A Phase 2 interventional study of GLP-1 receptor agonist and Total neoadjuvant therapy (TNT) in Rectal Cancer Patients, Obesity &Amp; Overweight and Locally Advanced Rectal Cancer (LARC), sponsored by St. James's Hospital, Ireland. Not yet recruiting. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-01-02.
Sponsored by St. James's Hospital, Ireland · Phase 2, Interventional, and Treatment
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
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:
Patients will complete their treatment and go on to have surgery as per standard methods for treating rectal cancer
This Phase II multicentre, open-label randomized controlled trial aims to determine whether adding a GLP-1 receptor agonist (GLP-1RA) to standard Total Neoadjuvant Therapy (TNT) improves oncological outcomes in Locally Advanced Rectal Cancer (LARC). We will evaluate whether metabolic modulation through GLP-1RA increases pathological complete response (pCR) rates, accelerates the clearance of circulating tumour DNA (ctDNA), and reduces the risk of recurrence. Secondary outcomes include toxicity profiles, surgical parameters and outcomes, ctDNA dynamics, and 2-year disease-free (DFS) and overall survival (OS). By combining innovative metabolic therapy with biomarker-driven monitoring, this study pioneers a precision oncology approach in the management of LARC.
Immune metabolism refers to the bioenergetic and biosynthetic processes that support immune cell function. Obesity significantly alters this metabolic programming. Obesity has a significant impact on cancer development and progression, in part due to its effects on the tumour microenvironment (TME) and immune metabolism. Understanding this connection is key in cancer biology and can also inform therapeutic strategies. There are many consequences of obesity-induced TME alterations, including immune suppression, increased tumour progression, metastasis, and resistance to immunotherapy.
Obesity is linked to an increased risk of developing 13 different cancers, including CRC cancer. 1 The mechanisms are complex, but elevated systemic inflammation and dysregulated immunity are major factors. Emerging evidence is beginning to show the potential benefits of GLP-1 therapies in cancer treatment; since this class of medications improves obesity, they might also help improve cancer outcomes. In a large retrospective cohort study with a 15-year follow-up, GLP-1 medication use was associated with a significant risk reduction in 10 of the 13 obesity-related cancers. 1 Mechanistically, the reasons for this reduction are unknown, but decreased inflammation and immune dysregulation are likely key factors in lowering this risk.
Our research group has extensively documented the harmful effects of obesity on the immune system, including its impact on anti-cancer immunity. Additionally, we have provided clinical and experimental evidence that GLP-1 therapy reduces inflammation and can significantly enhance anti-tumor immune cell populations. In this study, we will precisely assess the effects of two specific interventions-either TNT combined with GLP-1 RA (intervention group) or TNT alone (control group)-on the systemic inflammatory profile and circulating/tumor immune phenotype in stage III rectal cancer.
GLP-1-based treatments originally developed for type 2 diabetes and obesity, are now gaining attention for their potential impact on immune metabolism and even cancer therapy. There has been direct links between GLP-1 treatment and immune metabolism, with GLP reducing inflammation and improving systemic metabolism enhancing immune fitness. Some studies have also shown that GLP treatment can also indirectly modulate the TME by lowering leptin and insulin levels, reducing tumour-promoting signalling and reducing immunosuppressive cells in the TME. It is important to note that different cancers may respond differently to GLP-1 modulation based on the complexity, composition and level of immune infiltration. In this current study, we will profile the metabolic profiles and inflammatory profiles in the complex TME across the two defined interventions (either TNT + GLP-1 RA (intervention group) or TNT alone (control group)) in stage III rectal cancer patents enrolled in the trial.
GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide, have demonstrated strong effects on weight loss in individuals with obesity. In the STEP 1 trial, semaglutide led to an average weight loss of 14.9%, compared to 2.4% with placebo, over 68 weeks. Recent epidemiologic data also suggest a link between GLP-1 RA use and a reduced incidence of obesity-related cancers, including colorectal cancer. 3 Additionally, GLP-1 RAs may have anti-inflammatory and metabolic effects that could be beneficial in the context of cancer therapy.
Total neoadjuvant therapy (TNT) is increasingly utilized in managing locally advanced rectal cancer (LARC) to improve pathological complete response (pCR) rates, facilitate surgical downstaging, and support organ preservation. This trial aims to determine whether combining GLP-1 RAs with TNT leads to meaningful weight loss and better oncological outcomes compared to TNT alone in patients with BMI ≥30 and LARC.
11,522 studies on the registry are indexed under Obesity; 2,033 are open to participants now.
This study's planned enrollment of 42 is below the median of 67 across 9,006 interventional studies indexed under Obesity.
Browse Obesity studies →St. James's Hospital, Ireland is the lead sponsor of 28 studies on the registry; 6 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Histologically or cytologically confirmed
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
This arm will have patients with increased BMI and locally advanced rectal cancer having total neoadjuvant chemoradiotherapy. This arm will be given a GLP-1 receptor agonist
Drug: GLP-1 receptor agonist · Drug: Total neoadjuvant therapy (TNT)
Patients with a high BMI and locally advanced rectal cancer undergoing total neoadjuvant therapy with not receiving a GLP-1 receptor agonist
Drug: Total neoadjuvant therapy (TNT)
All 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 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
Time frame: 6 months
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.
Time frame: From enrolment to operation within 1 year
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.
Time frame: From enrolment to surgical resection within 1 year
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.
Time frame: From enrolment to surgical resection within 1 year
Mapping systemic inflammatory profiles
To definitively map the systemic inflammatory profile, we will investigate matched plasma samples (baseline and post-intervention) using a high dimensional approach (e.g Olink Target-96 Immunoncology panel or Olink Explore-396 inflammatory profile). Samples will be taken at the time of diagnosis and the time of surgery
Time frame: From enrolment to surgical resection within 1 year
Mapping circulating immune systems
Map the circulating immune system using spectral flow cytometry to include cell frequencies (e.g. T cells, Innate T cells, NK cells, Monocytes and DC subsets), activation/exhaustion phenotype (e.g. CD69, PD-1, TIM-3 etc) and cytokine profiles (e.g. interleukin (IL)-2, 4, 10 \& 17, interferon gamma, tumour necrosis factor, granzymes etc). Samples will be taken from pre treatment biopsies and from the tumour itself when removed at surgery.
Time frame: From enrolment to surgical resection within 1 year
Mapping tumour resident immune system
Map the tumour resident immune system using MACsima spatial imaging platform and their 61- parameter immuno-oncology antibody panel (which includes T cells, NK cells, Macrophages \& DCs plus tumour specific markers). Using this platform, in addition to deep immunopheotyping, we will allow perform neighbour analysis to determine cell-cell interactions. Tissue will be taken from pre treatment biopsies and from the tumour itself when removed at surgery.
Time frame: From enrolment to surgical resection within 1 year
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
Time frame: 5 years
Surgical Outcomes
To compare operative complexity (e.g., operative time, blood loss (millilitres), conversion rates).
Time frame: Enrolment to surgical intervention and 30 days post discharge
Metabolic and Physiologic Outcomes:
To measure changes in BMI, waist circumference, and visceral fat volume using imaging modalities. (kg/m2)
Time frame: From enrolment to surgical resection within 1 year
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
Time frame: 1 year
Patient-Reported Outcomes:
To compare quality of life (QoL) scores using validated instruments (e.g., EORTC QLQ-C30). This will happen at 3 monthly intervals from starting treatment To assess patient-reported functional status, fatigue, and appetite changes. This will happen at 3 monthly intervals from starting treatment To evaluate psychological well-being (e.g., depression, anxiety scores) in the context of body weight changes and cancer therapy.
Time frame: 2 years
Translational Component: to investigate the molecular and cellular effects of GLP-1 RA therapy during TNT through analysis of tissue and blood biomarkers.
To evaluate changes in tumor microenvironment, including immune cell infiltration (e.g., CD8+ T-cells, macrophages) via immunohistochemistry or multiplex immunofluorescence.
Time frame: From enrolment to surgical resection within 1 year
Radiomics
Standardize imaging and segmentation across sites with centralized protocols and ROI annotation for tumor and mesorectal fat. Extract baseline and post-TNT radiomic features and calculate delta-radiomics, alongside CT-based body composition measures. Develop predictive models combining radiomics with clinical and metabolic data to correlate with pCR, survival, and treatment toxicity.
Time frame: From enrolment to surgical resection within 1 year
Circulating Tumor DNA (ctDNA)
Longitudinal sampling: Plasma will be collected at baseline, mid-TNT, preoperatively, and postoperatively at defined follow-up intervals. Analytical methods: ctDNA will be quantified and profiled using next-generation sequencing (NGS)-based assays to detect mutations, copy number variations, and methylation patterns relevant to rectal cancer. Endpoints: Dynamics of ctDNA clearance and re-emergence will be evaluated as biomarkers of treatment response, minimal residual disease, and early recurrence. Integration: ctDNA data will be correlated with radiomic signatures, metabolic changes, and pathological outcomes to explore composite biomarker models that predict pCR, DFS, and OS.
Time frame: From enrolment to surgical resection within 1 year
Surgical Outcomes
To assess postoperative complications, including anastomotic leak, wound infection, and ileus (Clavien-Dindo classification).
Time frame: 30 days
Surgical Outcomes
To evaluate length of hospital stay and 30-day readmission rates
Time frame: 30 days
Metabolic and Physiologic Outcomes:
To assess changes in insulin sensitivity, lipid profile, and inflammatory markers (e.g., CRP, IL-6).
Time frame: From enrolment to 1 year
Metabolic and Physiologic Outcomes:
To evaluate resting metabolic rate (RMR) and body composition (e.g., lean mass vs. fat mass if DEXA or BIA is used).
Time frame: Enrolment to 1 year
Translational Component: to investigate the molecular and cellular effects of GLP-1 RA therapy during TNT through analysis of tissue and blood biomarkers.
To assess systemic inflammatory and metabolic markers, such as IL-6, TNF-α, adiponectin, leptin, and CRP, at baseline and post-TNT.
Time frame: From enrolment to1 year
Translational Component: to investigate the molecular and cellular effects of GLP-1 RA therapy during TNT through analysis of tissue and blood biomarkers.
To perform gene expression profiling of tumor samples (pre- and post-TNT) to identify signatures associated with treatment response or resistance.
Time frame: Enrolment to 1 year
Translational Component: to investigate the molecular and cellular effects of GLP-1 RA therapy during TNT through analysis of tissue and blood biomarkers.
To explore gut microbiome composition in relation to treatment arm and metabolic outcomes, using fecal metagenomic sequencing.
Time frame: Enrolment to 1 year
Translational Component: to investigate the molecular and cellular effects of GLP-1 RA therapy during TNT through analysis of tissue and blood biomarkers.
To assess circulating tumor DNA (ctDNA) dynamics pre-, during, and post-TNT as a potential predictor of minimal residual disease and recurrence.
Time frame: Enrolment to 1 year
No study locations are listed for this record.
Plan to share: No — De identified data will not be available to anyone outside the study. This is in line with our ethics department and GDPR
Start is estimated for Apr 2026; primary completion for Sep 2028, 29 months later.
Of 132 non-industry phase 2 interventional studies under Obesity, half reached primary completion within 35 months of starting (the median), counting those still running; a quarter within 15 and three quarters within 57. This study's planned 29 months is below that.
Counting every sponsor, half of 308 studies reached it within 16 months; a quarter within 10 and three quarters within 35.
How these figures are worked out, and which studies are left out of them.
This study is not yet recruiting, as verified in Dec 2025. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: GLP-1 Mimetic
St. James's Hospital, Ireland