Evaluation of Systemic Chemotherapy and Targeted Therapy with or without PIPAC in Advanced Colorectal Peritoneal Metastases: A Phase II Randomized Trial

The primary objective of this multicenter phase II randomized trial is to evaluate an improvement in **progression-free survival (PFS)** between two groups of patients with advanced colon cancer and peritoneal metastases (Peritoneal Cancer Index >15). One group receives a combination of systemic treatments, including chemotherapy and targeted therapy, along with pressurized intraperitoneal aerosol chemotherapy (PIPAC), while the other group receives systemic treatment alone. This objective is clinically relevant as it aims to determine the efficacy of adding PIPAC to standard systemic therapy in extending the time patients remain free from disease progression.

Secondary objectives include:

• Overall survival (OS)
• Impact on quality of life
• Tolerance
• Conversion rate to resectability
• Peritoneal progression-free survival (PPFS)
• Obstruction-free survival (OFS)
• Histological tumor response
• Impact of baseline Peritoneal Cancer Index (PCI) on PFS in both arms
• PIPAC arm: Impact on PFS according to initial extent of peritoneal metastases (assessed by PCI score)
• Evaluate the prognostic value of the best histological result obtained at the 2nd PIPAC (for biopsies performed at the second PIPAC)
• Relationship between mutational status and PFS in both groups

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on survival, quality of life, and other clinical outcomes, which are crucial for optimizing therapeutic strategies for patients with colorectal cancer and peritoneal metastases.

The clinical trial involves **patients with newly diagnosed advanced peritoneal metastasis from colorectal cancer**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a histopathologically confirmed diagnosis of colonic adenocarcinoma with synchronous or metachronous peritoneal metastasis. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are fully active or capable of self-care. The trial population was selected based on specific inclusion criteria, such as having unresectable peritoneal metastasis defined by a peritoneal cancer index (PCI) greater than 15, and no known risk of irinotecan toxicity. Participants must also have adequate organ function, as indicated by specific laboratory values, and must not have extended intraperitoneal adhesions. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information on the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of systemic antitumor treatment with or without **pressurized intraperitoneal aerosol chemotherapy (PIPAC)** in patients with advanced peritoneal metastasis from colorectal cancer. This is a multicenter, phase II, randomized, double-blind, controlled trial. The primary objective is to assess improvement in progression-free survival (PFS) between the group receiving systemic treatments combined with PIPAC and the group receiving systemic treatment alone. The trial is expected to commence recruitment in October 2024 and conclude by October 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and medical history. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or withdrawal. The expected duration of participant involvement is up to 12 months, depending on the treatment arm and individual response.

Participants may be withdrawn from the study early due to reasons such as significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will utilize a combination of oral and intravenous administration of chemotherapeutic agents, including **capecitabine**, **panitumumab**, **bevacizumab**, **fluorouracil**, **irinotecan hydrochloride trihydrate**, **cetuximab**, and **oxaliplatin**. The study will adhere to rigorous ethical standards, ensuring informed consent and compliance with regulatory requirements throughout the trial duration.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Capecitabine**, marketed as CAPECITABINE VIATRIS 150 mg, is provided in the form of a film-coated tablet. The active substance, capecitabine, is administered orally with a maximum daily dose of 625 mg/m². The treatment period for capecitabine is up to 6 months.

**Panitumumab**, under the brand name Vectibix, is a 20 mg/ml concentrate for solution for infusion. This protein-based targeted therapy is administered intravenously with a maximum daily dose of 6 mg/kg. The treatment duration is set for 6 months.

**Bevacizumab**, marketed as Abevmy 25 mg/mL, is also a concentrate for solution for infusion. This protein-based targeted therapy is administered intravenously with a maximum daily dose of 5 mg/kg, and the treatment period extends to 12 months.

**Fluorouracil** is provided as a 25 mg/ml solution for injection or infusion. This chemical-based antineoplastic agent is administered intravenously with a maximum daily dose of 2400 mg/m², and the treatment duration is up to 12 months.

**Irinotecan Hydrochloride Trihydrate**, marketed as IRINOTECAN VIATRIS 20 mg/ml, is a solution for infusion. This chemical-based targeted therapy is administered intravenously with a maximum daily dose of 180 mg/m², and the treatment period is up to 22 weeks.

**Cetuximab**, under the brand name Erbitux 5 mg/mL, is a solution for infusion. This protein-based targeted therapy is administered intravenously with a maximum daily dose of 400 mg/m², and the treatment duration is set for 6 months.

**Oxaliplatin**, marketed as OXALIPLATINE ARROW LAB 5 mg/mL, is a solution for infusion. This chemical-based antineoplastic agent is administered intraperitoneally using a pressurized intraperitoneal aerosol chemotherapy (PIPAC) method with a maximum daily dose of 90 mg/m². The treatment period is up to 4 weeks, and the administration involves the use of the Capnopen CP-001k device, an endoscopic nebulizer for medical delivery of therapeutic substances.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to evaluate the improvement in progression-free survival in patients with peritoneal metastases in advanced colon cancer, comparing systemic treatments with and without the addition of PIPAC.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression Free Survival (PFS)**. PFS is defined as the time in months from randomization until the date of disease progression or death from any cause. This primary endpoint will provide a direct measure of the treatment's impact on delaying disease progression in patients with peritoneal metastases from advanced colon cancer.

Secondary endpoints will include **Overall Survival (OS)**, which is the time elapsed between randomization and death from any cause, and patient-reported outcomes using the EORTC QLQ-C30 and EORTC QLQ-CR29 questionnaires. Additionally, the trial will assess toxicities related to chemotherapy, targeted therapy, and abdominal surgery using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and the CLAVIEN DINDO score. Other secondary endpoints include the resection rate, peritoneal progression-free survival, and the Peritoneal Regression Grading Score (PRGS) on biopsies.

The trial will also evaluate the PFS benefit of adding pressurized intraperitoneal aerosol chemotherapy (PIPAC) to systemic chemotherapy, with specific attention to baseline Peritoneal Cancer Index (PCI) scores. The efficacy assessments will be conducted at various time points throughout the trial, including during surgical explorations and PIPAC procedures, to ensure comprehensive data collection and analysis.