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

Primary Purpose

Pancreatic Cancer, Metastatic Pancreatic Cancer

Status

Recruiting

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Irreversible Electroporation (IRE)

Nivolumab

Toll-Like Receptor 9

About this trial

This is an interventional treatment trial for Pancreatic Cancer focused on measuring pancreatic cancer, metastatic pancreatic cancer, pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, PDAC

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Amsterdam University Medical Centre (location VUmc)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Arm A: Nivolumab

Arm B: IRE + Nivolumab

Arm C: CpG + IRE + Nivolumab

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Determined by the treatment related (serious) adverse events

Secondary Outcome Measures

Overall Survival

Overall survival in terms of months

Progression-Free Survival

Progression-free survival in terms of months

Immunomodulation (local)

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)

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

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

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

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

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

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

Based on the following questionnaire: QLQ-HAPINES Question types include: scale 1-10

Quality of Life throughout treatment based on anxiety and depression

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

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

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)

The pain questionnaire is based on the VAS and includes scale type questions (1 - 10) with higher scores referring to more pain.

Full Information

NCT ID

NCT04612530

First Posted

September 9, 2020

Last Updated

December 18, 2022

Sponsor

Amsterdam UMC, location VUmc

1. Study Identification

Unique Protocol Identification Number

NCT04612530

Brief Title

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

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 1, 2020 (Actual)

Primary Completion Date

April 1, 2023 (Anticipated)

Study Completion Date

June 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Amsterdam UMC, location VUmc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pancreatic Cancer, Metastatic Pancreatic Cancer

Keywords

pancreatic cancer, metastatic pancreatic cancer, pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, PDAC

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

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.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm A: Nivolumab

Arm Type

Active Comparator

Arm Description

Arm Title

Arm B: IRE + Nivolumab

Arm Type

Experimental

Arm Description

Arm Title

Arm C: CpG + IRE + Nivolumab

Arm Type

Experimental

Arm Description

Intervention Type

Device

Intervention Name(s)

Irreversible Electroporation (IRE)

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Toll-Like Receptor 9

Intervention Description

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.

Primary Outcome Measure Information:

Title

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

Description

Determined by the treatment related (serious) adverse events

Time Frame

From randomization until 1 year later

Secondary Outcome Measure Information:

Title

Overall Survival

Description

Overall survival in terms of months

Time Frame

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

Title

Progression-Free Survival

Description

Progression-free survival in terms of months

Time Frame

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

Title

Immunomodulation (local)

Description

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.

Time Frame

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

Title

Immunomodulation (systemic)

Description

The systemic immune response will be assessed using flow cytometry of peripheral blood. Markers include those of T-cells, dendritic cells, MDSCs, NK cells.

Time Frame

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

Title

Tumor Response on Imaging

Description

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.

Time Frame

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.

Title

Quality of Life throughout treatment based on overall health

Description

Based on the following EORTC questionnaire: EQ-5D-L5. Question types include: scale 1-5

Time Frame