Evaluation of ctDNA-Guided Genomic-Based Targeted Therapy Versus Conventional Adjuvant Chemotherapy in Stage III and High-Risk Stage II Colon Cancer

The primary objective of this study is to demonstrate that a personalized **ctDNA**-guided genomic-based targeted treatment strategy can enhance the clinical outcomes for patients with Stage III and high-risk Stage II colon cancer compared to a conventional adjuvant chemotherapy approach. This is clinically relevant as it aims to optimize treatment efficacy and potentially improve survival rates by tailoring therapy based on individual tumor genomics.

Secondary objectives include: - Comparing the 2-year recurrence-free survival (RFS) of the physician's prior declared chemotherapy choice versus a downsized treatment in **ctDNA**-negative patients. - Evaluating the toxicity and quality of life between personalized and conventional adjuvant strategies. - Assessing the economic toxicity of personalized versus conventional adjuvant strategies. - Establishing the false negative rate of serial liquid biopsies (LBs) in the experimental arms of the trials. These objectives aim to provide a comprehensive understanding of the benefits and limitations of personalized treatment strategies in terms of efficacy, safety, quality of life, and economic impact.

The clinical trial focuses on patients diagnosed with **colon cancer**, specifically targeting individuals with operable Stage III and High-Risk Stage II conditions. The study population includes both male and female participants aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of colon cancer located at least 12 cm from the anal verge and above the peritoneal reflection. The trial includes individuals 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. Participants must have normal organ functions and, for women of childbearing potential, a negative pregnancy test and a commitment to using highly effective contraceptive methods are necessary. The trial population was selected based on these criteria, although the total number of participants is not provided by the sponsor. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, emphasizing the need for careful ethical considerations in the study design and execution.

The clinical trial is designed to evaluate a personalized ctDNA-guided genomic-based targeted treatment strategy for patients with operable stage III and high-risk stage II **colon cancer**. The trial employs a randomized, double-blind, controlled design to compare the efficacy of this personalized approach against conventional adjuvant chemotherapy. The trial is expected to commence recruitment in September 2024 and conclude by September 2028, with a total duration of approximately four years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histologically confirmed diagnosis, and ECOG performance status. Following the screening, eligible participants will be randomized 1:1 to receive either the conventional or personalized treatment. The primary endpoint is the 2-year recurrence-free survival (RFS) in patients with post-surgery ctDNA positivity. Secondary endpoints include 2-year RFS in ctDNA-negative patients, 3 and 5-year RFS and overall survival (OS), safety and tolerability assessments, and quality of life evaluations using FACT-C and EQ-5D-5L questionnaires.

Study visits will include regular follow-up assessments to monitor treatment response, adverse events, and ctDNA status. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Participants are expected to be involved in the study for a maximum of six months of treatment, with additional follow-up extending up to five years. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Disodium Levofolinate** is provided as a solution for injection/infusion, with a maximum daily dose of 200 mg/m². It is administered via **intravenous infusion** over a treatment period of up to 6 months. This compound is classified under folic acid analogues.

**Temozolomide** is administered in the form of hard capsules, with a maximum daily dose of 150 mg/m² and a total dose of 750 mg/m² over the treatment period. The route of administration is **oral**, and it is categorized as an alkylating agent.

**Irinotecan** is provided as a concentrate for solution for infusion, with a maximum daily dose of 100 mg/m² and a total dose of 200 mg/m². It is administered via **intravenous infusion** and functions as an enzyme inhibitor.

**Trastuzumab** is supplied as a powder for concentrate for solution for infusion, with a maximum daily dose of 8 mg/kg. It is administered through **intravenous infusion** and has been specifically labeled for clinical trial use.

**Panitumumab** is available as a concentrate for solution for infusion, with a maximum daily dose of 6 mg/kg. It is administered via **intravenous infusion** and is a structurally diverse substance classified as an immunoglobulin.

**Capecitabine** is administered in the form of coated tablets, with a maximum daily dose of 2500 mg/m² and a total dose of 35000 mg/m². The route of administration is **oral**, and it is classified under pyrimidine analogues.

**Calcium Levofolinate** is provided as a solution for injection/infusion, with a maximum daily dose of 200 mg/m². It is administered via **intravenous infusion** and is categorized as a folic acid analogue.

**Pertuzumab** is supplied as a solution for infusion, with a maximum daily dose of 840 mg. It is administered through **intravenous infusion** and has been labeled for clinical trial use.

**Ipilimumab** is available as a concentrate for solution for infusion, with a maximum daily dose of 1 mg/kg. It is administered via **intravenous infusion** and is classified as a protein-based therapeutic.

**Folinic Acid** is provided as a solution for injection/infusion, with a maximum daily dose of 400 mg/m². It is administered via **intravenous infusion** and is categorized under folic acid analogues.

**Oxaliplatin** is supplied as a concentrate for solution for infusion, with a maximum daily dose of 85 mg/m² and a total dose of 170 mg/m². It is administered through **intravenous infusion** and functions as an alkylating agent.

**Fluorouracil** is administered as a solution for injection, with a maximum daily dose of 1600 mg/m² and a total dose of 2800 mg/m². The route of administration is **intravenous bolus injection/IV infusion**, and it is classified under pyrimidine analogues.

**Nivolumab** is provided as a solution for infusion, with a maximum daily dose of 3 mg/kg. It is administered via **intravenous infusion** and is a protein-based therapeutic.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. Each medication is administered according to its specific dosing schedule, with the treatment period extending up to 6 months. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the 2-year **Relapse-Free Survival (RFS)** in patients with post-surgery circulating tumor DNA (ctDNA) positivity, who are randomized 1:1 to receive either conventional adjuvant chemotherapy or a personalized targeted treatment strategy. Secondary endpoints include the 2-year RFS in patients with post-surgery ctDNA negativity, randomized to receive either a physician-choice adjuvant therapy or an intensive follow-up strategy. Additionally, 3 and 5-year RFS and Overall Survival (OS) will be evaluated in patients with both ctDNA positivity and negativity, randomized in either the conventional or experimental trials.

Further secondary endpoints involve the safety and tolerability assessed according to the Clinical Trials Criteria for Adverse Events (CTCAE) version 5.0, the number of false negative cases after three consecutive negative liquid biopsies (LBs), and the number of patients experiencing ctDNA seroconversion who remain disease-free at 2 and 3 years. Patient-reported outcomes will be measured using the FACT-C and EQ-5D-5L questionnaires across the whole study population. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, ensuring a comprehensive evaluation of the treatment strategies' impact on patient outcomes.