Evaluating the Impact of GLP-1 Receptor Agonists With Total Neoadjuvant Therapy in Rectal Cancer

NCT07314528 | Not Yet Recruiting Phase 2

• 1 other identifier: 435911714
• Study Type: interventional
• Target: 42
• Locations: 0 countries
• Sites: N/A

Brief Summary

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. 1.Does the drug increase weight loss in rectal cancer patients with a high BMI
2. 2.Does the drug improve response rates to chemotherapy and radiotherapy
3. 3.Does the drug improve survival outcomes and if cancer returns
4. 4.Baseline: Prior to initiation of semaglutide or TNT
5. 5.Pre-TNT: Start of TNT (for the intervention arm, this is 4 weeks after semaglutide initiation)
6. 6.Post-TNT: Within 7 days following completion of TNT and prior to definitive surgery

Conditions

Rectal Cancer Patients; Obesity &Amp; Overweight; Locally Advanced Rectal Cancer (LARC); Total Neoadjuvant Therapy; GLP-1

Keywords

Locally Advanced Rectal Cancer; Total Neoadjuvant Therapy; GLP-1 Receptor Agonist

Outcome Measures

Primary Outcomes (7)

• 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

Secondary Outcomes (16)

• Oncological outcomes

  5 years

• Surgical Outcomes

  Enrolment to surgical intervention and 30 days post discharge

• Metabolic and Physiologic Outcomes:

  From enrolment to surgical resection within 1 year

• Treatment Tolerability and Safety:

  1 year

• Patient-Reported Outcomes:

  2 years

Study Arms (2)

Total Neoadjuvant Therapy and GLP-1 Receptor Agonist

EXPERIMENTAL

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)

Locally advanced rectal cancer and total neoadjuvant therapy alone

ACTIVE COMPARATOR

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)

Interventions

GLP-1 receptor agonist DRUG

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 Neoadjuvant Therapy and GLP-1 Receptor Agonist

Total neoadjuvant therapy (TNT) DRUG

Total ne-adjuvant therapy is standard treatment for locally advanced rectal cancer

Locally advanced rectal cancer and total neoadjuvant therapy alone; Total Neoadjuvant Therapy and GLP-1 Receptor Agonist

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Imaging available for radiomics analysis
• Absence of metastatic disease at registration.
• Adequate renal function is defined as calculated creatinine clearance (CrCl) \>50ml/min.
• ANC \> 1.5 cells/mm3, HGB \> 8.0 gm/dl, PLT \> 150,000/mm3, total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's Syndrome who must have total bilirubin ≤ 3.0 x ULN), AST≤ 3 x ULN, ALT ≤ 3 x ULN
• Able to tolerate medication.
• ECOG 0-2

You may not qualify if:

• 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
• Metastatic disease at presentation
• Patients unable to undergo MRI
• Patients having already received weight-loss intervention (pharmacological or surgical)

Sponsors & Collaborators

• St. James's Hospital, Ireland: lead

Related Publications (12)

• Kazi T, McKechnie T, Lee Y, Alsayari R, Talwar G, Doumouras A, Hong D, Eskicioglu C. The impact of obesity on postoperative outcomes following surgery for colorectal cancer: analysis of the National Inpatient Sample 2015-2019. ANZ J Surg. 2024 Jul-Aug;94(7-8):1305-1312. doi: 10.1111/ans.19135. Epub 2024 Jun 18.

  PMID: 38888262 RESULT

• Martin-Carnicero A, Ramalle-Gomara E, Rubio-Mediavilla S, Alonso-Lago M, Zorrilla-Larraga M, Manrique-Abos I, de Las Heras-Duena ME, Larrayoz IM, Martinez A. Prognostic and Predictive Biomarkers in Patients with Locally Advanced Rectal Cancer (LARC) Treated with Preoperative Chemoradiotherapy. J Clin Med. 2022 Oct 16;11(20):6091. doi: 10.3390/jcm11206091.

  PMID: 36294412 RESULT

• Dizdarevic E, Hansen TF, Jakobsen A. The Prognostic Importance of ctDNA in Rectal Cancer: A Critical Reappraisal. Cancers (Basel). 2022 Apr 30;14(9):2252. doi: 10.3390/cancers14092252.

  PMID: 35565381 RESULT

• Chen C, Douglas MP, Ragavan MV, Phillips KA, Jansen JP. Clinical Validity and Utility of Circulating Tumor DNA (ctDNA) Testing in Advanced Non-small Cell Lung Cancer (aNSCLC): A Systematic Literature Review and Meta-analysis. Mol Diagn Ther. 2024 Sep;28(5):525-536. doi: 10.1007/s40291-024-00725-x. Epub 2024 Aug 2.

  PMID: 39093546 RESULT

• Ryan EJ, Creavin B, Sheahan K. Delivery of Personalized Care for Locally Advanced Rectal Cancer: Incorporating Pathological, Molecular Genetic, and Immunological Biomarkers Into the Multimodal Paradigm. Front Oncol. 2020 Aug 14;10:1369. doi: 10.3389/fonc.2020.01369. eCollection 2020.

  PMID: 32923389 RESULT

• Silverii GA, Marinelli C, Bettarini C, Del Vescovo GG, Monami M, Mannucci E. GLP-1 receptor agonists and the risk for cancer: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2025 Aug;27(8):4454-4468. doi: 10.1111/dom.16489. Epub 2025 May 29.

  PMID: 40437949 RESULT

• Ochiai K, Bhutiani N, Ikeda A, Uppal A, White MG, Peacock O, Messick CA, Bednarski BK, You YN, Skibber JM, Chang GJ, Konishi T. Total Neoadjuvant Therapy for Rectal Cancer: Which Regimens to Use? Cancers (Basel). 2024 May 31;16(11):2093. doi: 10.3390/cancers16112093.

  PMID: 38893212 RESULT

• Johnson GGRJ, Park J, Helewa RM, Goldenberg BA, Nashed M, Hyun E. Total neoadjuvant therapy for rectal cancer: a guide for surgeons. Can J Surg. 2023 Apr 21;66(2):E196-E201. doi: 10.1503/cjs.005822. Print 2023 Mar-Apr.

  PMID: 37085291 RESULT

• Lin A, Ding Y, Li Z, Jiang A, Liu Z, Wong HZH, Cheng Q, Zhang J, Luo P. Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence. Biomark Res. 2025 Mar 27;13(1):50. doi: 10.1186/s40364-025-00765-3.

  PMID: 40140925 RESULT

• Miousse IR. GLP-1 receptor agonists in the context of cancer: the road ahead. Am J Physiol Cell Physiol. 2025 Jun 1;328(6):C1822-C1828. doi: 10.1152/ajpcell.00245.2025. Epub 2025 Apr 26.

  PMID: 40285503 RESULT

• Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10.

  PMID: 33567185 RESULT

• Wang L, Xu R, Kaelber DC, Berger NA. Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes. JAMA Netw Open. 2024 Jul 1;7(7):e2421305. doi: 10.1001/jamanetworkopen.2024.21305.

  PMID: 38967919 RESULT

MeSH Terms

Conditions

Obesity; Overweight

Condition Hierarchy (Ancestors)

Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Michael Kelly, MB BAO BCH PHD FRCSI

  St. James Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michael Eamon Kelly, MB BAO BCH PhD FRCSI

CONTACT

00353876638956; kellym11@tcd.ie

Ben Creavin, MB BAO BCH MD FRCSI

CONTACT

00353877830130; bencreavin@rcsi.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Colorectal Surgeon

Study Record Dates

• First Submitted: August 28, 2025
• First Posted: January 2, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: January 2, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share