Evaluation of Intensive Versus Standard Adjuvant Chemotherapy with FOLFOXIRI and CAPOX in Stage II-III Localized Colon Cancer with Circulating Tumor DNA

The primary objective of this Phase II randomized trial is to analyze the potential effect of **FOLFOXIRI** as an intensive adjuvant treatment for circulating tumor DNA (ctDNA) clearance, serving as a surrogate biomarker of treatment efficacy in patients with localized colon cancer (stage II-III). Additionally, the study aims to investigate differences in the conversion rate between an intensive adjuvant treatment (FOLFOXIRI) and conventional adjuvant therapy (CAPOX). This is clinically relevant as ctDNA clearance may indicate a more effective eradication of residual disease, potentially leading to improved patient outcomes.

Secondary objectives include:

• Evaluating the impact of intensive chemotherapy treatment on disease-free survival in patients with positive ctDNA at 24 months after the end of treatment.
• Assessing disease-free survival at 12 months post-treatment, according to the seroconversion rate (ctDNA positive converting to ctDNA negative) in each treatment arm.
• Comparing the toxicity of triplet combination chemotherapy of FOLFOXIRI with conventional adjuvant treatment (CAPOX) for patients with localized colon cancer.
• Evaluating the impact of FOLFOXIRI compared with CAPOX on the quality of life in patients with localized colon cancer.

The clinical trial involves participants diagnosed with **localized colon cancer** at stages II-III. The study population includes both male and female subjects, aged between 18 and 75 years, who have a histologically confirmed diagnosis of operable stage II or stage III colon cancer. Participants are required to be postoperative and ctDNA positive, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have normal organ functions, including specific hematological and biochemical parameters. The sponsor has not provided the total number of participants involved in the trial. The selection criteria emphasize the need for normal organ function and a specific health status, but no specific lifestyle considerations such as diet or physical activity are mentioned.

The clinical trial is designed as a **randomized**, open-label, phase II study to evaluate the efficacy of intensive versus standard adjuvant chemotherapy in patients with localized colon cancer (stage II-III) who are positive for circulating tumor DNA (ctDNA). The trial aims to assess the potential effect of the FOLFOXIRI regimen as an intensive adjuvant treatment for ctDNA clearance, serving as a surrogate biomarker of treatment efficacy. The study will also compare the conversion rate between the intensive adjuvant treatment (FOLFOXIRI) and the conventional adjuvant therapy (CAPOX).

The trial is expected to run from January 12, 2022, to December 31, 2026. Participants will be involved for a maximum treatment period of six months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and adverse events, and an end-of-study visit to assess the primary and secondary endpoints. The primary endpoints include the proportion of patients who achieve ctDNA negativity after treatment, while secondary endpoints focus on disease-free survival and quality of life assessments.

Participants will be randomly assigned to either the intensive or standard treatment group. The intensive group will receive the FOLFOXIRI regimen, which includes **capecitabine**, **oxaliplatin**, **fluorouracil**, and **irinotecan hydrochloride trihydrate**, while the standard group will receive the CAPOX regimen. The trial will monitor for adverse events and assess the quality of life using the QLQ-C30 and QLQ-CR29 questionnaires at baseline, three months, and the end of treatment. Participants may be withdrawn from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Capecitabine**, marketed as Capecitabina KERN PHARMA, is available in film-coated tablet form with dosages of 150 mg, 300 mg, and 500 mg. The medication is administered orally with a maximum daily dose of 1000 mg/m². The treatment period is set for a maximum of 6 cycles. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Oxaliplatin**, provided as Oxaliplatin Hospira, is a concentrate for solution for infusion. It is administered via infusion with a maximum daily dose of 130 mg/m². The treatment is conducted over a maximum period of 6 cycles. The infusion route requires careful monitoring of infusion rates and participant response to ensure safety and efficacy.

**Fluorouracil**, marketed as Fluorouracilo Accord, is available as a solution for injection or infusion. It is administered intravenously with a maximum daily dose of 2400 mg/m² and a total dose of 3200 mg/m² over the treatment period. The administration is conducted over a maximum of 6 cycles, with participant compliance monitored through infusion records and clinical assessments.

**Irinotecan Hydrochloride Trihydrate**, provided as Irinotecán Hospira, is a concentrate for solution for infusion. It is administered via intravenous infusion with a maximum daily dose of 165 mg/m². The treatment is conducted over a maximum period of 6 cycles. Infusion protocols are followed to ensure participant safety and adherence to the dosing schedule.

**Folinic Acid**, marketed as FOLINATO CÁLCICO NORMON, is available as a solution for injection. It is administered via intravenous infusion with a maximum daily dose of 200 mg/m². The treatment is conducted over a maximum period of 6 cycles. Compliance is monitored through infusion records and clinical evaluations to ensure proper administration and participant adherence.

These experimental medications are part of a Phase II randomized trial assessing the effect of intensive versus standard adjuvant chemotherapy in localized colon cancer with circulating tumor DNA. The trial aims to evaluate the efficacy of these treatments in achieving ctDNA clearance and improving conversion rates compared to conventional therapies. Each medication is administered according to the specified dosing schedules, with participant compliance and safety closely monitored throughout the trial.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the proportion of patients who achieve **circulating tumor DNA (ctDNA)** negativity after treatment. This will be evaluated in both the intensive treatment group and the standard of care group. Secondary endpoints will focus on disease-free survival comparisons between the two treatment groups at 12 and 24 months post-treatment. Additionally, the trial will assess the proportion of patients experiencing adverse events when treated with the triplet combination chemotherapy of FOLFOXIRI compared to the conventional adjuvant treatment (CAPOX). Quality of life will also be measured using the QLQ-C30 and QLQ-CR29 scales, with scores compared between groups at baseline, 3 months, and the end of treatment.

The efficacy parameters will be collected and analyzed at specified timepoints, including baseline, 3 months, and the end of treatment. The use of validated scales such as QLQ-C30 and QLQ-CR29 will ensure the reliability of the quality of life assessments. The trial is designed to provide a comprehensive evaluation of the treatment's impact on ctDNA clearance, disease-free survival, adverse events, and quality of life, thereby offering a robust assessment of the treatment's efficacy in patients with localized colon cancer.