Padeliporfin VTP Treatment for Unresectable Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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This is a prospective, multicenter, non-randomized, open label light dose escalation phase I trial to evaluate the safety and preliminary efficacy of Padeliporfin vascular targeted photodynamic therapy (VTP) applied via endovascular fiber placement within a dilatation catheter, through the superior mesenteric artery (SMA) in patients with stage III, locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC). The investigators will evaluate safety and preliminary efficacy of Padeliporfin VTP administered endovascularly using light dose escalation.

Detailed Description
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This is a prospective, multicenter, non-randomized, open label light dose escalation phase I trial to evaluate the safety and preliminary efficacy of Padeliporfin vascular targeted photodynamic therapy (VTP) applied via endovascular fiber placement within a dilatation catheter, through the superior mesenteric artery (SMA) in patients with stage III, locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC) with SMA solid tumor encasement >180°. The investigators will evaluate safety and preliminary efficacy of Padeliporfin VTP administered endovascularly using light dose escalation. Study Intervention: Patients enrolled in the study will undergo endovascular VTP, using Padeliporfin (WST-11) activated via endovascular fiber placement through the SMA, with intravenous administration of Padeliporfin at a fixed dose of 4 mg/kg of padeliporfin di-potassium, followed by total of 10 min illumination at 753 nm. For light dose escalation (Part A), a 3+3 dose-escalation schema will be used. In a subsequent expansion phase (Part B), the optimal light dose as per light dose escalation, will be used in an additional cohort of patients to further evaluate preliminary efficacy.

Official Title
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A Multicenter Open-label Phase 1 Trial to Evaluate Safety and Preliminary Efficacy of Endovascularly Applied Vascular Targeted Photodynamic Therapy (VTP) for Patients With Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma

Conditions
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Locally Advanced Unresectable Pancreatic Adenocarcinoma

Intervention / Treatment
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* Combination Product: Padeliporfin Vascular Targeted Photodynamic (VTP) therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years of age and older Capable of giving written informed consent Patients with a diagnosis of Stage III pancreatic ductal adenocarcinoma, cytologically or histologically confirmed per American Joint Committee on Cancer (AJCC) staging criteria Patient has a unresectable tumor, evaluated as Stage III according to National Comprehensive Cancer Network (NCCN) guidelines resectability criteria, based on radiographic imaging or exploratory surgery as a locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) Patients with LA PDAC located in the head/uncinate process of the pancreas, with SMA encasement ˃180° for a total proximal SMA encasement length up to 3cm Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors according to RECIST 1.1 ECOG performance status </= 1 Life expectancy at least 3 months No evidence of metastatic disease by CT scan chest abdomen and pelvis performed within 14 days prior to treatment Adequate Hematological, biochemical, and organ (kidney, liver, cardiac) function International normalized ratio (INR) <1.5 unless the patient is receiving anticoagulation therapy, in which case a therapeutic INR is acceptable. Anticoagulation therapy with low-molecular-weight heparin or warfarin, whether medically indicated, is permitted. May have received prior neoadjuvant systemic therapy No prior external beam radiation therapy to the pancreas No comorbidities which would preclude access to the superior mesenteric artery by intravascular catheterization Exclusion Criteria: Metastatic (stage IV) disease (including involvement of the colon, adrenals, or kidney, or radiographic evidence of peritoneal seeding or pulmonary metastases) SMA anatomical variants (SMA origin not from aorta) Previous radiotherapy treatment for pancreatic cancer Cystic component >= 25% the total volume of the tumor Ascites detected by CT, ultrasound (US) or MRI; Diagnosis of islet cell tumor, lymphoma, metastatic lesion, acinar cell (or other atypical pathologic malignancy) History of other malignancy requiring treatment in the past 2 years Unable to receive or previously intolerant of moderate and/or deep sedation Any other medical or social condition deemed by the investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, and participate in the study or that is likely to interfere with the interpretation of the results Pregnant and/or nursing Active infection, with the exception of resolving cholangitis Known hypersensitivity to iodine contrast Receipt of concurrent investigational therapy or within 30 days of protocol initiation Any other medical or psychiatric comorbidities, including decompensated heart failure, unstable angina or coronary artery disease or severe pulmonary disease, that, in the opinion of the study investigator, would make the patient a poor candidate for the study Systemic chemotherapy treatment within less than 30 days prior to planned VTP or/and for VEGF-targeted therapy within less than 2 months prior to planned VTP treatment Prohibited medication that could not be adjusted or discontinued prior to study treatment Patients with photosensitive skin diseases or porphyria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part B recruitment will be opened upon completion of Part A light dose escalation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>will be a monotherapy light dose escalation with single dose of Padeliporfin at light laser doses of 200, 400 and 600 mW/cm for 10 minutes. Part A will proceed with light dose escalation and will continue until the maximum tolerated light dose (MTD) and/or recommended phase 2 dose (RP2D) is defined. | Combination Product: Padeliporfin Vascular Targeted Photodynamic (VTP) therapy<br>* The laser light fiber with inflatable balloon to dam SMA blood flow during light illumination will be placed by an Interventional Radiologist in the SMA via a transfemoral artery approach. The balloon will be inflated to impede blood flow for total of 10 minutes during light illumination<br>* Other names: Padeliporfin VTP;|
| Experimental: Part B<br>will be a dose expansion part at MTD/RP2D dose level identified in Part A to further assess the safety, tolerability, and treatment effect of the MTD and/ or RP2D | Combination Product: Padeliporfin Vascular Targeted Photodynamic (VTP) therapy<br>* The laser light fiber with inflatable balloon to dam SMA blood flow during light illumination will be placed by an Interventional Radiologist in the SMA via a transfemoral artery approach. The balloon will be inflated to impede blood flow for total of 10 minutes during light illumination<br>* Other names: Padeliporfin VTP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of endovascularly applied Padeliporfin VTP ablation | Safety of endovascularly applied Padeliporfin VTP ablation will be assessed using the CTCAE version 5.0. All adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) for being included in analyses. | Day 30 | 
| Determination of the Maximum Tolerated Light Dose (MTD) and/or Recommended Phase 2 light dose (RP2D) in Part A | MTD is defined as the dose level associated with <33% of DLT-evaluable patients experiencing a DLT. If the MTD is reached, the RP2D will be defined as MTD. If the MTD is not reached, the RP2D will be selected based on integrated evaluation of safety and clinical benefit for all dose levels tested. | Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Descriptive features of treatment response to ablation in tumor tissue based on pre- and post -VTP CT scans | Rate of resectability and downstaging (as per NCCN Clinical Practice Guidelines V1, May 4, 2023) | Day 2 | 
| Tumor Response by CT scans | Based on CT scan according to RECIST 1.1 | Day 30 | 
| Tumor Response by CT scans | Based on CT scan according to RECIST 1.1 | Day 60 |