Mitazalimab + IRE for Pancreatic Cancer
Recruiting in Palo Alto (17 mi)
Overseen ByRebekah R White, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of California, San Diego
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a phase I study of an agonistic CD40 antibody (mitazalimab) injected intratumorally at the time of surgical IRE in patients with locally advanced pancreatic cancer. Intratumoral delivery has potential to be more effective than systemic (intravenous) delivery while decreasing the systemic side effects of immunotherapy. We hypothesize that local delivery of mitazalimab at the time of IRE in patients with locally advanced pancreatic cancer will be safe, augment the immune effects of IRE, and decrease the risk of recurrence.
How does the treatment Mitazalimab + IRE for pancreatic cancer differ from other treatments?
The treatment combines Mitazalimab, an immunotherapy drug, with irreversible electroporation (IRE), a non-thermal technique that uses electrical pulses to kill cancer cells without harming surrounding tissues. This combination aims to enhance the immune response against pancreatic cancer, offering a novel approach compared to traditional treatments that may not effectively target the immune system.
16789Is the combination of Mitazalimab and Irreversible Electroporation (IRE) safe for humans?
Irreversible Electroporation (IRE) has been studied for safety in combination with other treatments for pancreatic cancer, showing potential as a non-thermal method to treat tumors. However, immune-related adverse events (irAEs) are possible when combining IRE with immune therapies, which can affect various organs, including the pancreas, and may require careful management.
23101112What data supports the effectiveness of the treatment Mitazalimab + IRE for Pancreatic Cancer?
Research shows that irreversible electroporation (IRE) can help the immune system fight pancreatic cancer by making the tumor environment less suppressive and allowing immune cells to attack the cancer more effectively. When combined with immune therapies, IRE has been shown to improve survival in animal models of pancreatic cancer.
458913Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive medications like corticosteroids at doses higher than 10 mg/day, you must stop them at least 2 weeks before the study treatment.
Eligibility Criteria
This trial is for individuals with locally advanced pancreatic cancer who are eligible for a procedure called IRE. The study aims to test the safety and effectiveness of injecting a drug directly into the tumor during this procedure.Inclusion Criteria
My cancer is confirmed as pancreatic ductal adenocarcinoma.
My cancer cannot be removed with surgery.
I have completed at least 4 months of FOLFIRINOX chemotherapy.
I can take care of myself and perform daily activities.
My tumor can be completely removed and is smaller than 4.0 cm.
Exclusion Criteria
I am not allergic to L-Histidine, trehalose, or polysorbate 20.
I have not had a fever over 38°C in the last 14 days.
I have had radiation therapy targeting my pancreas.
I have heart rhythm problems that can't be controlled.
My cancer has spread to distant parts of my body.
I cannot undergo major surgery with general anesthesia due to a health condition.
I have been treated with a CD40 antibody before.
Participant Groups
The trial is testing mitazalimab, an immune-stimulating antibody, given by direct injection into the tumor at the time of IRE surgery. It's compared with just having IRE (also known as NanoKnife), which uses electrical currents to destroy cancer cells.
1Treatment groups
Experimental Treatment
Group I: IRE + CD40 AntibodyExperimental Treatment2 Interventions
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
UCSD Moores Cancer CenterLa Jolla, CA
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Who is running the clinical trial?
University of California, San DiegoLead Sponsor
National Cancer Institute (NCI)Collaborator
University of California, Los AngelesCollaborator
References
Efficacy of irreversible electroporation in human pancreatic adenocarcinoma: advanced murine model. [2020]Irreversible electroporation (IRE) is a promising cell membrane ablative modality for pancreatic cancer. There have been recent concerns regarding local recurrence and the potential use of IRE as a debulking (partial ablation) modality. We hypothesize that incomplete ablation leads to early recurrence and a more aggressive biology. We created the first ever heterotopic murine model by inoculating BALB/c nude mice in the hindlimb with a subcutaneous injection of Panc-1 cells, an immortalized human pancreatic adenocarcinoma cell line. Tumors were allowed to grow from 0.75 to 1.5 cm and then treated with the goal of complete ablation or partial ablation using standard IRE settings. Animals were recovered and survived for 2 days (n = 6), 7 (n = 6), 14 (n = 6), 21 (n = 6), 30 (n = 8), and 60 (n = 8) days. All 40 animals/tumors underwent successful IRE under general anesthesia with muscle paralysis. The mean tumor volume of the animals undergoing ablation was 1,447.6 mm(3) ± 884). Histologically, in the 14-, 21-, 30-, and 60-day survival groups the entire tumor was nonviable, with a persistent tumor nodule completely replaced fibrosis. In the group treated with partial ablation, incomplete electroporation/recurrences (N = 10 animals) were seen, of which 66% had confluent tumors and this was a significant predictor of recurrence (P
Immune-Related Adverse Events From Immune Checkpoint Inhibitors. [2022]Immunotherapy for cancer treatment has come of age, specifically with the use of immune checkpoint antibodies directed against molecules such as CTLA-4, PD-1, and PD-L1. Single-agent and combinatorial approaches utilizing these agents and other immunotherapies that may enhance antitumor effects are under investigation. With increasing clinical use of these agents, an appreciation for their toxicities comes to the fore. Adverse events that occur as a result of the immunologic effects of these therapies are termed "immune-related adverse events" (irAEs), and range in both frequency and severity in reported single-agent and combination studies. Improvements in our understanding of how and why irAEs develop and how to effectively manage them are needed. Herein we provide a state-of-the-art synopsis of the incidence, clinical features, mechanisms, and management of selected irAEs with immune checkpoint inhibitors currently in use.
Irreversible electroporation in borderline resectable pancreatic adenocarcinoma for margin accentuation. [2020]Achieving clear microscopic resection margins following pancreaticoduodenectomy (PD) is challenging particularly in borderline resectable pancreatic carcinoma (BRPC). Positive resection margins has been identified as a major independent prognostic factor. Irreversible electroporation (IRE) has emerged as a promising non-thermal ablative method that could be used in the treatment of pancreatic cancer as an adjunct to chemotherapy and surgery. This case report describes the successful simultaneous intraoperative IRE and PD in a patient with BRPC, achieving clear microscopic resection margins. Technical aspects and histology showing the effect of IRE are presented. The role of IRE in the treatment of pancreatic adenocarcinoma should be further evaluated in prospective studies.
Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer. [2020]Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8+ T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC.
Irreversible electroporation combined with chemotherapy for unresectable pancreatic carcinoma: a prospective cohort study. [2022]We aimed to determine the safety and efficacy of irreversible electroporation (IRE) combined with chemotherapy for unresectable pancreatic carcinoma (stage III/IV).
Irreversible electroporation for liver metastasis from pancreatic cancer: A case report. [2020]Pancreatic cancer has a poor prognosis; 40%-50% of patients have liver metastases at the time of initial diagnosis and only 15%-20% undergo surgical resection. Irreversible electroporation (IRE) is a new, non-thermal local ablation method for solid tumors, which can induce cell membrane permeabilization, resulting in unrecoverable nanoscale perforation and apoptotic cell death without damaging the structural components of tissues.
Irreversible Electroporation for Locally Advanced Pancreatic Cancer. [2020]Several minimally invasive image guided tumor ablation techniques have been added to the treatment spectrum for locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) might have a significant additive value in the management of this difficult-to-treat disease. As opposed to thermal ablative techniques, IRE induces cell death by the delivery of high-voltage electrical pulses. The electrical energy disrupts the cellular membrane integrity, causes loss of cellular homeostasis and ultimately results in cell death. The extracellular matrix of connective tissue in surrounding delicate structures such as bile ducts, bowel wall, and larger blood vessels is spared. The preservation of these structures makes IRE attractive for the treatment of pancreatic cancers that are unresectable due to their anatomical location (ie, LAPC and local recurrence after surgical resection). In addition to its cytoreductive abilities, evidence is emerging on IRE's capability to induce systemic immunomodulation through active in vivo vaccination against pancreatic cancer cells. These effects in combination with immunotherapy may offer a new treatment paradigm for tumors with low immunogenic potential like pancreatic ductal adenocarcinoma (PDAC). This review discusses several practical and technical issues of IRE for LAPC: clinical evaluation, indications, patient preparations, procedural steps, imaging characteristics, clinical results, and "tricks of the trade" used to improve the safety and efficacy of the treatment. Future directions such as the combination of IRE with immunotherapy will be shortly addressed.
A phase 1b trial of concurrent immunotherapy and irreversible electroporation in the treatment of locally advanced pancreatic adenocarcinoma. [2023]Combining immune checkpoint blockade therapy with operative disruptive immunomodulation using irreversible electroporation may overcome the resistance to systemic therapy found in patients with locally advanced, unresectable pancreatic cancer. We describe the safety profile and efficacy of IRE with nivolumab.
Safety and efficacy of irreversible electroporation treatment in hepatobiliary and pancreatic tumours: a single-centre experience. [2021]To report initial experience with irreversible electroporation (IRE) in a single tertiary oncology centre and to describe its role in the management of liver and pancreatic tumours.
Irreversible Electroporation and Nivolumab Combined with Intratumoral Administration of a Toll-Like Receptor Ligand, as a Means of In Vivo Vaccination for Metastatic Pancreatic Ductal Adenocarcinoma (PANFIRE-III). A Phase-I Study Protocol. [2021]Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor's immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC's dismal prognosis.
Gastrointestinal disorders as immune-related adverse events. [2022]Immune checkpoint inhibitors, such as cytotoxic T-lymphocyte antigen 4 inhibitors, programmed cell death 1 inhibitors and programmed cell death-ligand 1 inhibitors, have recently emerged as novel drugs in the anti-cancer therapy. Their use in different types of advanced cancer has shown good results and an increase in survival rates. However, immune-related adverse events (irAEs) are frequent and often require special care. IrAEs may affect all the organs, but they are most commonly seen in skin, lungs, endocrine glands and in the gastrointestinal tract where small bowel, colon, the liver and/or the pancreas can be involved. Despite being usually mild and self-resolving, irAEs may present in severe and life-threatening forms, causing the withdrawal of anti-cancer therapy. IrAEs, therefore, represent a challenging condition to manage that often requires the cooperation between the oncologists and the gastroenterologists in order to identify and treat them adequately.
Pancreatic adverse events in patients treated with immune checkpoint inhibitors. [2023]The inhibition of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has been a target for multiple drugs to enhance the T-cell antitumor activity. However, these immune checkpoint inhibitors (ICIs) come with a panel of immune-related adverse events (irAEs) that include mainly endocrine, skin, and gastrointestinal effects. We report seven cases of pancreatic irAEs in patients treated with ICIs at our institute.
Irreversible electroporation combined with chemotherapy and PD-1/PD-L1 blockade enhanced antitumor immunity for locally advanced pancreatic cancer. [2023]Irreversible electroporation (IRE) is a novel local tumor ablation approach with the potential to stimulate an antitumor immune response. However, it is not effective in preventing distant metastasis in isolation. This study aimed to compare the potential of augmenting the antitumor immune response in patients with locally advanced pancreatic cancer (LAPC) who underwent IRE combined with chemotherapy and PD-1/PD-L1 blockade with those who underwent IRE combined with chemotherapy.