Evaluation of Adjuvant Therapy with Capecitabine in Stage II Colon and Rectal Cancer Patients with ctDNA Positivity Post-Resection

The primary objective of this study is to evaluate the efficacy of **adjuvant therapy** in patients with colon cancer UICC stage II by comparing the **disease-free survival (DFS)** in patients who are positive for circulating tumor DNA (**ctDNA**) after the resection of the primary tumor, with and without adjuvant therapy. This is clinically relevant as it aims to determine the potential benefit of adjuvant therapy in improving DFS in ctDNA-positive patients, which could guide treatment decisions and improve patient outcomes.

Secondary objectives include:

• Comparing the overall survival in colon cancer patients stage II who are ctDNA positive, with and without chemotherapy.
• Determining the disease-free survival in ctDNA negative patients.
• Determining the overall survival of ctDNA negative patients.
• Comparing the disease-free and overall survival in patients without adjuvant therapy according to their ctDNA status.
• Comparing the site of metastases according to the way of metastases (hematogenous vs. lymphogenic vs. local/peritoneal) and ctDNA status.
• Determining the chemotherapy safety.
• Determining the rate and time of conversion to ctDNA negativity during chemotherapy.
• Assessing ctDNA level before recurrence.
• Determining the DFS according to the ctDNA level.
• Exploring further molecular tissue and plasma markers that are prognostic for recurrence or predictive for the chemotherapy effect, such as CDX2 in the tissue, immune infiltrating cells, and immune-related polymorphisms.

The clinical trial involves participants diagnosed with **colon cancer stage II** or **rectal cancer stage II**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are required to have undergone resection of the primary tumor, with specific criteria for rectal cancer patients regarding the absence of indication for radiotherapy. The trial does not include vulnerable populations. The sponsor has not provided the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. Key inclusion criteria include a known microsatellite or mismatch repair status and the availability of ctDNA results. The trial population was selected based on these medical and procedural criteria, ensuring a focus on individuals who have undergone specific surgical interventions for their cancer treatment.

The clinical trial is designed to evaluate the efficacy of **adjuvant therapy** in patients with **colon cancer stage II** and **rectal cancer stage II**. This is a multicenter, prospective, randomized, controlled study. The primary objective is to compare the disease-free survival (DFS) in patients who are positive for circulating tumor DNA (ctDNA) after the resection of the primary tumor, with and without adjuvant therapy. The trial is expected to run from June 2020 to June 2029, with the primary endpoint being the DFS of ctDNA-positive patients, measured from randomization to any recurrence, metastasis, second colorectal or non-colorectal cancer, and death from any cause.

The trial involves several key phases, beginning with an inclusion (screening) visit where patients with resected colon or rectal cancer stage II are assessed for eligibility. Inclusion criteria include a known microsatellite or mismatch repair status and confirmation that the ctDNA result is available. Patients must provide signed informed consent for both the screening and the randomized phase. Following the screening, eligible participants are randomized into either the adjuvant therapy group or the follow-up group. The study drug, **capecitabine**, is administered orally with a maximum daily dose of 2500 mg/m² for a treatment period of up to six months.

Participants will undergo regular follow-up visits to monitor their health status and assess the primary and secondary endpoints, which include overall survival and DFS in ctDNA-negative patients. The trial will also evaluate the frequency of adverse events and the rate of patients in which ctDNA becomes non-measurable during or after chemotherapy. The end-of-study visit will occur at the conclusion of the trial or upon early termination, which may occur due to adverse events, withdrawal of consent, or other protocol-specified conditions. The expected length of participant involvement is approximately nine years, contingent upon individual health outcomes and adherence to the study protocol.

The clinical trial involves the use of **capecitabine**, an oral chemotherapeutic agent, as the experimental medication. Capecitabine is administered in the form of tablets, with a pharmaceutical form code of PHF00009MIG. The active substance, capecitabine, is a chemical compound classified under the ATC code L01BC06. The maximum daily dose of capecitabine is 2500 mg/m², and the total dose should not exceed 2500 mg/m². The treatment period is limited to a maximum of 6 months. The administration route is oral, and the medication is not formulated for pediatric use. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapy, which includes chemotherapy. The trial aims to evaluate the efficacy of adjuvant therapy in patients with colon cancer at UICC stage II, specifically focusing on those who are positive for circulating tumor DNA (ctDNA) after the resection of the primary tumor. The study compares disease-free survival (DFS) in patients receiving adjuvant therapy versus those who do not. The trial does not involve the use of a placebo or comparator treatment, as the focus is on the experimental use of capecitabine in conjunction with standard chemotherapy protocols.

The clinical trial titled "Circulating tumour DNA based decision for adjuvant treatment in colon cancer stage II evaluation (CIRCULATE) AIO-KRK-0217" aims to assess the efficacy of adjuvant therapy in patients with colon cancer UICC stage II. The primary endpoint for evaluating efficacy is **disease-free survival (DFS)** in patients who are positive for circulating tumor DNA (ctDNA) after the resection of the primary tumor. This will be measured from randomization to any recurrence, metastasis, second colorectal or non-colorectal cancer, and death from any cause. The primary endpoint will be analyzed using a stratified log-rank test in all randomized ctDNA positive patients.

Secondary endpoints include overall survival in ctDNA positive patients with adjuvant therapy versus follow-up, measured from randomization to death from any cause. Additionally, disease-free survival in ctDNA negative patients randomized to follow-up will be assessed, with the rate of patients disease-free and alive three years after randomization estimated using Kaplan-Meier analysis with a 95% confidence interval. Overall survival in ctDNA negative patients randomized to follow-up will also be evaluated, with the rate of patients alive five years after randomization estimated similarly. Further analyses will include disease-free and overall survival comparisons between ctDNA positive and negative patients, site of metastases, frequency of adverse events, rate of patients in which ctDNA becomes non-measurable, ctDNA level before recurrence, DFS according to ctDNA level at enrollment, and correlation of molecular markers to recurrence risk or chemotherapy effect.