Phase II Evaluation of Sequential Gemcitabine and Paclitaxel Albumin-Bound Followed by FOLFIRINOX and MRI-Guided Radiotherapy in Locally Advanced Pancreatic Adenocarcinoma

The primary objective of this Phase II study is to evaluate the **efficacy** of the chemotherapy sequence involving GEMBRAX followed by FOLFIRINOX in patients with locally advanced pancreatic adenocarcinoma. This is clinically relevant as it aims to determine the potential benefits of this sequential treatment approach in improving patient outcomes. Additionally, the study seeks to assess the tolerability of MRI-guided adaptive stereotactic radiotherapy in patients who do not show disease progression after the initial chemotherapy sequence.

The secondary objectives of the study include:

• Assessing the tolerability of the chemotherapy sequence.
• Evaluating the acute toxicity of radiotherapy.
• Evaluating dosimetric results and correlating them with tolerance and survival.
• Evaluating progression-free survival and overall survival of radiotherapy.
• Assessing local disease control of radiotherapy.
• Evaluating progression-free survival and overall study survival.
• Evaluating the tolerability and late toxicity of the overall treatment.
• Evaluating resection rate and quality, histological response to treatment, and evolution of the CA 19.9 marker.
• Evaluating Quality of Life.
• Establishing a biological database to search for biological predictive factors based on circulating tumor DNA (ctDNA) and immune cells, as well as characterizing the immune consequences of treatment based on immune cells.

The clinical trial involves participants diagnosed with **locally advanced pancreatic adenocarcinoma**. The study population includes both male and female subjects, aged between 18 and 75 years, who have a confirmed histological or cytological diagnosis of pancreatic adenocarcinoma. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance status of 1 or less, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial excludes individuals with metastatic disease, as confirmed by TAP scan and liver MRI, and those with CA 19.9 levels exceeding 1000 IU/mL unless specific imaging criteria are met. The selection process ensures that participants meet non-resectability criteria according to NCCN 1.2015 recommendations and that MRI-guided radiotherapy is feasible. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations. The trial does not include vulnerable populations.

The clinical trial is designed to evaluate the efficacy and tolerability of a sequential chemotherapy regimen followed by **stereotactic MRI-guided radiotherapy** in patients with locally advanced pancreatic adenocarcinoma. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to last until June 2030, with recruitment having commenced in June 2021. Participants will be involved in the study for a maximum treatment period of 16 weeks, with the possibility of early termination if specific conditions arise, such as disease progression or unacceptable toxicity levels.

The trial involves several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of pancreatic adenocarcinoma, and non-resectability status. Following the screening, participants will undergo a series of treatment cycles with **GEMBRAX** and **FOLFIRINOX** chemotherapy regimens. The primary endpoint is the non-progression rate at four months, assessed according to RECIST 1.1 criteria. Secondary endpoints include the tolerance of the chemotherapy sequence and the radiotherapy sequence, as well as progression-free survival and overall survival.

Follow-up visits will be scheduled to monitor the participants' response to treatment and assess any adverse events using the NCI CTC AE v5.0 classification. The end-of-study visit will occur after the completion of the treatment regimen and will include a final assessment of the participant's health status and any long-term effects of the treatment. Participants may be withdrawn from the study if they experience significant adverse effects or if the treating physician deems it necessary for their safety. The trial aims to provide valuable insights into the treatment of locally advanced pancreatic adenocarcinoma, potentially improving patient outcomes through a novel therapeutic approach.

The clinical trial involves the administration of several **chemotherapy** agents, each with specific pharmaceutical forms, dosages, and administration routes. **Abraxane**, containing the active substance **paclitaxel albumin-bound**, is provided as a powder for dispersion for infusion. It is administered via **IV infusion** at a maximum daily dose of 125 mg/m², with a total dose not exceeding 750 mg/m² over a treatment period of 16 weeks. This product is manufactured by Bristol-Myers Squibb Pharma EEIG and is not a pediatric formulation.

**Irinotecan Viatris**, with the active substance **irinotecan hydrochloride trihydrate**, is supplied as a solution for infusion. It is administered through **IV infusion** with a maximum daily dose of 180 mg/m² and a total dose of 720 mg/m² over the same treatment period. This product is produced by Viatris Sante.

**Fluorouracile Accord** is available as a solution for infusion, containing the active substance **fluorouracil**. It can be administered either as an **intravenous bolus injection** or via **IV infusion**. The maximum daily dose is 400 mg/m², with a total dose of 1600 mg/m² over 16 weeks. Accord Healthcare France SAS is the manufacturer.

**Gemcitabine Accord** is provided as a solution for infusion, with **gemcitabine** as the active substance. It is administered via **IV infusion** at a maximum daily dose of 1000 mg/m², with a total dose of 6000 mg/m² over the treatment period. This product is manufactured by Accord Healthcare B.V.

**Oxaliplatine Arrow Lab** is a solution for infusion containing **oxaliplatin**. It is administered through **IV infusion** with a maximum daily dose of 85 mg/m² and a total dose of 340 mg/m² over 16 weeks. Eugia Pharma (Malta) Ltd is responsible for its production.

Another formulation of **Fluorouracile Accord** is also used, with a higher maximum daily dose of 2400 mg/m² and a total dose of 9600 mg/m², administered via **IV infusion**. This product is also manufactured by Accord Healthcare France SAS.

**Levofolinate de Calcium Zentiva**, containing **levoleucovorin**, is provided as a solution for injection, suitable for both **IM and IV** administration. The maximum daily dose is 200 mg/m², with a total dose of 800 mg/m² over the treatment period. Zentiva France is the manufacturer. This agent is categorized under **detoxifiants** and is used to mitigate the toxic effects of chemotherapy.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoints include the non-progression rate at 4 months, evaluated according to RECIST 1.1 criteria, and the rate of RT-related acute digestive non-toxicity within 90 days, assessed by the NCI CTC AE v5.0 classification. Secondary endpoints encompass a range of measures, including the tolerance of the chemotherapy and radiotherapy sequences, progression-free survival, overall survival, and local disease control rate. These will be evaluated using various methods such as dosimetric results, correlation of dose to organs at risk with digestive toxicities, and histological response rate according to the CAP score. Additionally, the prognostic impact of CA 19.9 evolution on survival and the evolution of Quality of Life scores will be assessed using the EORTC QLQ-C30 and PAN 26 questionnaires.