治験レーダー

Weight Loss

Change in weight loss (Kilograms) between groups at 2 time points * Baseline * Pre TNT starting * Post TNT starting

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.

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.

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.

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

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.

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.

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

5 years

Surgical Outcomes

To compare operative complexity (e.g., operative time, blood loss (millilitres), conversion rates).

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)

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

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.

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.

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.

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.

From enrolment to surgical resection within 1 year

Surgical Outcomes

To assess postoperative complications, including anastomotic leak, wound infection, and ileus (Clavien-Dindo classification).

30 days

Surgical Outcomes

To evaluate length of hospital stay and 30-day readmission rates

30 days

Metabolic and Physiologic Outcomes:

To assess changes in insulin sensitivity, lipid profile, and inflammatory markers (e.g., CRP, IL-6).

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).

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.

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.

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.

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.

Enrolment to 1 year