Phase II Randomized Study of 5-Fluorouracil/Leucovorin, Irinotecan, Gemcitabine, and Paclitaxel in Metastatic Pancreatic Cancer

The primary objective of this randomized phase II study is to compare the **progression-free survival** at 6 months among different treatment arms in patients with **metastatic pancreatic cancer**. The experimental arms include Arm A, which involves a sequential regimen of Nal-Iri plus 5FU/LV followed by Nab-Paclitaxel plus Gemcitabine, and Arm B, which consists of Nal-Iri plus 5FU/LV. These are compared against the reference Arm C, which includes Nab-Paclitaxel plus Gemcitabine. The comparison is conducted according to the RECIST 1.1 criteria. This objective is clinically relevant as it aims to identify the most effective treatment regimen for extending progression-free survival in this patient population.

Secondary objectives include: - Progression-free survival at 6 months according to central review - Best objective response rate - Depth of response - Early tumor shrinkage - Progression-free survival according to the investigator and central review - Overall survival - Time to treatment failure - Safety - Quality of life assessed by the EORTC QLQ-C30 - Monitoring of CA 19-9 and CEA levels.

The clinical trial involves participants diagnosed with **metastatic pancreatic cancer**. The study population includes both male and female subjects, with an age range of 18 to 75 years. Participants are required to have a normal ECG or one without clinically significant findings, and they must be able to understand and sign an informed consent. Females of child-bearing potential must test negative for pregnancy at enrollment, and all participants of reproductive potential must agree to use reliable birth control during the study and for seven months after the last dose of the study drug. The trial does not include a vulnerable population. Participants must have a life expectancy greater than 12 weeks and a WHO performance status of less than 2. They should not have received prior chemotherapy, except for specific adjuvant treatments that ended at least 12 months before inclusion. Pain must be well controlled before inclusion, and participants must meet specific hematological and hepatic function criteria. The sponsor has not provided information on the total number of participants in the trial.

The clinical trial is designed as a **randomized**, phase II study to evaluate the efficacy of different treatment regimens in patients with **metastatic pancreatic cancer**. The trial involves three arms: Arm A, which includes a sequential regimen of Nal-Iri plus 5FU/LV followed by Nab-Paclitaxel plus Gemcitabine; Arm B, which consists of Nal-Iri plus 5FU/LV; and Arm C, which serves as the reference arm with Nab-Paclitaxel plus Gemcitabine. The primary objective is to compare the progression-free survival at six months across these arms, utilizing the RECIST 1.1 criteria. The trial is double-blind and controlled, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias.

The trial is expected to last until December 2026, with participant recruitment having commenced in November 2018. Participants will be involved in the study for a maximum treatment period of 12 months. The study includes several key visits: an initial **screening** visit to confirm eligibility based on criteria such as histopathologically confirmed pancreatic adenocarcinoma, adequate organ function, and performance status. Follow-up visits will occur regularly to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the final outcomes, including survival and quality of life, using the EORTC QLQ-C30 questionnaire.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. Additionally, any significant protocol deviations or non-compliance may lead to early termination from the study. The trial's primary endpoint is the rate of patients alive without progression at six months post-inclusion. Secondary endpoints include best objective response, overall survival, and safety, with toxicities evaluated according to NCI-CTC v4.0. The trial aims to provide valuable insights into the optimal treatment strategy for metastatic pancreatic cancer, potentially improving patient outcomes.

The clinical trial involves the administration of several **experimental medications** and comparator treatments for the management of metastatic pancreatic cancer. **Folinic Acid** is utilized in the study as a **solution for injection/infusion**. It is administered via **intravenous infusion** with a maximum daily dose of 400 mg/m² and a total dose not exceeding 800 mg/m² over a treatment period of up to 12 months. Folinic Acid acts as a metabolite and is not a pediatric formulation.

**Onivyde pegylated liposomal 4.3 mg/ml concentrate for dispersion for infusion** contains the active substance **Irinotecan**. This formulation is administered through **intravenous infusion**. The maximum daily dose is 70 mg/m², with a total dose limit of 840 mg/m² over a 12-month period. Onivyde is classified as an antineoplastic agent and is not intended for pediatric use.

**Paclitaxel**, also known by synonyms such as Oncogel and ABI-007, is provided in a pharmaceutical form coded as PHF00230MIG. It is administered via **intravenous infusion** with a maximum daily dose of 125 mg/m² and a total dose cap of 4500 mg/m² over 12 months. Paclitaxel is categorized as an antineoplastic agent and is not formulated for pediatric patients.

**Fluorouracil** is supplied as a **concentrate for solution for injection/infusion** and is administered through **intravenous administration**. The maximum daily dose is 2400 mg/m², with a total dose limit of 4800 mg/m² over a 12-month treatment period. Fluorouracil functions as an antineoplastic agent and is not a pediatric formulation.

**Gemcitabine** is provided as a **powder for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 1000 mg/m², with a total dose limit of 36000 mg/m² over a 12-month period. Gemcitabine is classified as an antimetabolite and is not intended for pediatric use.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The study aims to compare the efficacy of these treatments in terms of progression-free survival at 6 months, following the RECIST 1.1 criteria.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the rate of patients alive without progression at 6 months after inclusion, evaluated according to the RECIST 1.1 criteria. Secondary endpoints include Best Objective Response (BOR), which is defined as the complete or partial response rate according to scans and RECIST v1.1 criteria over the entire treatment period. Progression Free Survival (PFS) will be measured as the time between the date of randomization and the date of the first radiological and/or clinical progression or the date of death. Overall Survival (OS) is defined as the time between the date of randomization and the date of death from any cause.

Additional secondary endpoints include the Depth of Response, which is the relative difference between the sum of the largest diameters of target lesions in the NADIR and at inclusion, and Early Tumor Shrinkage, defined as a relative difference of more than 20% in the sum of the largest diameters of target lesions at 8 weeks compared to inclusion. Time to Treatment Failure is the time between randomization and discontinuation of all protocol treatments or the date of last news for patients alive under treatment. Safety will be evaluated according to NCI-CTC v4.0, and Quality of Life will be assessed using the EORTC QLQ-C30 questionnaire. The evolution of **tumoral markers** will be analyzed graphically at each time point, showing the percentage change from baseline.