Preoperative treatment with mFOLFIRINOX (or Gem-Nab-P) +/- isotoxic high-dose Stereotactic Body Radiation Therapy (iHD-SBRT) for borderline resectable pancreatic adenocarcinoma: a randomised comparative multicentre phase II study (STEREOPAC)

The primary objective of this study is to compare the **R0 resection** rate (defined as a margin greater than 1 mm) and disease-free survival (DFS) between two treatment arms in patients with borderline resectable **pancreatic adenocarcinoma**. Arm A involves 'standard' chemotherapy, while Arm B includes 'experimental' chemotherapy combined with Stereotactic Body Radiation Therapy (SBRT). This comparison is conducted through an intention-to-treat analysis. The clinical relevance of this objective lies in determining the efficacy of adding SBRT to the chemotherapy regimen, potentially improving surgical outcomes and long-term survival in this patient population.

Secondary objectives include evaluating the following: - Resection rate - Overall survival - Locoregional failure-free interval - Distant metastases-free interval - Complete feasibility of the therapeutic sequence - Pathologic complete response rate - Toxicity (early and late) - Postoperative complications rate - Quality of life (QoL) assessment - Technical and quality success rate of EUS-delivered fiducials

The clinical trial involves participants diagnosed with **pancreatic adenocarcinoma**, specifically targeting individuals with cytologic or histologic proof of adenocarcinoma of the pancreatic head, uncinated process, body, or tail. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. The selection criteria ensure that participants have not received prior chemotherapy or radiation for pancreatic cancer, except as part of a specified neoadjuvant regimen. The sponsor has not provided the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Key laboratory parameters are required to meet specific thresholds, including adequate neutrophil and platelet counts, hemoglobin levels, and liver function tests. The trial population was selected based on these stringent criteria to ensure the safety and efficacy of the treatment being studied.

The clinical trial is designed to evaluate the efficacy of preoperative treatment regimens in patients with **pancreatic adenocarcinoma**. This is a randomized, double-blind, controlled, multicenter phase II study. The trial aims to compare the outcomes of standard chemotherapy against an experimental regimen that includes isotoxic high-dose Stereotactic Body Radiation Therapy (iHD-SBRT). The primary endpoints are R0 resection and disease-free survival (DFS), with secondary endpoints including resection rate, locoregional failure-free interval, and overall survival, among others. The trial is expected to run from October 2022 to October 2032, with participant involvement lasting up to 16 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as cytologic or histologic proof of adenocarcinoma, specific cTNM stage, and adequate laboratory parameters. Following the screening, participants will be randomized into one of the two treatment arms. Regular follow-up visits will be scheduled to monitor treatment response, manage any adverse events, and assess the primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

The expected length of participant involvement is approximately 16 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the development of grade ≥ 2 neuropathies, significant adverse events, or any deviation from the inclusion criteria. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

**Fluorouracil** is administered as a **solution for injection or infusion**. The maximum daily dose is 2400 mg/m², with a total maximum dose of 19200 mg/m² over a treatment period of 16 weeks. The route of administration is via infusion. This medication is used as part of chemotherapy regimens and is not a pediatric formulation. Compliance with dosing schedules is monitored throughout the trial.

**Gemcitabine** is provided as a **solution for infusion** with a concentration of 40 mg/ml. The maximum daily dose is 1000 mg/m², and the total maximum dose is 12000 mg/m² over 16 weeks. It is administered through infusion and is used in chemotherapy protocols. Participant adherence to the dosing regimen is closely monitored.

**Folinic Acid**, also known as **Calcium Folinate**, is available as a **solution for injection**. The maximum daily dose is 400 mg/m², with a total maximum dose of 3200 mg/m² over the course of 16 weeks. It is administered via infusion and is used to enhance the effect of 5-fluorouracil chemotherapy. Dosing compliance is tracked throughout the study.

**Irinotecan Hydrochloride Trihydrate** is administered as a **solution for infusion**. The maximum daily dose is 165 mg/m², with a total maximum dose of 1320 mg/m² over a 16-week period. The infusion route is utilized for administration, and it is part of the chemotherapy regimen. Participant compliance with the dosing schedule is monitored.

**Oxaliplatin** is provided as a **solution for infusion**. The maximum daily dose is 85 mg/m², with a total maximum dose of 680 mg/m² over 16 weeks. It is administered via infusion and is used in chemotherapy treatments. Compliance with the dosing regimen is ensured through regular monitoring.

**Paclitaxel Albumin-Bound** is available as a **dispersion for infusion**. The maximum daily dose is 125 mg/m², with a total maximum dose of 1500 mg/m² over the treatment period of 16 weeks. It is administered through infusion and is part of the chemotherapy protocol. Participant adherence to the dosing schedule is closely monitored.

The efficacy of the clinical trial will be assessed using co-primary endpoints, which include **R0 resection** (defined as a resection margin greater than 1 mm) and disease-free survival (DFS). These endpoints will be evaluated in an intention-to-treat analysis to compare the outcomes between the two study arms: arm A, which receives 'standard' chemotherapy, and arm B, which receives 'experimental' chemotherapy combined with Stereotactic Body Radiation Therapy (SBRT).

Secondary endpoints will further assess efficacy through various parameters, including resection rate, locoregional failure-free interval, distant metastases-free interval, incidence of adverse events, and overall survival. Additional assessments will include pathologic complete/major response rate (pCR), quality of life, postoperative complications rate, and the technical and quality success rate of EUS-delivered fiducials. These parameters will provide a comprehensive evaluation of the treatment's impact on patients with borderline resectable pancreatic adenocarcinoma.