Locally Advanced Rectal Cancer (LARC)

The FORTRESS trial (NG-350A-03) is an open-label, single-arm, and multicentre trial of NG-350A in combination with chemoradiotherapy (CRT) in adult patients with locally advanced rectal cancer (LARC) and at least one risk factor for local or distant recurrence.

Standard treatment for patients with proficient mismatch repair (pMMR) / microsatellite stable (MSS) locally advanced rectal cancer (LARC) consists primarily of neoadjuvant chemoradiotherapy followed by radical surgery. Several studies (including the UNION, STELLAR, TORCH, and SPRING-01 trials, etc) have demonstrated that the neoadjuvant strategy of short-course radiotherapy followed by chemotherapy combined with immunotherapy can improve pCR rate in patients with pMMR/MSS LARC, and might also provide higher organ preservation rates and long-term survival benefits. The study aims to explore the efficacy and safety of a TNT regimen comprising short-course radiotherapy combined with chemotherapy, cetuximab N01 (for patients with wild-type RAS/BRAF) or bevacizumab (for patients with mutant RAS/BRAF), and sintilimab in patients with high-risk LARC.

In this prospective, multicentre, randomized phase III trial, 612 locally advanced rectal cancer (LARC, T3-4/N+M0) patients with at least one high-risk features (lower location (≤5cm), cT4, cN2, MRF+, EMVI+, TD+) will be included, and randomly assigned to TNT group and iTNT group (1:1). TNT group receives long-course chemoradiotherapy (50Gy/25Fx concurrent with oral capecitabine) followed by 6 cycles of CAPOX. iTNT group receives short-course radiotherapy (25Gy/5Fx) followed by 6 cycles of Serplulimab combined with CAPOX. After the efficacy evaluation, the patients who achieves clinical complete response (cCR) will be managed by a watch and wait (W\&W) protocol and non-cCR patients will be recommended surgery. The primary endpoint is 3-year event-free survival rate (3yEFS%). The secondary endpoints include the complete response (CR, pathological complete response \[pCR\] plus cCR) rate, 3-year organ preservation rate, 3-year disease-free survival rate (3yDFS%), 3-year local recurrence free survival rate (3yLRFS%), 3-year distant metastasis free survival rate (3yDMFS%), 3-year overall survival rate (3yOS%), grade 3-4 acute adverse effects (AE) rate, rate of surgical complications, anal functions and quality of life, etc.

This study is a single-center, prospective, observational clinical trial enrolling patients with locally advanced rectal cancer (cT3-4aN0M0 and cT1-4aN1-2M0). By collecting tissue and blood samples at multiple timepoints, and integrating multi-omics data including ctDNA mutations, copy number variations, and mtDNA profiles, a multi-omics model will be constructed to predict the efficacy of neoadjuvant therapy for rectal cancer.

This is a phase II, multicenter, randomized (2:1) controlled, clinical trial to evaluate the preliminary efficacy and safety of consolidation chemotherapy (XELOX) plus dostarlimab after standard long-course CRT (ARM A) compared to XELOX alone (ARM B) in patients with pMMR/MSS or MSI-Low LARC (cT3-4 cN0, any cT cN+) candidate to receive standard long course CRT followed by TME. After the surgery, the patients in ARM A will be randomized (1:1) to receive adjuvant dostarlimab (ARM A1) versus follow-up (ARM A2), and in ARM B only follow-up. If clinical complete responses (cCR) are documented after consolidation treatment, the patient may choose not to proceed with surgery and pursue nonoperative management (NOM).

Colorectal cancer ranks as the third most prevalent malignancy worldwide and the second leading cause of cancer-related mortality. For patients with locally advanced rectal cancer (LARC) classified as T3-4/N+ without distant metastasis, achieving organ preservation and functional integrity while pursuing curative treatment remains a formidable clinical challenge. This study aims to evaluate the efficacy and organ preservation rates of a novel neoadjuvant regimen comprising short-course radiotherapy followed by four cycles of CAPEOX combined with Iparomlimab and Tuvonralimab in patients with microsatellite stable (MSS) or mismatch repair proficient (pMMR) LARC. Furthermore, the project will investigate potential predictive biomarkers for complete response (CR) within this immunotherapy-based total neoadjuvant therapy (iTNT) paradigm.

In a single-center, prospective, phase II study (ClinicalTrials registration number: \[to be filled in\]) initiated by our center to evaluate the safety and preliminary efficacy of short-course radiotherapy followed by sequential CAPOX chemotherapy combined with serplulimab and bevacizumab as total neoadjuvant therapy for MSS-type mid-low locally advanced rectal cancer, patients with mid-low MSS-type locally advanced rectal adenocarcinoma were enrolled. They received short-course radiotherapy combined with CAPEOX, serplulimab, and bevacizumab as preoperative total neoadjuvant therapy. It is anticipated that 30 subjects with locally advanced rectal cancer will be enrolled between September 2025 and September 2027. This phase II exploratory study targets patients with locally advanced mid-low MSS/pMMR rectal cancer. It employs short-course radiotherapy combined with CAPEOX, serplulimab, and bevacizumab as preoperative total neoadjuvant therapy, aiming to clarify the efficacy and safety of this new combined radiotherapy, chemotherapy, targeted therapy, and immunotherapy approach, while also assessing the rectal/anal preservation rate and quality of life of patients. After neoadjuvant therapy, patients will undergo imaging and endoscopic evaluations to determine subsequent treatment strategies. Radical surgical resection will be performed on patients after neoadjuvant immunotherapy, followed by further analysis of the pathological complete response (pCR) rate. The primary study endpoint is the pCR rate, and secondary study endpoints include the objective response rate, organ preservation rate, 3-year disease-free survival (DFS), 3-year overall survival (OS), incidence of adverse events, and quality of life scores (EORTC QLQ-C30, EORTC QLQ-CR29, Wexner).

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

This is an observational, retrospective-prospective, multicentre trial enrolling all patients included in the AIFA monitoring registry of Dostarlimab for the indication in rectal cancer. The aims of the study are to describe the clinical outcomes and safety of patients with dMMR/MSI-H locally advanced rectal cancer (LARC) receiving neoadjuvant dostarlimab in the real-world setting.

This study is a prospective, multi-cohort clinical trial designed to evaluate the preliminary efficacy and safety of zanidatamab in combination with tislelizumab and chemotherapy/radiotherapy for patients with HER2-positive locally advanced or metastatic gastrointestinal tumors.

This is a multicenter, prospective, phase II study evaluating total neoadjuvant therapy (TNT) consisting of short-course radiotherapy (SCRT; 5×5 Gy) followed by QL1706 (a bifunctional MabPair antibody targeting PD-1 and CTLA-4, code name only) plus mFOLFOX6 chemotherapy in patients with locally advanced rectal cancer (LARC) with proficient mismatch repair/microsatellite-stable (pMMR/MSS) biology. Patients with pMMR/MSS disease derive limited benefit from immune checkpoint inhibition alone. Preclinical and clinical evidence suggests that SCRT and oxaliplatin-based chemotherapy can enhance antitumor immunity (e.g., antigen release, T-cell infiltration), providing a biological rationale for combining QL1706 with SCRT-primed TNT. Eligible adults with cT3-4 and/or N+ mid-to-low rectal adenocarcinoma (without distant metastasis), confirmed pMMR/MSS, and ECOG 0-1 will receive: SCRT (total 25 Gy over 5 fractions), then several cycles of QL1706 plus mFOLFOX6 as neoadjuvant systemic therapy. Definitive total mesorectal excision (TME) is planned per multidisciplinary assessment; a watch-and-wait approach may be considered for patients achieving a stringent clinical complete response per institutional criteria. Standard perioperative care and postoperative follow-up will be performed. Primary endpoint is pathologic complete response (pCR, ypT0N0) rate at surgery. Key secondary endpoints include: clinical complete response (cCR) rate, major pathologic response rate, R0 resection rate, tumor downstaging, radiologic response, disease-free survival (DFS), overall survival (OS), organ preservation rate (for patients managed non-operatively), surgical morbidity, and safety/tolerability (CTCAE v5.0). Exploratory endpoints include correlations between efficacy and baseline clinicopathologic features; optional translational analyses may investigate immune-inflammation markers related to response and resistance. This trial aims to determine whether SCRT-primed QL1706 plus mFOLFOX6 TNT can improve tumor eradication and organ preservation while maintaining acceptable safety in pMMR/MSS LARC-a population with unmet need for effective immunotherapy-based strategies.

This prospective, multi-center, phase II randomized controlled trial will evaluate the actual benefit of adding immunotherapy with tislelizumab to the currently most effective approach against LARC, namely TNT. In this trial, we will harness several elements that may each potentially contribute to an overall high efficacy, at least in local outcomes: nCRT rather than SCRT, full length (8 cycles of mFOLFOX6) of consolidation chemotherapy, CIMT following nCRT (exploiting the upregulation of the immune response induced by the latter) and tislelizumab (with its theoretical advantage over other CPIs). In line with the changing treatment paradigms in LARC, in which high therapeutic efficacy translates into the possibility to avoid TME, the trial will have a novel primary endpoint of long-term unmaintained cCR, i.e. 3 year TME-free survival.

This study explores the key clinical issues in the field of neoadjuvant therapy for locally advanced rectal cancer. There are three core problems with the currently recommended total neoadjuvant therapy (TNT) in the guidelines: the lack of evidence-based consensus on the timing of radiotherapy and chemotherapy, the undefined number of chemotherapy cycles, and the uncertainty in the selection of the precise radiotherapy mode. In recent years, the combination of immune checkpoint inhibitors (ICIs) with the PD-1/PD-L1 inhibitors as the core and the TNT regimen has shown a trend of further enhancing tumor regression, providing a possibility for the organ function preservation of rectal cancer. However, existing clinical studies exhibit a high degree of heterogeneity in treatment strategies. In particular, there is a lack of high-quality evidence-based medical evidence in core aspects such as the timing of ICIs intervention and the combination of treatment regimens. This study is designed as a prospective, multicenter, randomized controlled phase II study. The "pick the winner" strategy for screening the optimal regimen is adopted to evaluate the efficacy of four neoadjuvant regimens (Group SCRT-4: short-course radiotherapy → 4 cycles of chemotherapy + ICIs; Group SCRT-6: short-course radiotherapy → 6 cycles of chemotherapy + ICIs; Group LCRT-4: concurrent chemoradiotherapy → 4 cycles of chemotherapy + ICIs; Group LCRT-6: concurrent chemoradiotherapy → 6 cycles of chemotherapy + ICIs). By evaluating indicators such as the complete response rate, organ preservation rate, safety, long-term survival, as well as the anal function and quality of life of patients, treatment strategies with clinical advantages will be screened out, providing an evidence-based basis for subsequent phase III confirmatory trials.

The study is a multicenter, randomized controlled, phase III clinical study, and the purpose of the study is to explore the complete response rate (CR, Defined as pathological complete response (pCR) + Clinical complete response (cCR) sustained for over one year) of patients with locally advanced rectal cancer(LARC) treated with personalized long-course radiotherapy plus chemotherapy with or without Serplulimab. A total of 184 patients were included in this study.

This interventional, non-randomized, prospective trial aims to evaluate the role of endoscopic resection following neoadjuvant treatment in patients with locally advanced rectal cancer. Phase I focuses on assessing the feasibility, safety and efficacy of endoscopic resection of residual scar or superficial residual neoplastic tissue following neoadjuvant treatment. Phase II explores the potential of this approach to guide patient selection for total mesorectal excision and to serve as a definitive treatment option for those with limited residual disease.

This study plans to include LARC patients receiving neoadjuvant therapy at this center, conducting PET/CT and PET/MR examinations before treatment, and PET/MR examinations before surgery after neoadjuvant therapy. The changes in the lesion before and after treatment will be compared to evaluate the efficacy of neoadjuvant therapy, including: the relief situation of the rectal primary lesion ; lymph node metastasis; local infiltration around the tumor; peritoneal and other distant metastases , etc. The pathological relief diagnosed by surgical pathology is the gold standard, and the predictive efficacy of PET/MR will be evaluated, comparing the advantages and disadvantages of 18F-FDG and 68Ga-FAPI PET/MR, and comparing with traditional PET/CT and rectal MRI to explore the value of PET/MRI in predicting the efficacy of neoadjuvant therapy in LARC patients.