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

NCT04612530 | Unknown Phase 1 DMC

• 1 other identifier: 2020.231 - NL73415.029.20
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Pancreatic Cancer; Metastatic Pancreatic Cancer

Keywords

pancreatic cancer; metastatic pancreatic cancer; pancreatic ductal adenocarcinoma; metastatic pancreatic ductal adenocarcinoma; PDAC

Outcome Measures

Primary Outcomes (1)

• Safety of the combination treatment IRE + immunotherapy based on adverse events

  Determined by the treatment related (serious) adverse events

  From randomization until 1 year later

Secondary Outcomes (14)

• Overall Survival

  From date of randomization until death, assessed up to 5 years

• Progression-Free Survival

  From date of randomization until unequivocal disease progression, assessed up to 5 years

• Immunomodulation (local)

  Biopsies taken at T=0 (prior to treatment), T=2 weeks and T=6 weeks

• Immunomodulation (systemic)

  Blood taken at T=0 (prior to treatment), T=2 weeks and T=6 weeks

• 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.

Study Arms (3)

Arm A: Nivolumab

ACTIVE COMPARATOR

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.

Drug: Nivolumab

Arm B: IRE + Nivolumab

EXPERIMENTAL

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.

Device: Irreversible Electroporation (IRE); Drug: Nivolumab

Arm C: CpG + IRE + Nivolumab

EXPERIMENTAL

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.

Device: Irreversible Electroporation (IRE); Drug: Nivolumab; Drug: Toll-Like Receptor 9

Interventions

Irreversible Electroporation (IRE) DEVICE

Irreversible electroporation (IRE) is a local ablative technique that utilizes electrical pulses to destroy tumor tissue

Arm B: IRE + Nivolumab; Arm C: CpG + IRE + Nivolumab

Nivolumab DRUG

Nivolumab is an immune checkpoint inhibitor targeting the PD-1 receptor on T-cells. Binding of the PD-1 monoclonal antibody onto the PD-1 receptor blocks the brake signal on the T-cells, allowing them to attack the cancer cells.

Arm A: Nivolumab; Arm B: IRE + Nivolumab; Arm C: CpG + IRE + Nivolumab

Toll-Like Receptor 9 DRUG

Toll-Like Receptor 9 (CpG) is an oligodeoxynucleotide that stimulates dendritic cells to release IFN type I, activating natural killer and infiltrating T cells. This creates a more pro-immunogenic tumor environment.

Arm C: CpG + IRE + Nivolumab

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Age ≥ 18 years.
• World Health Organisation scale (WHO) performance status 0 - 2;
• Adequate bile drainage in case of biliary obstruction.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead

Study Sites (1)

Amsterdam University Medical Centre (location VUmc)

Amsterdam, North Holland, 1081HV, Netherlands

RECRUITING

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

Electroporation; Nivolumab; Toll-Like Receptor 9

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques; Electrochemical Techniques; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; DNA-Binding Proteins; Toll-Like Receptors; Receptors, Pattern Recognition; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins

Study Officials

• Martijn R Meijerink, MD, PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Florentine EF Timmer, MSc

CONTACT

+3120 444 4571; f.timmer1@amsterdamumc.nl

Bart Geboers, MD

CONTACT

+3120 444 4571; b.geboers@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Interventional Oncology

Model Details: Step-up design. Arms A (monotherapy Nivolumab, 6 patients) and B (IRE + Nivolumab, 6 patients) will open first. A safety and toxicity analysis will be performed after the inclusion of patient 6 and patient 12. Arm C (CpG + IRE + Nivolumab, 6 patients) will open if the interim results demonstrate safety of arms A and B.

Study Record Dates

• First Submitted: September 9, 2020
• First Posted: November 3, 2020
• Study Start: September 1, 2020
• Primary Completion: April 1, 2023
• Study Completion: June 1, 2023
• Last Updated: December 20, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)