Randomized Double-Blind Placebo-Controlled Trial of Acetylsalicylic Acid in Colorectal Cancer with PIK3CA, PIK3R1, or PTEN Mutations

The primary objective of this study is to evaluate whether adjuvant treatment with 160 mg of **Acetylsalicylic Acid (ASA)** once daily for 3 years can improve **Time To Recurrence (TTR)** in patients with colorectal cancer exhibiting somatic alterations in the **PIK3CA** gene (specifically exon 9 and 20), compared with placebo. This is clinically relevant as improving TTR could potentially enhance long-term outcomes and reduce recurrence rates in this patient population.

Secondary objectives include:

• To determine whether the same ASA regimen can improve **Disease-Free Survival (DFS)** in patients with colorectal cancer with somatic alterations in the PIK3CA (other than exon 9 and 20), **PIK3R1**, or **PTEN** genes, compared with placebo.
• To assess whether ASA treatment can improve TTR in patients with colorectal cancer with somatic alterations in the PIK3CA (other than exon 9 and 20), PIK3R1, or PTEN genes compared with placebo.
• To compare **Overall Survival (OS)** at 5 years from randomization in patients receiving low-dose ASA compared with placebo.
• To assess overall safety and tolerability of the ASA treatment.

The clinical trial involves participants diagnosed with **colon and rectal cancer** at tumor stages II-III, specifically those with somatic alterations in PIK3CA, PIK3R1, or PTEN. The study population includes both male and female subjects, aged between 18 and 80 years. Participants are required to have undergone radical surgery and possess a Karnofsky performance status of at least 60%. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include a clean colonoscopy or CT colon within three months preoperatively or postoperatively, and participants must be able to swallow tablets and provide informed consent. The trial population includes individuals from a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **acetylsalicylic acid** (ASA) in patients with colorectal cancer exhibiting somatic alterations in the PI3K signaling pathway. The primary objective is to assess whether adjuvant treatment with 160 mg of ASA once daily for a period of three years can improve Time To Recurrence (TTR) in these patients compared to a placebo. The trial will involve participants with colon and rectal cancer at tumor stages II-III, specifically those with somatic alterations in PIK3CA, PIK3R1, or PTEN. The study is expected to conclude by July 31, 2026, with recruitment having commenced on April 1, 2016.

Participants will be involved in the study for a maximum of 36 months, during which they will undergo a series of study visits. The initial visit will be a screening visit to confirm eligibility based on criteria such as tumor stage, genetic alterations, and overall health status, including a Karnofsky performance status of at least 60% and adequate platelet count. Following successful screening, participants will be randomized to receive either the active treatment or placebo. Subsequent follow-up visits will be scheduled to monitor the participants' health, adherence to the treatment regimen, and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Early termination from the study may occur if participants experience significant adverse effects, fail to adhere to the study protocol, or withdraw consent. The study will ensure that both the active and placebo tablets are identical in appearance and size to maintain the double-blind nature of the trial. The primary endpoint is the TTR at three years in patients with tumors harboring PIK3CA mutations in exon 9 and 20. The trial is categorized as a phase III study, indicating its advanced stage in the clinical research process.

The clinical trial involves the administration of **Acetylsalicylic Acid** (ASA), marketed under the name Trombyl 160 mg tabletter, as the experimental medication. The pharmaceutical form of this medication is a tablet, and it is administered orally. The dosage is set at 160 mg once daily, with a maximum treatment period of 36 months. The active substance, **Acetylsalicylic Acid**, is of chemical origin and is provided by Pfizer AB. The trial aims to evaluate the efficacy of ASA in improving Time To Recurrence (TTR) in patients with colorectal cancer who have somatic alterations in the PIK3CA gene.

The study also includes a placebo group to serve as a comparator. The placebo tablets are composed of colloidal silicone dioxide, magnesium stearate, carmellose sodium, and cellulose powder. The appearance and size of the placebo tablets are identical to those of the active medication to maintain the double-blind nature of the trial. The placebo is administered orally at the same frequency and duration as the active treatment, which is 160 mg once daily for up to 36 months. This design ensures that any observed effects can be attributed to the active substance rather than other variables.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the **Time To Recurrence (TTR)** at 3 years in patients with colorectal cancer harboring PIK3CA mutations in exon 9 and 20. The trial is designed as a randomized, double-blind, placebo-controlled study to determine whether adjuvant treatment with 160 mg of Acetylsalicylic Acid (ASA) once daily for 3 years can improve TTR compared to placebo. The efficacy assessment will involve regular monitoring and data collection throughout the treatment period, with the final analysis conducted at the end of the 3-year timeframe. The study will ensure that all measurements and data collection adhere to rigorous clinical standards to accurately determine the impact of ASA on the recurrence of colorectal cancer in the specified patient population.