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

Official title

A Phase II Multi-institutional Randomized Trial Evaluating the Impact of GLP-1 Receptor Agonists in Combination With Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

Overview

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

Detailed description

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.

Interventions

• Drug GLP-1 receptor agonist
  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
• Drug Total neoadjuvant therapy (TNT)
  Total ne-adjuvant therapy is standard treatment for locally advanced rectal cancer

Primary outcome measures

• Weight Loss [Time frame: 6 months]
• Metabolic Profile of the Tissue [Time frame: From enrolment to operation within 1 year]
• Inflammatory Mediators [Time frame: From enrolment to surgical resection within 1 year]
• GLP-1 effects on mitochondrial fitness [Time frame: From enrolment to surgical resection within 1 year]
• Mapping systemic inflammatory profiles [Time frame: From enrolment to surgical resection within 1 year]
• Mapping circulating immune systems [Time frame: From enrolment to surgical resection within 1 year]
• Mapping tumour resident immune system [Time frame: From enrolment to surgical resection within 1 year]

Secondary outcome measures (12)

• Oncological outcomes [Time frame: 5 years]
• Surgical Outcomes [Time frame: Enrolment to surgical intervention and 30 days post discharge]
• Metabolic and Physiologic Outcomes: [Time frame: From enrolment to surgical resection within 1 year]
• Treatment Tolerability and Safety: [Time frame: 1 year]
• Patient-Reported Outcomes: [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. [Time frame: From enrolment to surgical resection within 1 year]
• Radiomics [Time frame: From enrolment to surgical resection within 1 year]
• Circulating Tumor DNA (ctDNA) [Time frame: From enrolment to surgical resection within 1 year]
• Surgical Outcomes [Time frame: 30 days]
• Surgical Outcomes [Time frame: 30 days]
• Metabolic and Physiologic Outcomes: [Time frame: From enrolment to 1 year]
• Metabolic and Physiologic Outcomes: [Time frame: Enrolment to 1 year]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT07314528 · 435911714

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗