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Surgical IRE will be performed using the NanoKnife System with intraoperative ultrasound guidance via laparotomy under general anesthesia. Mitazalimab (CD40 antibody) will be administered 5 minutes after completion of IRE by slow injection into the center of the ablated zone using a small needle. Core needle biopsies of the tumor will be obtained immediately prior to IRE for identification of candidate tumor antigens. Peripheral blood will be obtained immediately prior to and 12 weeks after the study intervention for analysis of systemic immune effects.

IRE + intratumoral mitazalimab (CD40 antibody) injection

Non-thermal tumor ablation using short pulses of high voltage electrical current delivered using 19-gauge needles placed via laparotomy using ultrasound guidance

NanoKnife

Shakeela Dad

Rebekah R White, MD

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.

Irreversible electroporation (IRE) is a form of non-thermal ablation (tissue destruction) that is being used to treat locally advanced pancreatic cancers. Locally advanced pancreatic cancers are tumors that have not spread (metastasized to distant locations) but cannot be surgically resected. There is evidence that IRE can help to generate anti-tumor immune responses by releasing tumor antigens in the setting of inflammation. CD40 is an immune receptor that helps to stimulate antigen presentation to the immune system. Preclinical data from the PI's laboratory have shown that combination of IRE with an antibody that stimulates the CD40 receptor improves responses to IRE and inhibits metastatic tumor growth.

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.

Phase IA is a limited dose-escalation study. We will use an interval 3 + 3 dose escalation design, which allows rapid dose escalation and de-escalation while maintaining good overdose control. The starting intratumoral dose of mitazalimab in the first-in-human study was 22.5 µg/kg, but no serious adverse events were observed until the third dose level (200 µg/kg). As such, we conservatively propose to start at the second dose level (75 µg/kg) with a single dose escalation to 200 µg/kg, and de-escalation to 25 µg/kg if dose-limiting toxicities are encountered at 75 µg/kg. Phase IB will be an expansion cohort at the recommended phase II dose to establish preliminary evidence of efficacy.

Intra-tumoral Mitazalimab (CD40 Antibody) With Irreversible Electroporation (IRE) in Locally Advanced Pancreas Cancer

Phase 1 Clinical Trial of Intra-tumoral Mitazalimab (CD40 Antibody) With Irreversible Electroporation (IRE) in Locally Advanced Pancreas Cancer

Rates of dose-limiting toxicities (DLTs) and treatment-related adverse events (AEs). AE's will be graded by CTCAE v4, including grading for cytokine release syndrome. A DLT will be defined as any treatment emergent Grade 3 or higher AE that is potentially attributable to mitazalimab or the combination of IRE and mitazalimab. Exceptions will include AE's attributable to normal disease progression.

Progression-free survival (PFS), defined as the time from the date of IRE and mitazalimab administration to date of first observed disease progression or death from any cause

Overall survival (OS), defined as the time from the date of IRE and mitazalimab administration to death from any cause.

Neoantigen-specific T-cell responses will be compared between peripheral blood samples obtained pre- and 12 weeks post-IRE using neoantigens identified from tumor biopsies.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Intra-tumoral Mitazalimab (CD40 Antibody) With Irreversible Electroporation (IRE) in Locally Advanced Pancreas Cancer	NCT06205849	Pancreatic Canc...	IRE + intratumo... NanoKnife	18 Years -	University of California, San Diego
Intra-tumoral Mitazalimab (CD40 Antibody) With Irreversible Electroporation (IRE) in Locally Advanced Pancreas Cancer	NCT06205849	Pancreatic Canc...	IRE + intratumo... NanoKnife	18 Years -	University of California, San Diego

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