Phase IV Multicentre Trial Evaluating Efficacy of HIPEC with Mitomycin-C Post-Surgical Debulking in Peritoneal Metastases of Colorectal Cancer

The primary objective of this multicentre Phase IV clinical trial is to evaluate whether there are differences in **peritoneal recurrence** in patients with peritoneal metastases of colorectal cancer treated with complete surgical resection and chemotherapy, with or without hyperthermic intraoperative chemotherapy (HIPEC) using Mitomycin-C. This is clinically relevant as it aims to determine the efficacy of HIPEC in reducing the risk of cancer recurrence in the peritoneal cavity, which is a significant concern in the management of colorectal cancer metastases.

Secondary objectives include:

• Evaluating differences in overall recurrence at any location between the two groups, focusing on Disease-Free Survival.
• Assessing the toxicity of the treatments and comparing postoperative complications between the groups.
• Determining prognostic factors for peritoneal and other levels of recurrence.
• Comparing Overall Survival between the groups.
• Studying Quality of Life in both groups using the EORTC QLQ-C30 and QLQ-CR29 questionnaires.
• Investigating the correlation between surgical and pathological Peritoneal Cancer Index (PCI), comparing their respective prognostic values.

The clinical trial focuses on patients with **peritoneal metastases of colorectal cancer**. The study population includes both male and female participants, aged 18 years and older, who are not considered part of a vulnerable population. Participants are required to have histologically proven colon cancer, excluding those with a significant presence of signet ring cells. The trial excludes individuals with current or previously treated extraperitoneal metastases, such as distant adenopathies, liver, or pulmonary metastases. Eligible participants must have synchronous or metachronous peritoneal carcinomatosis of mild or moderate extension, with a Peritoneal Cancer Index (PCI) of 20 or less, and must achieve a macroscopically complete surgical cytoreduction (CCS-0). Additionally, participants should have undergone perioperative systemic chemotherapy and possess an acceptable anesthetic/surgical risk, classified as ASA 1-3 and ECOG 0-1, with stable hematological, renal, and hepatic function. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **Phase IV** study designed to evaluate the efficacy of hyperthermic intraoperative chemotherapy (HIPEC) with **Mitomycin-C** following complete surgical debulking in patients with peritoneal metastases of colorectal cancer. The trial employs a randomized, controlled design to compare outcomes between two groups: one receiving HIPEC with Mitomycin-C and the other not receiving HIPEC. The primary objective is to assess differences in peritoneal recurrence in these patients. The trial is expected to run until January 2027, with recruitment having commenced in February 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven colon cancer, absence of extraperitoneal metastases, and acceptable anesthetic/surgical risk. Following the screening, eligible participants will be randomized into one of the two study groups. The trial includes follow-up visits at 1, 2, and 3 years to evaluate primary and secondary endpoints, including peritoneal recurrence-free survival, overall recurrence, and quality of life assessments using the EORTC QLQ-C30 and QLQ-CR29 questionnaires. The end-of-study visit will occur at the conclusion of the 3-year follow-up period.

Participant involvement is expected to last for the duration of the study, approximately five years, including follow-up. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The study aims to provide valuable insights into the efficacy of HIPEC with Mitomycin-C in improving outcomes for patients with peritoneal metastases of colorectal cancer.

The clinical trial involves the use of **Mitomycin**, marketed under the name Mitomicina Accord 40 mg polvo para solución inyectable y para perfusión EFG. This experimental medication is a chemotherapeutic agent formulated as a **solution for injection/infusion**. The active substance, **mitomycin**, is of chemical origin. The pharmaceutical form is a powder intended for reconstitution into a solution for injection or infusion. The medication is administered via **intraperitoneal use**. The maximum daily and total dose is 40 mg, with a treatment period limited to one day. The product is manufactured by Accord Healthcare S.L.U. and is not a pediatric formulation.

In this trial, the experimental treatment is compared against a standard-of-care therapy, which involves complete surgical resection and chemotherapy (QTS) without the addition of hyperthermic intraoperative chemotherapy (HIPEC) with Mitomycin-C. This comparator group serves as the control to evaluate the efficacy of the experimental treatment in reducing peritoneal recurrence in patients with peritoneal metastases of colon cancer. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **peritoneal recurrence-free survival** at 1, 2, and 3 years. Secondary endpoints include overall recurrence at the same time intervals, locoregional and distant recurrence, and overall survival. Postoperative complications will be assessed using the CTCAE v5.0 90-day adverse event classification system, with particular attention to those related to hyperthermic intraoperative chemotherapy (HIPEC). Prognostic factors for peritoneal and global recurrence will also be analyzed, including synchronous/metachronous peritoneal metastases, perioperative chemotherapy, use of biological agents or immunotherapy, stratified peritoneal cancer index (PCI), postoperative complications, tumor location, degree of differentiation, and genetic markers such as RAS/RAF status and microsatellite instability.

Quality of life will be evaluated using the EORTC QLQ-C30 and QLQ-CR29 questionnaires at the specified time points. The correlation between surgical PCI and pathological PCI will also be studied. Data collection will occur at 1, 2, and 3 years post-treatment, with the use of validated scales and questionnaires to ensure accurate and reliable measurement of outcomes. The trial aims to determine differences in peritoneal recurrence in patients with colon cancer peritoneal metastases treated with complete surgical resection and chemotherapy, with or without HIPEC with Mitomycin-C.