Evaluation of Neoadjuvant Aspirin and Metformin in Combination with Induction Chemotherapy and Chemoradiotherapy for Locally Advanced Rectal Cancer

The primary objective of the NeoAspMet trial is to evaluate the effect of three experimental interventions—**aspirin**, **metformin**, or both—when combined with neoadjuvant induction chemotherapy (ICT) and preoperative chemoradiation (CRT) on Good Pathological Response (GPR) in patients with locally advanced stage II/III rectal cancer. GPR is defined as tumor downstaging to ypT0 or ypT1, regardless of the pathological N stage. This objective is clinically relevant as achieving a good pathological response is associated with improved long-term outcomes and may influence surgical decision-making and patient prognosis.

The secondary objectives are to assess the effect of the experimental interventions compared to the standard neoadjuvant treatment with ICT followed by CRT on several clinical outcomes:

• Tumor Regression Grade (TRG)
• Pathological complete responses (pCR)
• Neo-Adjuvant Rectal (NAR) score
• MRI Tumor Downstaging (mr TGR) rate
• Event-Free Survival (EFS)
• Overall Survival (OS)
• Time to Distant Recurrence (TDR)
• Rate of local recurrence at 3 years
• Abdominal Perineal Resection (APR) rate
• Organ preservation rate at 3 years
• Post-operative complications
• Quality of Life (QoL)
• Treatment-related toxicity
• Simplified-ESMO class risk shift after induction chemotherapy

The clinical trial involves participants diagnosed with **locally advanced stage II/III rectal cancer**. 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. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on a pathologically proven diagnosis of adenocarcinoma of the rectum, confirmed by endoscopic biopsy within 56 days prior to randomization. The trial includes individuals who are able to undergo induction chemotherapy, chemoradiotherapy, and total mesorectal excision. The study population is noted to include a vulnerable population, although specific lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is a prospective, randomized, 4-arm, open-label, multicenter phase 2/3 study designed to evaluate the efficacy of **aspirin**, **metformin**, or both, in combination with neoadjuvant induction chemotherapy (ICT) and preoperative chemoradiation (CRT) for patients with locally advanced stage II/III rectal cancer. The primary objective is to assess the effect of these interventions on Good Pathological Response (GPR), defined as tumor downstaging (ypT0 or ypT1) irrespective of the pathological N stage, compared to standard neoadjuvant ICT followed by preoperative CRT. The trial is expected to conclude by December 31, 2026, with recruitment having commenced on February 11, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on a pathologically proven diagnosis of adenocarcinoma of the rectum, determined by endoscopic biopsy within 56 days prior to randomization. The inclusion criteria require a locally advanced tumor, defined as TNM Stage II or III, confirmed through MRI of the pelvis and contrast-enhanced CT of the abdomen and chest. Participants must be able to undergo induction chemotherapy, chemoradiotherapy, and total mesorectal excision (TME).

Following the screening visit, participants will be randomized into one of the four study arms. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the primary and secondary endpoints, including tumor regression rate, pathological complete responses, and overall survival. The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events or withdrawal of consent.

The trial's secondary endpoints encompass a range of outcomes such as the NeoAdjuvant Rectal (NAR) score, MRI tumor downstaging rate, event-free survival, time to distant recurrence, and quality of life. The study aims to provide comprehensive data on the efficacy and safety of the experimental interventions, contributing to the optimization of treatment strategies for locally advanced rectal cancer.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Oxaliplatin** is utilized as an intravenous chemotherapeutic agent. It is administered in a pharmaceutical form identified as PHF00230MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 130 mg/m² and a total maximum dose of 21,840 mg/m² over a treatment period of 24 weeks. The administration is conducted intravenously, and participant compliance is monitored through regular assessments.

**Capecitabine** is another chemotherapeutic agent used in this trial, administered orally in the form PHF00009MIG. The maximum daily dose is 2000 mg, with a total maximum dose of 336,000 mg over the 24-week treatment period. Compliance is ensured through patient diaries and pill counts during follow-up visits.

**Metformin embonate** is included as a comparator treatment, administered orally in the form PHF00245MIG. The maximum daily dose is 1700 mg, with a total maximum dose of 285,600 mg over the course of the trial. Participant adherence is monitored through regular consultations and medication logs.

**Carbasalate calcium**, also known as **acetylsalicylic acid**, is used as a test treatment in the trial. It is administered orally in the form PHF00059MIG. The maximum daily dose is 100 mg, with a total maximum dose of 16,800 mg over the 24-week period. Compliance is tracked through patient self-reports and periodic checks by the study team.

All substances are of chemical origin and are not formulated for pediatric use. The trial aims to evaluate the effects of these treatments in combination with neoadjuvant induction chemotherapy and preoperative chemoradiation for locally-advanced rectal cancer. The study ensures rigorous monitoring of dosing schedules and participant compliance to maintain the integrity of the trial outcomes.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **Good Pathological Response (GPR)**, defined as tumor downstaging to ypT0 or ypT1, irrespective of the pathological N stage. This primary endpoint will be used to compare the effects of three experimental interventions—aspirin, metformin, or both—in combination with neoadjuvant induction chemotherapy (ICT) and preoperative chemoradiation (CRT) against the standard neoadjuvant ICT followed by preoperative CRT.

Secondary endpoints include a range of parameters such as Tumor Regression Rate, Pathological Complete Responses (pCR), NeoAdjuvant Rectal (NAR) score, MRI Tumor Downstaging (mr TGR) rate, Event-Free Survival (EFS), Overall Survival (OS), Time to Distant Recurrence (TDR), Rate of local recurrence at 3 years, Abdominal Perineal Resection (APR) rate, Organ preservation rate at 3 years, Post-operative complications, Treatment-related toxicity, and Quality of Life (QoL). These endpoints will provide a comprehensive assessment of the treatment's efficacy and impact on patient outcomes.