC questionnaire: QLQ-PAN26 Question types include: scale 1-4
Quality of Life throughout treatment based on the patient's happiness and emotional functioning	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following questionnaire: QLQ-HAPINES Question types include: scale 1-10
Quality of Life throughout treatment based on anxiety and depression	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following questionnaire: QLQ-HADS Question types include: scale 1-4
Quality of Life throughout treatment based on a patient's psychological state regarding their disease	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following questionnaire: QLQ-WOPS Question types include: scale 1-4, scale 1-10, yes/no, open
Quality of Life throughout treatment based on (decreased) pancreatic functionality	Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	Based on the following questionnaire: EPI Question types include: 5 optional answers, scale, 1-4, scale 1-5, yes/no, open
Pain based on the Visual Analog Score (VAS)	Pain will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year	The pain questionnaire is based on the VAS and includes scale type questions (1 - 10) with higher scores referring to more pain.

Trial Locations

Locations (1)

Amsterdam University Medical Centre (location VUmc); 🇳🇱 Amsterdam, North-Holland, Netherlands