Phase II Evaluation of 5-Fluorouracil, Panitumumab, and Sotorasib in First-Line Treatment of Advanced KRAS G12C Mutated Colorectal Adenocarcinoma

The primary objective of this study is to evaluate the **progression-free survival** (PFS) at 8 months in patients with advanced unresectable KRAS G12C mutated colorectal adenocarcinoma who are not eligible for doublet/triplet chemotherapy. This is clinically relevant as it aims to determine the efficacy of a combination treatment involving 5-fluorouracil, Panitumumab (an anti-EGFR agent), and Sotorasib (a KRAS G12C inhibitor) in extending the time patients live without disease progression, which is crucial for improving patient outcomes in this specific population.

The secondary objectives include:

• Median progression-free survival (PFS)
• Disease control rate (DCR)
• Time to progression (TTP)
• Overall survival (OS)
• Best objective response rate (ORR)
• Duration of response (DoR)
• Safety profile
• Quality of life (QoL) and FACIT-GP5 questionnaires
• Geriatric assessment (G8 and Geriatric COre Data sEt (G-CODE))

The clinical trial focuses on patients with **colorectal cancer**, specifically those with advanced unresectable KRAS G12C mutated colorectal adenocarcinoma. The study population includes both male and female participants aged 18 years and older. Participants are required to have a life expectancy greater than six months and must provide written informed consent. The trial does not include a vulnerable population. Participants must have histologically proven advanced-stage unresectable locally advanced or metastatic colorectal adenocarcinoma and must be unfit for doublet/triplet chemotherapy regimens. This includes frail patients with a WHO performance status of 2, patients aged between 70 and 75 years with a WHO performance status of 1 to 2, and patients aged 75 years or older with a WHO performance status of 0 to 2. The trial requires participants to have a proven KRAS G12C mutation, measurable lesions according to RECIST 1.1 criteria, and adequate organ function. Prior adjuvant chemotherapy is allowed, but no prior treatment for metastatic disease is permitted. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **single-arm phase II study** to evaluate the efficacy of a combination therapy involving **5-fluorouracil**, **panitumumab**, and **sotorasib** in patients with advanced unresectable **KRAS G12C mutated colorectal adenocarcinoma**. The trial aims to assess progression-free survival at 8 months in patients who are not eligible for doublet or triplet chemotherapy regimens. The study is expected to commence recruitment on September 1, 2025, and conclude by September 3, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, life expectancy, and specific medical conditions. The inclusion criteria require participants to be 18 years or older, with a life expectancy greater than 6 months, and a histologically confirmed diagnosis of advanced-stage colorectal adenocarcinoma with a **KRAS G12C mutation**. Adequate organ function and agreement to participate in biological studies are also necessary. The trial excludes any prior treatment for metastatic disease, although prior adjuvant chemotherapy is permitted.

Following the screening, participants will receive treatment over a maximum period of 24 months, with regular follow-up visits to monitor treatment efficacy and safety. These visits will include assessments of progression-free survival, disease control rate, overall response rate, and quality of life, among other endpoints. The primary endpoint is the rate of patients alive without progression 8 months post-inclusion. Secondary endpoints include time to progression, overall survival, and toxicity, evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

The expected length of participant involvement is up to 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial employs a rigorous methodology to ensure the reliability of results, with imaging assessments conducted according to RECIST v1.1 criteria. The study's design and procedures are structured to provide comprehensive data on the safety and efficacy of the treatment regimen in the specified patient population.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Folinic Acid**, marketed as Folinate de Calcium Hikma 10 mg/mL, is provided as a solution for injection or infusion. It is administered via intravenous infusion with a maximum daily dose of 400 mg/m². The treatment period for this medication is up to 24 weeks. Folinic Acid is utilized as a detoxifying agent in cytostatic treatment.

**Panitumumab**, marketed under the name Vectibix 20 mg/mL, is a concentrate for solution for infusion. It is administered through intravenous infusion with a maximum daily dose of 6 mg/kg. The treatment duration is also up to 24 weeks. Panitumumab is classified under antineoplastics and is used in the study as an anti-EGFR agent.

**Fluorouracil** is available in multiple formulations, including Fluorouracile AHCL 50 mg/mL and Fluorouracil Accord 50 mg/mL, both provided as solutions for injection or infusion. The administration routes include intravenous bolus injection and intravenous infusion. The maximum daily dose for Fluorouracil is 2400 mg/m², with a treatment period extending up to 24 weeks. This medication is categorized as an antineoplastic agent.

**Sotorasib** is administered in the form of film-coated tablets, with a maximum daily dose of 960 mg. The route of administration is oral, and the treatment period is up to 12 weeks. Sotorasib is included in the study as a KRAS G12C inhibitor, classified under antineoplastics.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study aims to evaluate the efficacy of these medications in the first-line treatment of patients with advanced unresectable KRAS G12C mutated colorectal adenocarcinoma who are not eligible for doublet or triplet chemotherapy regimens.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the rate of patients alive without progression 8 months after inclusion. Secondary endpoints include several measures: Progression-Free Survival (PFS), which is defined as the time between the date of inclusion and the date of the first radiological progression using RECIST v1.1 criteria or death; Disease Control Rate (DCR), evaluated at each time-point as complete response, partial response, stability, progression, or not evaluable with imaging; Objective Response Rate (ORR) and Best Overall Response (BOR), both evaluated throughout the treatment using RECIST v1.1 criteria; Duration of Response (DoR), defined as the time between the first response and the date of radiological progression or death; Time to Progression (TTP), defined as the time between the date of inclusion and the date of the first radiological progression, with cancer-related death also considered an event; and Overall Survival (OS), defined as the time between the date of inclusion and the date of death, regardless of cause.

Quality of life will be assessed using the EORTC QLQC30 questionnaire, completed before the first treatment and during the study. Geriatric assessments will be conducted at baseline and during treatment using the G-CODE and G8-SCORE. Toxicity will be recorded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 until 30 days after the last administration of treatment. These assessments will provide a comprehensive evaluation of the treatment's efficacy in patients with advanced unresectable **KRAS G12C** mutated colorectal adenocarcinoma.