Sponsors

Commanditaire principal:

VU University Medical Center

La source VU University Medical Center Bref résumé

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.

Description détaillée

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.

Situation globale Recruiting Date de début September 1, 2020 Date d'achèvement October 1, 2022 Date d'achèvement principale April 1, 2022 Phase Phase 1 Type d'étude Interventional Résultat primaire
Mesure Plage de temps
Safety of the combination treatment IRE + immunotherapy based on adverse events From randomization until 1 year later
Résultat secondaire
Mesure Plage de temps
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.
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
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
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
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
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
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
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
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
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
Inscription 18 État Intervention


Type d'intervention:

Device


Nom de l'intervention:

Irreversible Electroporation (IRE)


La description:

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


Type d'intervention:

Drug


Nom de l'intervention:

Nivolumab


La 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.


Type d'intervention:

Drug


Nom de l'intervention:

Toll-Like Receptor 9


La 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.


Étiquette du groupe d'armements:

Arm C: CpG + IRE + Nivolumab

Admissibilité


Critères:

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 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 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 70% (relative contra-indication) - Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study.


Le sexe:

All


Âge minimum:

18 Years


Âge maximum:

100 Years


Volontaires en santé:

No

Officiel général
Nom de famille Rôle Affiliation
Martijn R Meijerink, MD, PhD Principal Investigator Amsterdam UMC (location VUmC)
Contact général


Nom de famille:

Florentine EF Timmer, MSc


Téléphone:

+3120 444 4571


Email:

[email protected]

Emplacement
Établissement: Statut: Contact: Sauvegarde de contact: Enquêteur: Amsterdam University Medical Centre (location VUmc) Florentine EF Timmer, MSc
+3120 444 4571
[email protected]
Martijn R Meijerink, MD, PhD
Principal Investigator
Florentine EF Timmer, MSc
Sub-Investigator
Bart Geboers, MD
Sub-Investigator
Pays d'implantation

Netherlands

Date de vérification

October 2020

Partie responsable


Type:

Principal Investigator


Affiliation des enquêteurs:

VU University Medical Center


Nom complet de l'enquêteur:

Dr. M.R. Meijerink


Titre d'enquêteur:

Professor of Interventional Oncology

Mots clés A un accès étendu No Parcourir l'état Nombre d'armes 3 Groupe d'armes


Étiquette:

Arm A: Nivolumab


Type:

Active Comparator


La 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.


Étiquette:

Arm B: IRE + Nivolumab


Type:

Experimental


La description:

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.


Étiquette:

Arm C: CpG + IRE + Nivolumab


Type:

Experimental


La description:

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.

Données patient No Informations sur la conception de l'étude


Allocation:

Randomized


Modèle d'intervention:

Parallel Assignment


Description du modèle d'intervention:

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.


Objectif principal:

Treatment


Masquage:

None (Open Label)



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