Phase 3 Randomized Study of Adagrasib and Cetuximab Versus Chemotherapy in Advanced Colorectal Cancer with KRAS G12C Mutation Post-First-Line Therapy

The primary objective of this study is to compare the **efficacy** of **adagrasib** in combination with **cetuximab** versus chemotherapy (FOLFIRI or mFOLFOX6) in the second-line treatment setting for patients with advanced colorectal cancer (CRC) harboring the **KRAS G12C mutation**. This objective is clinically relevant as it aims to determine the potential superiority of a targeted therapy combination over standard chemotherapy, which could lead to improved treatment outcomes for this specific patient population.

Secondary objectives include:

• Evaluating secondary efficacy endpoints in the study population.
• Assessing the **safety** and tolerability of the treatment regimen.
• Investigating the **pharmacokinetics** (PK) of adagrasib when administered with cetuximab.
• Evaluating health-related quality of life (HRQOL) and cancer-related symptoms in the study population.

The clinical trial involves a total of **378 participants** diagnosed with **Advanced Colorectal Cancer with KRAS G12C Mutation**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on a histologically confirmed diagnosis of colorectal carcinoma with a KRAS G12C mutation in tumor tissue. All participants have previously received first-line treatment for advanced colorectal cancer with a fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan, and have shown radiographically documented progression of disease on or after treatment. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of all participants.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of **adagrasib** in combination with **cetuximab** compared to chemotherapy in patients with advanced colorectal cancer with KRAS G12C mutation. The trial aims to assess overall survival and progression-free survival as primary endpoints, with secondary endpoints including adverse events, objective response rate, duration of response, patient-reported outcomes, and quality of life assessment. The trial is expected to run from its start date on December 17, 2021, to its estimated end date on May 25, 2025, with recruitment having commenced on March 15, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of colorectal carcinoma with a G12C mutation and prior receipt of first-line treatment. Follow-up visits will be scheduled to monitor treatment response and safety, with the end-of-study visit marking the conclusion of the participant's involvement. The expected length of participant involvement is up to 48 weeks, with conditions for early termination including significant adverse events or disease progression.

The trial involves the administration of investigational products, including **aflibercept**, **bevacizumab**, **ramucirumab**, **fluorouracil**, **oxaliplatin**, and **irinotecan**, primarily through intravenous use, except for **adagrasib**, which is administered orally. The maximum treatment period for each participant is 48 weeks, with specific dosing regimens tailored to each product. The trial is conducted under strict regulatory oversight to ensure participant safety and data integrity.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Aflibercept** is utilized in the trial as a **concentrate for solution for infusion**. It is administered via **intravenous use** with a maximum daily dose of 4 mg/ml and a total dose of 384 mg/ml over a treatment period of 48 weeks. The active substance is a protein of other origin, and it is classified as a biological medicinal product.

**Bevacizumab** is another biological agent used in the trial, also in the form of a **concentrate for solution for infusion**. It is administered intravenously with a maximum daily dose of 5 mg/kg and a total dose of 480 mg/kg over 48 weeks. The active substance is a protein of other origin.

**Ramucirumab** is included in the trial as a **concentrate for solution for infusion**, administered intravenously. The maximum daily dose is 8 mg/ml, with a total dose of 769 mg/ml over the treatment period. It is classified as a biological product, with the active substance origin unspecified.

**Adagrasib** is administered as a **film-coated tablet** for oral use. The maximum daily dose is 1200 mg, with a total dose of 1,710,000 mg over 48 weeks. It is a chemical entity, and the active substance is of chemical origin.

**Fluorouracil** is used as a **solution for injection**, administered intravenously. The maximum daily dose is 2800 mg/m², with a total dose of 268,800 mg/m² over the treatment period. It is classified as a chemical entity.

**Cetuximab**, marketed as Erbitux 5 mg/mL solution for infusion, is administered intravenously. The maximum daily dose is 500 mg/m², with a total dose of 48,000 mg/m² over 48 weeks. It is a biological product, with the active substance being a protein of other origin.

**Calcium folinate** is administered as a **solution for injection** via intravenous use. The maximum daily dose is 400 mg/m², with a total dose of 38,400 mg/m² over the treatment period. It is classified as a chemical entity.

**Oxaliplatin** is used as a **concentrate for solution for infusion**, administered intravenously. The maximum daily dose is 85 mg/ml, with a total dose of 8160 mg/ml over 48 weeks. It is a chemical entity.

**Irinotecan** is administered as a **concentrate for solution for infusion** via intravenous use. The maximum daily dose is 180 mg/m², with a total dose of 17,280 mg/m² over the treatment period. It is classified as a chemical entity.

Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules. The trial aims to compare the efficacy of these treatments in patients with advanced colorectal cancer with KRAS G12C mutation, following disease progression on or after standard first-line therapy.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include **Overall Survival (OS)** and **Progression-free Survival (PFS)**. These endpoints are critical in evaluating the effectiveness of the treatment regimen in patients with advanced colorectal cancer harboring the KRAS G12C mutation. Secondary endpoints will encompass a range of measures including Adverse Events, Objective Response Rate (ORR), Duration of Response (DOR), Patient Reported Outcomes (PROs), and Quality of Life Assessment. These secondary endpoints provide additional insights into the treatment's impact on patient health and well-being.

The trial is designed to compare the efficacy of adagrasib in combination with cetuximab versus chemotherapy (FOLFIRI or mFOLFOX6) in a second-line treatment setting. The trial will involve patients who have previously received a fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan and have shown disease progression. The trial's estimated end date is May 25, 2025, with recruitment having started on March 15, 2021. The trial is categorized as a phase 3 study, and the publication of data and documents is deferred for five years post-trial to protect commercially sensitive information.