Evaluation of Perioperative mFOLFIRINOX and Surgical Resection Versus mFOLFIRINOX Monotherapy in Oligometastatic Pancreatic Cancer: A Randomized Controlled Trial

The primary objective of this study is to evaluate whether **overall survival** in patients with oligometastatic pancreatic cancer is superior when treated with perioperative mFOLFIRINOX followed by complete surgical resection, compared to standard-of-care mFOLFIRINOX first-line chemotherapy alone. This is clinically relevant as it may provide insights into the most effective treatment strategy for improving survival outcomes in this patient population.

Secondary objectives include:

• Development of image-based biomarkers for therapy response prediction and disease outcome.
• Identification of biomarkers for better identification of a potential target population which may benefit from intensified multimodal treatment strategies.
• Identification of biomarkers (e.g., molecular, radiological) associated with progression or resistance to study treatment.
• Identification of biomarkers adding to the understanding of pancreatic ductal adenocarcinoma tumor biology.

The clinical trial involves participants diagnosed with **oligometastatic pancreatic cancer**, specifically targeting individuals aged between 18 and 80 years. Both male and female subjects are included in the study, with no vulnerable populations being selected. The trial population was chosen based on specific inclusion criteria, such as having a histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas, and the medical and technical operability of the primary tumor. Participants must have a limited synchronous or metachronous liver metastatic status, with no more than three resectable or ablatively treatable liver metastases. Additionally, individuals who have previously undergone neo-adjuvant or adjuvant anti-cancer therapy for non-metastatic pancreatic ductal adenocarcinoma (PDAC) are eligible, provided the last dose was administered at least six months before the start of the study treatment. Adequate hematological, hepatic, and renal function parameters are required, along with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Written informed consent is mandatory, and participants must have measurable disease according to RECIST v1.1 prior to induction therapy. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **overall survival** in patients with oligometastatic pancreatic cancer, comparing perioperative mFOLFIRINOX followed by complete surgical resection to standard-of-care mFOLFIRINOX first-line chemotherapy alone. This is a Phase III, randomized, controlled, open-label, multicenter trial. The trial is expected to run from March 31, 2023, to October 1, 2031, with a maximum treatment period of 24 months for each participant. The study involves the administration of **folinic acid**, **oxaliplatin**, **irinotecan hydrochloride trihydrate**, and **fluorouracil**, all delivered via direct intravenous injection.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed diagnosis of metastatic adenocarcinoma of the pancreas, and adequate organ function. Following randomization, participants will receive treatment according to their assigned group. Follow-up visits will be scheduled to monitor progression-free survival, procedure-related complications, and quality of life, using tools such as the EORTC QLQ-C30, PAN-26, and CIPN20. The end-of-study visit will assess the primary endpoint of overall survival and secondary endpoints, including safety and quality-adjusted time without symptoms and toxicity.

Participant involvement is expected to last up to 24 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of the treatment regimens, contributing valuable insights into the management of oligometastatic pancreatic cancer.

The clinical trial involves the administration of **Calcium Folinate**, also known as **Folinic Acid**. This medication is provided in the form of a **solution for injection**. The active substance, folinic acid, is chemically derived and is administered via **direct intravenous injection**. The maximum daily dose is 400 mg/m², with a total maximum dose of 4800 mg/m² over a treatment period of up to 24 months. This medication is not a pediatric formulation and is not classified as an orphan drug.

**Oxaliplatin** is another experimental medication used in this trial. It is provided as a **solution for infusion** and contains the active substance oxaliplatin, which is chemically synthesized. The administration route is **direct intravenous injection**. The maximum daily dose is 85 mg/m², with a total maximum dose of 1020 mg/m² over a 24-month treatment period. This formulation is not intended for pediatric use and is not designated as an orphan drug.

The trial also includes **Irinotecan**, specifically in the form of **Irinotecan Hydrochloride Trihydrate**. This medication is available as a **solution for infusion** and is administered through **direct intravenous injection**. The maximum daily dose is 180 mg/m², with a total maximum dose of 2160 mg/m² over a 24-month period. It is a chemically derived substance, not formulated for pediatric use, and is not classified as an orphan drug.

Lastly, **Fluorouracil** is utilized in the trial, provided as a **solution for injection**. The active substance, fluorouracil, is chemically synthesized and administered via **direct intravenous injection**. The maximum daily dose is 1200 mg/m², with a total maximum dose of 2400 mg/m² over a treatment period of up to 24 months. This medication is not a pediatric formulation and is not designated as an orphan drug.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the time from randomization to death from any cause or the end of the study (EOS). Secondary endpoints include **Progression-free Survival (PFS)**, which measures the time from randomization to cancer progression, death, or EOS. Additional secondary endpoints involve the evaluation of procedure-related complications and mortality, quality of life assessments using EORTC QLQ-C30, PAN-26, and CIPN20 scales, and the Quality-adjusted Time without Symptoms and Toxicity (Q-TWIST). The general safety of surgical removal of tumors and metastases in patients with oligometastatic pancreatic cancer will also be assessed.

The trial will employ validated scales and patient-reported outcomes to measure these parameters. The schedule for measuring and collecting data will be aligned with the trial's timeline, ensuring comprehensive data collection at specified intervals. The analysis will focus on comparing the efficacy of perioperative mFOLFIRINOX followed by complete surgical resection against standard-of-care mFOLFIRINOX first-line chemotherapy alone in patients with oligometastatic pancreatic cancer. The trial is designed as a Phase III, randomized, controlled, open-label, multicentre study, with an estimated end date of October 1, 2031.