Standard versus Prolonged Neoadjuvant (Conversion) Chemotherapy to prolong survival of patients with Borderline and Locally Advanced Pancreatic Cancer: a phase III randomized controlled trial; ADVANTAGE

The primary objective of this study is to evaluate the optimal duration of preoperative **chemotherapy** before conversion surgery in patients with borderline and locally advanced pancreatic ductal adenocarcinoma, with the aim of improving survival outcomes. This is clinically relevant as determining the most effective chemotherapy duration could enhance treatment efficacy and potentially increase survival rates in patients with advanced pancreatic cancer.

Secondary objectives include:

• Assessing overall survival in intention-to-treat and per protocol treated groups.
• Evaluating progression-free survival.
• Determining overall survival among non-resected patients at 24 months.
• Comparing overall survival among patients with borderline resectable (BR) and locally advanced pancreatic cancer (LAPC) in both treatment arms in intention-to-treat analysis.
• Analyzing overall and progression-free survival among resected patients with BR and LAPC in both treatment arms.
• Investigating differences in overall and progression-free survival between BR and LAPC patients in intention-to-treat analysis among all treated and resected patients.
• Measuring resection rate and dose intensity.
• Monitoring toxicity levels.
• Evaluating chemotherapy start-rate and completion rate.
• Assessing surgical complications within 90 days using Clavien-Dindo and ISGPS classifications.
• Evaluating quality of life using EORTC QLQ-PAN26 and PACADI questionnaires.
• Measuring biochemical response through CA19-9, CEA, and CA125 levels.
• Assessing histopathologic response using the CAP system.
• Determining N0 resection rate.

The clinical trial involves participants diagnosed with **advanced pancreatic cancer**, specifically focusing on borderline and locally advanced pancreatic ductal adenocarcinoma. The study population includes both male and female subjects aged 18 years and older, who are in good general health as indicated by an ECOG performance status of 0-1, making them fit for the planned chemotherapy and surgery. The trial does not include vulnerable populations. Participants were selected based on histo- or cytologically confirmed adenocarcinoma, with a classification of T1-4, Nx, M0 according to the AJCC 8th edition. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the optimal duration of preoperative chemotherapy for patients with **advanced pancreatic cancer**, specifically those with borderline and locally advanced pancreatic ductal adenocarcinoma. This is a phase III randomized controlled trial, employing a double-blind methodology to ensure unbiased results. The trial aims to assess the impact of standard versus prolonged neoadjuvant chemotherapy on patient survival. The study is expected to run until December 31, 2032, with recruitment having commenced on January 2, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma, age of at least 18 years, and an ECOG performance status of 0-1. Following successful screening, participants will be randomized to receive either standard or prolonged chemotherapy regimens. The chemotherapy agents involved include **oxaliplatin**, **paclitaxel**, **fluorouracil**, **irinotecan hydrochloride trihydrate**, **gemcitabine**, and **calcium folinate**, all administered via intravenous infusion.

Study visits will include regular follow-up assessments to monitor treatment response and adverse events. The primary endpoint is overall survival at 24 months post-randomization, with secondary endpoints including progression-free survival and overall survival in various subgroups. The expected length of participant involvement is up to 24 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent by the participant.

The clinical trial involves the administration of several **experimental medications**. **Oxaliplatin** is provided as a 5 mg/ml concentrate for solution for infusion, manufactured by Hospira UK Ltd. It is administered via **intravenous infusion** with a maximum daily dose of 85 mg/m² and a total dose not exceeding 1020 mg/m² over a treatment period of up to 12 weeks. The pharmaceutical form is a solution for infusion, and the active substance is of chemical origin.

**Paclitaxel** is another experimental medication used in the trial, available as a 6 mg/ml concentrate for solution for infusion, also produced by Hospira UK Ltd. It is administered intravenously with a maximum daily dose of 125 mg/m² and a total dose of 2250 mg/m² over a 24-week period. The pharmaceutical form is a solution for infusion, and the active substance is chemically derived.

**Fluorouracil** is provided as a 50 mg/ml solution for injection, manufactured by Hospira UK Ltd. It is administered via intravenous infusion with a maximum daily dose of 1200 mg/m² and a total dose of 28800 mg/m² over a 24-week period. The active substance is of chemical origin.

**Irinotecan Hydrochloride Trihydrate** is available as a 20 mg/ml concentrate for solution for infusion, produced by Hospira UK Ltd. It is administered intravenously with a maximum daily dose of 150 mg/m² and a total dose of 1800 mg/m² over a 24-week period. The pharmaceutical form is a solution for infusion, and the active substance is chemically derived.

**Gemcitabine** is provided as a 100 mg/ml concentrate for solution for infusion, manufactured by Accord Healthcare B.V. It is administered via intravenous infusion with a maximum daily dose of 1000 mg/m² and a total dose of 18000 mg/m² over a 24-week period. The pharmaceutical form is a solution for infusion, and the active substance is of chemical origin.

**Calcium Folinate** is available as a 10 mg/ml solution for injection, produced by STADA Arzneimittel AG. It is administered intravenously with a maximum daily dose of 400 mg/m² and a total dose of 4800 mg/m² over a 24-week period. The active substance is chemically derived.

All medications are administered via intravenous infusion, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of these experimental medications in the treatment of borderline and locally advanced pancreatic cancer.

Efficacy in this clinical trial will be assessed primarily through the measurement of overall survival at 24 months after randomization. This endpoint will be evaluated for all patients, as well as specifically among those who have undergone resection. Secondary endpoints include overall survival in intention-to-treat and per protocol treated groups, progression-free survival, and overall survival among non-resected patients at 24 months. Additionally, the trial will assess overall and progression-free survival among patients with borderline resectable (BR) and locally advanced pancreatic cancer (LAPC) in both treatment arms, as well as differences in survival outcomes between BR and LAPC patients.

The trial is designed to determine the optimal duration of preoperative chemotherapy before conversion surgery in patients with borderline and locally advanced pancreatic ductal **adenocarcinoma**. The study will utilize a randomized controlled trial format to compare standard versus prolonged neoadjuvant chemotherapy regimens. The trial's main objective is to improve survival outcomes for these patients. The trial is expected to conclude by December 31, 2032, with recruitment having started on January 2, 2023.