Phase III Randomized Study of Trifluridine/Tipiracil and Bevacizumab Versus Capecitabine and Bevacizumab in Metastatic Colorectal Cancer Unfit for Intensive Therapy

The primary objective of this study is to demonstrate the superiority of **S 95005** (trifluridine/tipiracil) in combination with **bevacizumab** over **capecitabine** in combination with bevacizumab in terms of **progression-free survival (PFS)** based on Investigator assessment. This is evaluated in the first-line treatment of patients with unresectable **metastatic colorectal cancer** who are not candidates for intensive therapy. The clinical relevance of this objective lies in potentially improving the management and outcomes for this patient population by identifying a more effective treatment regimen.

Secondary objectives include confirming the clinical benefit of the treatment through evaluations of **overall survival (OS)**, **overall response rate (ORR)**, **disease control rate (DCR)**, **duration of response (DoR)**, and **time to treatment failure (TTF)**. Additionally, the study aims to compare the safety and impact on quality of life of S 95005 in combination with bevacizumab to capecitabine in combination with bevacizumab. These secondary objectives are crucial for providing a comprehensive understanding of the treatment's efficacy and safety profile, as well as its impact on patients' quality of life.

The clinical trial involves a total of **382 participants** diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a definitive histological confirmation of adenocarcinoma of the colon or rectum, and the availability of RAS status from a local biological assessment. The trial targets individuals who are not candidates for intensive therapy, such as standard full-dose combination chemotherapy with irinotecan or oxaliplatin, or curative resection of metastatic lesions. Participants must not have received previous systemic anticancer therapy for unresectable metastatic colorectal cancer and must have an ECOG performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Adequate organ function is also required. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as an open-label, randomized, phase III study to evaluate the efficacy of **trifluridine/tipiracil** in combination with **bevacizumab** compared to **capecitabine** in combination with bevacizumab for the first-line treatment of patients with metastatic colorectal cancer who are not candidates for intensive therapy. The primary objective is to demonstrate the superiority of the trifluridine/tipiracil and bevacizumab combination in terms of progression-free survival (PFS) based on investigator assessment. Secondary endpoints include overall survival (OS), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), time to treatment failure (TTF), safety and tolerability, and quality of life (QoL).

The trial is expected to run from March 2019 to June 2025. Participants will be randomly assigned to one of the two treatment arms. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have histologically confirmed adenocarcinoma of the colon or rectum, known RAS status, and adequate organ function, among other conditions. Participants are expected to be involved in the study for the duration of the treatment period, which is up to one year, unless they meet criteria for early termination, such as disease progression or unacceptable toxicity.

Study visits are structured to ensure comprehensive monitoring and data collection. The screening visit will involve assessments to confirm eligibility, including histological confirmation and RAS status determination. Follow-up visits will occur at regular intervals to evaluate treatment efficacy and safety through clinical assessments, laboratory tests, and imaging studies. The end-of-study visit will consolidate all data collected and provide a final evaluation of the treatment's impact on the participant's condition. Early termination from the study may occur if a participant experiences significant adverse events, disease progression, or withdraws consent. The trial's design ensures rigorous evaluation of the investigational treatment's potential benefits and risks in the specified patient population.

The clinical trial involves the administration of several treatments, including **Lonsurf** and **Avastin**, as well as a comparator treatment, **Xeloda**. **Lonsurf** is available in two formulations: 20 mg/8.19 mg and 15 mg/6.14 mg film-coated tablets. The active substances in **Lonsurf** are **trifluridine** and **tipiracil hydrochloride**, both of chemical origin. The tablets are administered orally, with a maximum daily dose of 70 mg/m². The treatment period is limited to one cycle, with the dosage adjusted based on the patient's body surface area. **Lonsurf** is manufactured by Les Laboratoires Servier (Suresnes) and is not a paediatric formulation.

**Avastin** is provided as a 25 mg/ml concentrate for solution for infusion, containing the active substance **bevacizumab**, a protein of non-chemical origin. The administration route is intravenous, with a maximum daily dose of 7.5 mg/kg. The treatment period is also limited to one cycle. **Avastin** is produced by Roche Registration GmbH and is not intended for paediatric use.

The comparator treatment, **Xeloda**, is available in two dosages: 150 mg and 500 mg film-coated tablets. The active substance is **capecitabine**, of chemical origin. **Xeloda** is administered orally, with a maximum daily dose of 2500 mg/m², adjusted according to the patient's body surface area. The treatment period is restricted to one cycle. **Xeloda** is manufactured by Cheplapharm Arzneimittel GmbH and is not a paediatric formulation.

The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, as determined by investigator judgment. This endpoint is crucial in evaluating the effectiveness of the treatment regimen involving trifluridine/tipiracil in combination with bevacizumab compared to capecitabine in combination with bevacizumab for patients with metastatic colorectal cancer who are not candidates for intensive therapy. Secondary endpoints include Overall Survival (OS), Overall Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), and Time to Treatment Failure (TTF). Additionally, safety and tolerability will be assessed through the incidence of adverse events, laboratory tests, physical examinations, performance status (ECOG), vital signs, and 12-lead ECG parameters. Quality of Life (QoL) will also be evaluated as part of the secondary endpoints.