Locally Advanced Colorectal Cancer

Title:A Single-Arm, Single-Center, Phase II Exploratory Study of Serplulimab Combined with Decitabine plus CAPOX as Neoadjuvant Therapy for Locally Advanced Colorectal Cancer Background:Colorectal cancer is one of the most common gastrointestinal malignancies worldwide. Patients with locally advanced colorectal cancer remain at high risk of recurrence and distant metastasis after surgery. Although perioperative chemotherapy has improved clinical outcomes, the pathological complete response rate remains limited. Immune checkpoint inhibitors have shown remarkable efficacy in dMMR/MSI-H colorectal cancer; however, most pMMR/MSS tumors respond poorly to immunotherapy alone. Decitabine, a DNA methyltransferase inhibitor, may enhance tumor immunogenicity by promoting tumor antigen expression, improving antigen presentation, increasing immune cell infiltration, and reshaping the tumor immune microenvironment. CAPOX chemotherapy may further induce immunogenic cell death and enhance antitumor immune responses. Therefore, the combination of serplulimab, decitabine, and CAPOX may provide a synergistic neoadjuvant treatment strategy for locally advanced colorectal cancer. Objective:This study aims to evaluate the efficacy and safety of serplulimab combined with decitabine plus CAPOX as neoadjuvant therapy for patients with locally advanced colorectal cancer. The primary endpoint is pathological complete response rate. Secondary endpoints include R0 resection rate, tumor downstaging, objective response rate, disease-free survival, and safety outcomes. Methods:This is a prospective, single-center, single-arm, phase II exploratory clinical study. A total of 35 patients with previously untreated locally advanced colorectal adenocarcinoma will be enrolled. Eligible patients are adults aged ≥18 years with histologically or pathologically confirmed cT3/cT4N+M0 colorectal adenocarcinoma according to the AJCC/UICC 8th edition, at least one measurable lesion according to RECIST 1.1, ECOG performance status of 0-1, adequate organ function, and an expected survival of more than 3 months. The study includes a safety lead-in stage and a dose-expansion stage. In the safety lead-in stage, decitabine dose escalation will follow a conventional 3+3 design, with two planned dose levels: 10 mg and 15 mg intravenously on Days 1-2 of each 3-week cycle. Serplulimab will be administered at 300 mg intravenously on Day 1 of each 3-week cycle. CAPOX consists of oxaliplatin 130 mg/m² intravenously on Day 1 and capecitabine 1000 mg/m² orally twice daily on Days 1-14 of each 3-week cycle. The maximum tolerated dose or recommended phase II dose of decitabine will be determined based on dose-limiting toxicity. In the dose-expansion stage, patients will receive serplulimab combined with decitabine and CAPOX for four cycles as neoadjuvant therapy. Patients without distant metastasis and considered suitable for surgery will undergo radical colorectal cancer resection 2-4 weeks after completion of neoadjuvant treatment. Postoperative adjuvant therapy will be determined by the investigator according to pathological findings and clinical practice. Endpoints and Analysis:The primary endpoint is pathological complete response, defined as the absence of residual viable tumor cells in the primary tumor and resected lymph nodes after neoadjuvant therapy. Secondary endpoints include R0 resection rate, tumor downstaging rate, objective response rate assessed by RECIST 1.1, and disease-free survival. Safety assessments include adverse events, serious adverse events, immune-related adverse events, laboratory abnormalities, vital signs, 12-lead ECG, ECOG performance status, thyroid function, and physical examination findings. Adverse events will be graded according to NCI-CTCAE version 5.0. Descriptive statistics will be used for analysis. Continuous variables will be summarized by mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized by frequency and percentage. Time-to-event outcomes will be analyzed using the Kaplan-Meier method. Expected Significance:This study will explore whether the combination of PD-1 blockade, epigenetic modulation, and CAPOX chemotherapy can improve pathological response while maintaining acceptable safety in locally advanced colorectal cancer. The results may provide preliminary evidence for a new neoadjuvant treatment strategy and support future multicenter clinical studies.

The main objective of this randomized and controlled trial is to determine whether the use of a proactive strategy, systemic neoadjuvant treatment (FOLFOX) with or without hyperthermic intraperitoneal chemoterapy (HIPEC) with mitomycin C followed by postoperative systemic adjuvant treatment, increases disease-free survival at 36 months in patients with locally advanced colon cancer compared to standard treatment. Therefore, a phase III, randomized, academic, multicenter, controlled trial will be conducted. Patients with locally advanced colon adenocarcinoma (cT4, cT3 with invasion \>5mm) Nx and no metastases will be included. Control group (n=361) will receive standard treatment (surgery and adjuvant chemotherapy FOLFOX x 12 based); Experimental group 1 (n=361) = Neoadjuvant chemotherapy (FOLFOX x6) + surgery (associating HIPEC) and FOLFOX x 6; Experimental group 2 (n=361): Neoadjuvant chemotherapy (FOLFOX x6) + surgery and FOLFOX x 6. Randomization will be 1:1:1, stratified and centralized. The primary outcome will be disease-free survival at 36 months. Secondary outcomes will be tumor regression rate, ctDNA negativization, peritoneal relapse rate at 36 months, pattern of relapse, toxicity, morbidity and overall survival. Considering the results obtained with these two independent strategies (FOLFOX and HIPEC), a new trial is justified in order to provide strong evidence for this proactive treatment. The aim is to combine both to obtain a better benefit, which opens the direct possibility of increasing the current percentage of disease-free survival. The results of this study will have important scientific and social impact, since is aimed at improving the outcomes of one subpopulation of patients with locally advanced colon cancer whose current treatment, is not enough to avoid the recurrence of disease.

This is a phase 1, open-label, multicentric study evaluating the safety, feasibility and efficacy of ODI-2001, a personnalized therapeutic cancer vaccine composed of DNA neoantigen vaccine, Modified Vaccinia virus Ankara (MVA) viral adjuvant and anti-CTLA4 (ipilimumab), in patients with metastatic or locally advanced colorectal or pancreatic cancer. The study includes a dose-escalation phase to determine the maximum tolerated dose (MTD) followed by an expansion phase to evaluate efficacy in terms of progression-free survival

This is a prospective, open-label, single-center, phase II umbrella trial designed to evaluate the efficacy and safety of neoadjuvant therapy for locally advanced colorectal cancer. Patients will be stratified into four cohorts based on microsatellite instability (MSI) status, KRAS mutation status, and the consensus molecular subtypes (CMS). Six arms are included across four cohorts and each arm will be assigned to a specific treatment regimen. The primary endpoint is the complete response rate. Secondary endpoints include safety, organ preservation rate (for rectal cancer only), R0 resection rate, surgical complications, treatment compliance, 3-year survival, and quality of life (QoL) score.

This is a single site, open-label, single-arm phase II study to determine feasibility, tolerability, and preliminary efficacy of neoadjuvant ADG126 and pembrolizumab in stage II or III colorectal cancer.

This prospective, single-arm study aims to investigate the efficacy and safety of pembrolizumab plus bevacizumab and chemotherapy as neoadjuvant treatment in pMMR/MSS locally advanced rectal cancer patients

To explore the efficacy and safety of pembrolizumab in combination with bevacizumab and CapeOX neoadjuvant therapy for the treatment of RAS-mutated, BRAF wild-type, microsatellite-stabilized, locally advanced colorectal cancer. Methods and analysis: A prospective, open-label, single-arm, phase 2 clinical study protocol will enroll a total of 20 patients. The study is designed as a Simon II Optimal study involving 20 locally advanced rectal cancer (LACRC) patients. Initially, 9 patients will be recruited in the Simon I phase, and if more than 1 patient achieves a pathological complete response (pCR), the study will proceed to the II phase. Recruit up to 20 patients in Phase II, and if more than 4 patients achieve pCR, the trial will be considered successful. All enrolled patients will receive 2-4 cycles of neoadjuvant therapy with pembrolizumab + bevacizumab and CapeOX (bevacizumab + oxaliplatin + capecitabine). The primary efficacy endpoint is the pathological complete response (pCR) of the cancer following neoadjuvant therapy. Secondary efficacy endpoints include major pathological response (MPR), objective response rate (ORR), and assessment of adverse events (AEs). Ethics: Ethics approval has been obtained from the Ethics Committee at the First Affliated Hospital (Xijing Hospital)(KY20232402-F-1)

This study aims to explore the role of Traditional Chinese Medicine (TCM) based on syndrome differentiation in reducing chemotherapy side effects, lowering the risk of metastasis and recurrence, and improving survival rates in postoperative colorectal cancer patients through a prospective, single-arm interventional clinical trial.