Evaluation of Perioperative Systemic Therapy with Bevacizumab, Folinic Acid, Oxaliplatin, Capecitabine, Fluorouracil, and Irinotecan in Resectable Colorectal Peritoneal Metastases

The primary objectives of this study are twofold. In the **phase II** component, the study aims to explore the feasibility of accrual, as well as the feasibility, safety, and tolerance of perioperative systemic therapy in patients with resectable peritoneal metastases of colorectal origin. This is clinically relevant as it assesses the practicality and patient tolerance of integrating systemic therapy into the perioperative setting, which could potentially enhance treatment outcomes. In the **phase III** component, the primary objective is to compare overall survival between two treatment arms: perioperative systemic therapy combined with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) versus upfront cytoreductive surgery with HIPEC alone. This comparison is crucial for determining the most effective treatment strategy to improve survival outcomes in this patient population.

The clinical trial involves participants diagnosed with **resectable peritoneal metastases of a colorectal origin**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are required to have a World Health Organisation (WHO) performance status of 1 or less, indicating they are ambulatory and capable of self-care. The trial does not include vulnerable populations. The sponsor has not provided the total number of participants. Selection criteria emphasize the absence of systemic colorectal metastases and no prior systemic therapy for colorectal cancer within six months before enrollment. Participants must not have contraindications for CRS-HIPEC or concurrent malignancies that could interfere with the study treatment. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of perioperative systemic therapy combined with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) compared to cytoreductive surgery with HIPEC alone in patients with **resectable peritoneal metastases of colorectal origin**. This study is a multicenter, open-label, parallel-group, phase II-III, randomized, superiority trial. The trial aims to explore the feasibility of accrual, as well as the feasibility, safety, and tolerance of the perioperative systemic therapy in the phase II component, while the phase III component focuses on comparing overall survival between the two treatment arms. The estimated duration of the trial is from June 15, 2017, to June 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as a World Health Organization performance status of ≤1, histological or cytological confirmation of peritoneal metastases, and resectable disease as determined by diagnostic imaging. Follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. The end-of-study visit will evaluate the overall outcomes and survival data. The expected length of participant involvement is up to 12 months, with conditions for early termination including the development of systemic metastases, contraindications for the planned treatment, or the occurrence of concurrent malignancies that interfere with the study protocol.

The trial employs a randomized, open-label design, ensuring that participants are randomly assigned to one of the two treatment arms. The study drugs include **bevacizumab**, **folinic acid**, **oxaliplatin**, **capecitabine**, **fluorouracil**, and **irinotecan hydrochloride trihydrate**, administered either intravenously or orally, depending on the specific medication. The maximum treatment period for each participant is 12 months, with specific dosing regimens tailored to each drug's pharmacological profile. The primary endpoint is to determine the difference in overall survival between the treatment groups, calculated from the diagnosis of peritoneal metastases until death or last follow-up.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Avastin** (bevacizumab) is provided as a 25 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 7.5 mg/kg and a maximum total dose of 22.5 mg/kg over a treatment period of 12 months. This medication is classified as a targeted therapy and is produced by Roche Registration GmbH.

**Leucovorin-Teva** (folinic acid) is available as a 10 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 400 mg/m² and a maximum total dose of 2400 mg/m² over a 12-month period. This cytotoxic chemotherapeutic drug is manufactured by Teva Pharma B.V.

**Oxaliplatin Eugia** is provided as a 5 mg/ml concentrate for solution for infusion. The administration is intravenous, with a maximum daily dose of 130 mg/m² and a maximum total dose of 520 mg/m² over 12 months. This medication is a cytotoxic chemotherapeutic drug produced by Eugia Pharma (Malta) Ltd.

**Xeloda** (capecitabine) is available in the form of 150 mg film-coated tablets. It is administered orally with a maximum daily dose of 2000 mg/m² and a maximum total dose of 8000 mg/m² over a 12-month period. This cytotoxic chemotherapeutic drug is produced by Cheplapharm Arzneimittel GmbH.

**5-Fluorouracil Sandoz** is provided as a 50 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 2800 mg/m² and a maximum total dose of 16800 mg/m² over a 12-month period. This cytotoxic chemotherapeutic drug is manufactured by Sandoz Hungária Kft.

**IRINOTECAN MYLAN GENERICS** (irinotecan hydrochloride trihydrate) is available as a 20 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 180 mg/m² and a maximum total dose of 1080 mg/m² over a 12-month period. This cytotoxic chemotherapeutic drug is produced by Mylan S.p.A.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial aims to evaluate the feasibility, safety, and tolerance of these treatments in the context of perioperative systemic therapy for resectable colorectal peritoneal metastases.

The efficacy of the clinical trial will be assessed primarily by comparing **overall survival** between the two treatment arms. This endpoint is defined as the time from the diagnosis of peritoneal metastases until death or the last follow-up. The trial is structured as a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study, focusing on patients with resectable colorectal peritoneal metastases. The primary objective of the phase III study is to evaluate the difference in overall survival between the treatment groups.

The trial will involve the administration of various medicinal products, including **bevacizumab**, **folinic acid**, **oxaliplatin**, **capecitabine**, **fluorouracil**, and **irinotecan hydrochloride trihydrate**. These products will be administered either intravenously or orally, depending on their pharmaceutical form. The maximum treatment period for each product is 12 months. The study will explore the feasibility, safety, and tolerance of perioperative systemic therapy in the phase II component, while the phase III component will focus on the primary endpoint of overall survival.