Evaluation of Bevacizumab, Encorafenib, and Cetuximab in BRAF V600E-Mutated Metastatic Colorectal Cancer: A Phase II Study with Safety Lead-In

The primary objective of this study is to evaluate the **antitumor activity** of the combination of encorafenib, cetuximab, and bevacizumab in subjects with BRAF V600E-mutant metastatic colorectal cancer (mCRC) who have progressed after one or two chemotherapeutic regimens. This is clinically relevant as it aims to provide insights into the potential efficacy of this combination therapy in a specific genetic subset of mCRC, which is known for its poor prognosis and limited treatment options.

Secondary objectives include:

• Assessing the **safety** and tolerability of the combination of encorafenib, cetuximab, and bevacizumab.
• Evaluating the **activity** of the combination therapy.
• Assessing the **efficacy** of the treatment regimen.
• Evaluating patient-reported outcome (PRO) measures.

The clinical trial involves participants diagnosed with **metastatic colorectal cancer** who have progressed after one or two prior chemotherapeutic regimens. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on the presence of a BRAF V600E mutation in tumor tissue, confirmed histologically or cytologically, and eligibility to receive cetuximab according to local guidelines regarding tumor RAS status. The trial includes a vulnerable population, although specific lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to evaluate the **antitumor activity** of a combination therapy involving **encorafenib**, **cetuximab**, and **bevacizumab** in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) who have progressed after one or two prior chemotherapeutic regimens. This phase II study includes a safety lead-in cohort to assess the safety and tolerability of the drug combination. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from December 31, 2023, to December 31, 2027, with participant involvement expected to last up to 42 weeks, depending on individual response and tolerance to the treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically- or cytologically-confirmed mCRC, presence of the BRAF V600E mutation, and progression after prior regimens. Following the screening, participants will be randomized to receive the study treatment. Regular follow-up visits will be scheduled to monitor the progression-free survival (PFS) and assess any dose-limiting toxicities (DLTs) during the initial month. Secondary endpoints include the incidence and severity of adverse events (AEs), overall response rate (ORR), time to response, duration of response (DOR), overall survival (OS), and changes in patient-reported outcomes (PROs).

The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be necessitated by factors such as unacceptable toxicity, disease progression, or withdrawal of consent. Participants will be closely monitored for changes in clinical laboratory parameters, vital signs, and electrocardiograms (ECGs) throughout the study. The trial aims to provide comprehensive data on the efficacy and safety of the combination therapy in this specific patient population, contributing valuable insights into the management of metastatic colorectal cancer.

The clinical trial involves the administration of **MVASI**, a **bevacizumab**-based medication, which is provided as a 25 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous use**. The dosing regimen for MVASI is set at a maximum daily dose of 5 mg/kg, with a total maximum dose of 420 mg/kg over a treatment period of 42 days. The administration of MVASI is conducted via intravenous infusion, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

**Braftovi**, containing the active substance **encorafenib**, is administered in the form of 75 mg hard capsules. This medication is taken orally, with a maximum daily dose of 300 mg and a total maximum dose of 378,000 mg over the course of 42 days. Encorafenib acts as a small molecule BRAF inhibitor targeting key enzymes in the MAPK signaling pathway. Compliance with the oral dosing schedule is monitored to ensure accurate adherence to the prescribed regimen.

**Erbitux**, which contains **cetuximab**, is provided as a 5 mg/mL solution for infusion. This medication is administered via **intravenous use**. The dosing schedule allows for a maximum daily dose of 500 mg/m², with a total maximum dose of 42,000 mg/m² over a 42-day treatment period. Cetuximab is a chimeric IgG1 monoclonal antibody produced in a mammalian cell line. The administration of Erbitux is closely monitored to ensure compliance with the infusion protocol.

In this trial, no placebo or comparator treatments are utilized. The focus is on evaluating the antitumor activity and safety of the combination of encorafenib, cetuximab, and bevacizumab in subjects with BRAF V600E-mutant metastatic colorectal cancer. The trial includes a safety lead-in phase to assess the tolerability of the combination therapy. Compliance monitoring is integral to the study to ensure that participants adhere to the prescribed dosing regimens and administration routes.

The efficacy of the combination of **encorafenib**, **cetuximab**, and **bevacizumab** in treating BRAF V600E-mutant metastatic colorectal cancer (mCRC) will be assessed through several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, evaluated by local radiologist or investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. For the safety lead-in phase, the incidence of dose-limiting toxicity (DLTs) during the first month will also be considered a primary endpoint.

Secondary endpoints include the incidence and severity of adverse events (AEs) graded according to the NCI CTCAE v5.0, as well as changes in clinical laboratory parameters, vital signs, and ECGs during treatment and up to 30 days post end-of-treatment (EOT). Additional secondary endpoints are the Overall Response Rate (ORR) per RECIST v1.1, time to response, Duration of Response (DOR), and Overall Survival (OS). Patient-reported outcomes (PROs) will be measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30) and the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C).