Clinical trial NCT04612530: PANFIRE-3 Trial: Assessing Safety and Efficacy of Irreversible Electroporation (IRE) + Nivolumab + CpG for Metastatic Pancreatic Cancer
Official title: Irreversible Electroporation and Nivolumab Combined With Intratumoral Administration of a Toll-like Receptor Ligand as a Means of in Vivo Vaccination for Oligometastatic Pancreatic Ductal Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Pancreatic Cancer
Metastatic Pancreatic Cancer
Keywords: pancreatic cancer
metastatic pancreatic cancer
pancreatic ductal adenocarcinoma
metastatic pancreatic ductal adenocarcinoma
PDAC
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2020-11-03
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety of the combination treatment IRE + immunotherapy based on adverse events
timeFrame: From randomization until 1 year later
Secondary outcomes:
measure: Overall Survival
timeFrame: From date of randomization until death, assessed up to 5 years
measure: Progression-Free Survival
timeFrame: From date of randomization until unequivocal disease progression, assessed up to 5 years
measure: Immunomodulation (local)
timeFrame: Biopsies taken at T=0 (prior to treatment), T=2 weeks and T=6 weeks
measure: Immunomodulation (systemic)
timeFrame: Blood taken at T=0 (prior to treatment), T=2 weeks and T=6 weeks
measure: Tumor Response on Imaging
timeFrame: 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.
measure: Quality of Life throughout treatment based on overall health
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Quality of Life throughout treatment based on specific health questions
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Quality of Life throughout treatment based on Chemotherapy-Induced Peripheral Neuropathy
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Quality of Life throughout treatment specifically in patients with pancreatic cancer
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Quality of Life throughout treatment based on the patient's happiness and emotional functioning
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Quality of Life throughout treatment based on anxiety and depression
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Quality of Life throughout treatment based on a patient's psychological state regarding their disease
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Quality of Life throughout treatment based on (decreased) pancreatic functionality
timeFrame: Quality of Life will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
measure: Pain based on the Visual Analog Score (VAS)
timeFrame: Pain will be assessed every 3 months (T=0 (baseline), T=3months, etc) up to 1 year
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centre (location VUmc)
state: North-Holland
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Martijn R Meijerink, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: