Phase III Multicenter Randomized Trial of Dose-Reduced Chemotherapy with Fluorouracil, Folinic Acid, Capecitabine, and Oxaliplatin in Metastatic Colorectal Cancer

The primary objective of the DOSAgE study is to demonstrate that **upfront dose-reduced chemotherapy** is non-inferior to full-dose treatment concerning progression-free survival in patients with metastatic colorectal cancer. This is clinically relevant as it aims to maintain treatment efficacy while potentially reducing the risk of adverse effects associated with full-dose chemotherapy, particularly in older patients who may have a higher risk of toxicity.

Secondary objectives include:

• Determining whether upfront dose reduction of chemotherapy improves quality of life and physical functioning.
• Assessing if dose reduction reduces grade 3-5 toxicity.
• Studying whether dose reduction is non-inferior to full-dose treatment regarding overall survival.
• Evaluating if dose reduction leads to more treatment completion, fewer dose reductions, and lower unplanned hospital admission rates.
• Investigating whether dose reduction leads to an increase in received cumulative dosage and its association with progression-free survival.
• Identifying predictive geriatric markers of poor outcomes using a geriatric assessment.
• Assessing the cost-effectiveness of upfront dose reduction.

The clinical trial involves participants diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects aged 70 years or older. Participants are required to have distant metastases without localized treatment options and must be candidates for first-line palliative chemotherapy as determined by their treating oncologist. The trial does not involve a vulnerable population. Participants must be able to understand the Dutch language and provide written informed consent. Adequate bone marrow and organ function is necessary, as defined by specific laboratory values. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, phase III study to evaluate the efficacy of dose-reduced chemotherapy in patients aged 70 years or older with **metastatic colorectal cancer**. The trial aims to demonstrate that reduced-dose chemotherapy is non-inferior to full-dose treatment concerning progression-free survival. The study will stratify patients based on their risk of toxicity, allowing for either mono-chemotherapy or doublet chemotherapy regimens. The trial is expected to commence recruitment in June 2024 and conclude by December 2028.

Participants will be randomly assigned to receive one of the following treatments: **Fluorouracil**, **Calcium Folinate**, **Capecitabine**, or **Oxaliplatin**. These treatments are administered via intravenous infusion or orally, depending on the specific medication. The trial will follow a double-blind methodology to ensure unbiased results. The maximum treatment period for participants is set at two to three months, depending on the specific drug regimen.

The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis, and organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The primary endpoint is progression-free survival, with secondary endpoints including quality of life, physical functioning, and overall survival. The end-of-study visit will assess the cumulative effects of the treatment and gather final data on the endpoints.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up visits as required. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent. The trial is classified as low-intervention, as all investigational medicinal products are authorized and used according to their marketing authorization, posing minimal additional risk compared to standard clinical practice.

The clinical trial involves the administration of several **chemotherapeutic agents** for the treatment of metastatic colorectal cancer. The first experimental medication is **Fluorouracil**, provided as a 50 mg/ml solution for injection or infusion. This pharmaceutical form is administered intravenously. The maximum daily dose is 1200 mg/m², with a total maximum dose of 2800 mg/m² over a treatment period of up to 2 weeks. The administration schedule is designed to ensure optimal therapeutic efficacy while monitoring for potential adverse effects.

Another treatment used in the trial is **Calcium Folinate**, also known as **Folinic Acid** or Leucovorin, which is provided as a 10 mg/ml solution for injection or infusion. This medication is administered via intravenous infusion. The maximum daily dose is 400 mg/m², with a total maximum dose of 400 mg/m² over a treatment period of up to 2 weeks. Calcium Folinate is used to enhance the therapeutic effects of Fluorouracil and mitigate its toxicity.

**Capecitabine** is administered in the form of 500 mg film-coated tablets. This medication is taken orally, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 14000 mg/m² over a treatment period of up to 3 weeks. Capecitabine is a prodrug that is metabolized into Fluorouracil in the body, providing a targeted approach to cancer treatment.

Lastly, **Oxaliplatin** is provided as a 5 mg/ml concentrate for solution for infusion. This medication is administered intravenously, with a maximum daily dose of 130 mg/m² and a total maximum dose of 130 mg/m² over a treatment period of up to 3 weeks. Oxaliplatin is used in combination with other chemotherapeutic agents to enhance the overall efficacy of the treatment regimen.

Throughout the trial, participant compliance with the dosing schedules is closely monitored to ensure adherence to the treatment protocol. The trial aims to evaluate the non-inferiority of dose-reduced chemotherapy compared to full-dose treatment, with a focus on progression-free survival in patients with metastatic colorectal cancer.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival** in patients with metastatic colorectal cancer. This endpoint will determine the duration during which patients remain free from disease progression. Secondary endpoints include assessments of Quality of Life, Physical Functioning, Grade 3-5 chemotherapy-related toxicity, Overall Survival, the number of completed treatment cycles, dose reductions during treatment, unplanned hospitalizations, cumulative received dosage, and cost-effectiveness. These parameters will provide a comprehensive evaluation of the treatment's impact on patients' health and well-being.

The trial is designed to compare dose-reduced chemotherapy with full-dose treatment, stratified by mono-chemotherapy versus doublet chemotherapy based on individual risk of toxicity. The study will involve the administration of authorized medicinal products, including Fluorouracil, Calcium Folinate, Capecitabine, and Oxaliplatin, which are used in accordance with their marketing authorizations. The trial is categorized as low-intervention, as it involves minimal additional risk or burden compared to standard clinical practice. The estimated recruitment start date is June 1, 2024, with an estimated end date of December 1, 2028.