The goal of this clinical trial is to see if adding a weight loss medication (GLP-1 receptor drug) to patients with an increased BMI receiving treatment for rectal cancer prior to surgery (total neoadjuvant chemoradiotherapy) improves cancer outcomes. The main questions it aims to answer is
1. Does the drug increase weight loss in rectal cancer patients with a high BMI 2. Does the drug improve response rates to chemotherapy and radiotherapy 3. Does the drug improve survival outcomes and if cancer returns
Researchers will compare this drug in one group against a group of patients receiving preoperative total neoadjuvant chemoradiotherapy without the drug
Patients will be required to
1\) take the GLP-1 receptor agonist drug during TNT or just having TNT alone as per standard hospital protocols
Body weight will be measured at three predefined time points:
1. Baseline: Prior to initiation of semaglutide or TNT 2. Pre-TNT: Start of TNT (for the intervention arm, this is 4 weeks after semaglutide initiation) 3. Post-TNT: Within 7 days following completion of TNT and prior to definitive surgery
Patients will complete their treatment and go on to have surgery as per standard methods for treating rectal cancer
Written informed consent according to local guidelines obtained prior to any study-related activities.
Histologically confirmed mismatch repair protein proficient adenocarcinoma of the rectum.
BMI ≥25 kg/m²
Radiological confirmed >T2, Node positive, Threatened Surgical Margin and/or EMVI+ by MRI
Received prior chemotherapy or radiotherapy
Previous or concurrent active malignancy ≤ 5 years prior to registration, with the exception of non-melanotic skin cancer or carcinoma in situ of any type, or other cancers that the treating investigator does not feel will impact the study objectives.
Locally advanced disease T3N+ or T4 disease.
Recurrent rectal cancer
Parallel
GLP-1 receptor agonist
DrugAll patients will receive standard total neoadjuvant therapy for rectal cancer as per local standards. One group will receive a GLP-1 rector agonist in addition to the standard treatment for rectal cancer
Total neoadjuvant therapy (TNT)
DrugTotal ne-adjuvant therapy is standard treatment for locally advanced rectal cancer
Weight Loss
Change in weight loss (Kilograms) between groups at 2 time points * Baseline * Pre TNT starting * Post TNT starting
Metabolic Profile of the Tissue
Using a human ex vivo explant model (3D), we will assess in real time the metabolic profiles of the tissues from patents in the control and interventions groups. Detailed metabolic profiling data using Seahorse technology. These metabolic profile data will be correlated with detailed clinical, pathology and outcome data for each patient in the trial.
Inflammatory Mediators
Using human ex vivo explant model (3D) system, we will profile the secretions of inflammatory mediators from the TME and how these cross talks to immune cells. This data will be directly correlated with the detailed metabolic signatures.
GLP-1 effects on mitochondrial fitness
Determine of GLP-1 treatment alters mitochondrial fitness ex vivo in explants by assessing ATP levels (Relative Light Units), stress responses and adaptations to metabolic demands using tissues from both arms of the trial.
Oncological outcomes
To compare pathological complete response (pCR) rates at the time of surgical resection. To assess overall survival (OS) at 3 and 5 years post-treatment. To assess disease-free survival (DFS) at 3 and 5 years post-treatment. To evaluate local recurrence rates at 1, 3 and 5 years
Surgical Outcomes
To compare operative complexity (e.g., operative time, blood loss (millilitres), conversion rates).
Metabolic and Physiologic Outcomes:
To measure changes in BMI, waist circumference, and visceral fat volume using imaging modalities. (kg/m2)
Treatment Tolerability and Safety:
To compare the incidence and severity of adverse events (graded by CTCAE v5.0). This will be assessed while on treatment and post surgery for 30-days To assess treatment compliance and any dose modifications or interruptions due to toxicity. This will be measured continually during treatment To evaluate GLP-1 RA-related side effects, particularly gastrointestinal symptoms and hypoglycemia. This will be assessed at the end of treatment
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This trial is not recruiting at the moment. You can still explore other options:
