Phase II Multicenter Trial of Neoadjuvant Intraperitoneal Irinotecan and Systemic mFOLFOX4-Bevacizumab in Resectable Colorectal Peritoneal Metastases

The primary objective of this study is to evaluate the **feasibility** of administering a combination of intravenous mFOLFOX4-bevacizumab and intraperitoneal irinotecan to patients with colorectal peritoneal metastases, followed by two cycles of intravenous mFOLFOX4 and intraperitoneal irinotecan, prior to undergoing a cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) procedure. This is clinically relevant as it aims to determine the practicality and potential benefits of this treatment regimen in preparing patients for CRS-HIPEC, which is a critical intervention for managing isolated resectable colorectal peritoneal metastases.

The secondary objectives include:

• Assessing the **safety** of the administered treatment.
• Evaluating the **pathological response** after treatment.
• Determining the **radiological response** after treatment.
• Comparing the **superiority** of disease progression assessment using PET-CT versus CT.
• Assessing the **quality of life** of patients undergoing the treatment.
• Evaluating **disease-free survival** following the treatment regimen.

The clinical trial involves **patients with colorectal peritoneal metastases** with a peritoneal cancer index (PCI) score ranging from 1 to 20. The study population includes both male and female participants aged 18 years and older, with a World Health Organization (WHO) performance score of 0 to 1, indicating a relatively good general health status and a life expectancy of at least three months. Participants must have histologically confirmed colorectal carcinoma with pathologically or radiologically confirmed non-appendiceal adenocarcinoma with peritoneal metastases. The trial does not include a vulnerable population, and systemic metastases are absent at enrollment. The sponsor has not provided information regarding the total number of participants. Participants are required to provide written informed consent, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the feasibility of a treatment regimen for patients with colorectal peritoneal metastases. The trial involves the administration of intravenous mFOLFOX4-bevacizumab and intraperitoneal irinotecan, followed by two cycles of intravenous mFOLFOX4 and intraperitoneal irinotecan, prior to a CRS-HIPEC procedure. The trial is set to commence recruitment on October 1, 2024, and is expected to conclude by January 1, 2026. The total duration of the trial for each participant is anticipated to be approximately three months, with the treatment period spanning up to three cycles.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed colorectal carcinoma, a peritoneal cancer index score between 1 and 20, and a WHO performance score of 0 to 1. Following the screening, participants will attend regular follow-up visits to monitor treatment response and assess any adverse events. The primary endpoint is the number of patients able to complete all trial treatments, including at least four cycles of chemotherapy followed by CRS-HIPEC. Secondary endpoints include the measurement of treatment toxicity, pathological response, radiologic response, and quality of life assessments.

The end-of-study visit will evaluate the overall treatment efficacy and safety, with a focus on disease-free survival six months post-CRS-HIPEC. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial aims to provide valuable insights into the treatment regimen's feasibility and its potential to improve outcomes for patients with colorectal peritoneal metastases.

The clinical trial involves the administration of several **experimental medications**. The first medication is **Oxaliplatin Eugia 5 mg/ml**, a concentrate for solution for infusion. It is administered via **intravenous administration**. The maximum daily dose is 85 mg/m², with a total maximum dose of 510 mg/m² over a treatment period of 3 cycles. Oxaliplatin is a platinum-based chemotherapy agent, and its role in the trial is to act as a cytotoxic agent targeting cancer cells.

**Calcium Folinate 10 mg/ml** is another medication used in the trial, available as a solution for injection or infusion. It is also administered intravenously. The maximum daily dose is 200 mg/m², with a total maximum dose of 1200 mg/m² over 3 cycles. Calcium Folinate acts as a chemotherapy-modulating agent, enhancing the efficacy of other chemotherapeutic drugs.

The trial also includes **Fluorouracil Accord 50 mg/ml**, a solution for injection or infusion, administered intravenously. The maximum daily dose is 600 mg/m², with a total maximum dose of 3600 mg/m² over 3 cycles. Fluorouracil is an anti-neoplastic chemotherapy agent, which inhibits cancer cell growth by interfering with DNA synthesis.

**Irinotecanhydrochloridetrihydraat Hikma 20 mg/ml** is used as a concentrate for solution for infusion, administered via **intraperitoneal use**. The maximum daily dose is 180 mg/m², with a total maximum dose of 1080 mg/m² over 3 cycles. Irinotecan is a DNA topoisomerase I inhibitor, which prevents DNA replication in cancer cells, leading to cell death.

Lastly, **Avastin 25 mg/ml** is a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 10 mg/kg, with a total maximum dose of 40 mg/kg over 2 cycles. Avastin is a monoclonal anti-vascular endothelial growth factor antibody, which inhibits angiogenesis, thereby reducing the blood supply to tumors and inhibiting their growth.

Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the treatment protocol. The trial aims to evaluate the feasibility and efficacy of these combined treatments in patients with isolated resectable colorectal peritoneal metastases.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the number of patients able to undergo all trial treatments, which includes a minimum of four cycles of intraperitoneal and systemic chemotherapy, followed by cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Secondary endpoints include the measurement of toxicity during trial treatments, assessed by the number of adverse events (AE), serious adverse events (SAE), and suspected unexpected serious adverse reactions (SUSAR). Pathological response will be evaluated using the MANDARD scoring system and the Tumor Regression Grading System. Radiologic response will be measured by RECIST and PERCIST criteria, comparing contrast-enhanced computed tomography (ceCT) with positron emission tomography/computed tomography (PET/CT).

Additional secondary endpoints involve the comparison of peritoneal cancer index (PCI) scores from diagnostic laparoscopy, CRS-HIPEC, PET-CT, and CT. Quality of life will be assessed using the EQ-5D-5L, QLQ-C30, QLQ-CR29, iMTA productivity cost questionnaire (PCQ), and iMTA medical consumption questionnaire (MCQ) at selected points during the trial. Disease-free survival will be monitored after CRS-HIPEC with a follow-up period of six months. These efficacy parameters will be collected and analyzed at various timepoints throughout the trial to determine the treatment's impact on patients with isolated resectable colorectal peritoneal metastases.