Exploration of the Dynamic Changes and Mechanisms of the Immune Microenvironment in Advanced Colorectal Cancer Treated With IBI363 Combination Therapy

NCT06946745 | Recruiting

• 1 other identifier: IBI363 Combination Therapy
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Colorectal cancer (CRC) ranks as the fifth most common malignant tumor in the Chinese population. In current clinical practice, standard first- and second-line treatments for metastatic microsatellite-stable (MSS)/proficient mismatch repair (pMMR) CRC are based on multi-drug combination chemotherapy regimens combined with targeted therapies. These regimens include fluoropyrimidine-based chemotherapy (5-fluorouracil \[5-FU\], leucovorin, or capecitabine) in combination with oxaliplatin or irinotecan, with or without targeted monoclonal antibodies. After disease progression following second-line treatment, the approved treatment options in China include regorafenib, fruquintinib, and TAS-102; however, their clinical benefits remain unsatisfactory, with objective response rates (ORR) of 1-4%, progression-free survival (PFS) of 2-3 months, and overall survival (OS) of 6-9 months according to the respective drug labels. Immunotherapy is currently approved only for metastatic CRC with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status. In summary, the treatment efficacy for advanced CRC remains limited, highlighting the urgent need for novel drugs and therapeutic strategies to improve patient outcomes. IBI363 is a recombinant bispecific molecule consisting of an anti-programmed death receptor 1 (PD-1) antibody fused with interleukin-2 (IL-2), administered as an injectable formulation. It blocks the PD-1/PD-L1 pathway while activating the IL-2 signaling pathway, thereby reversing T-cell exhaustion and promoting T/NK cell activation. As of July 31, 2023, a total of 169 participants were enrolled in the CIBI363A102 study, including 22 participants in Part A (accelerated titration and BOIN phase) and 147 in Part B (dose expansion phase). Regarding efficacy, in the dose-escalation phase, 21 participants were evaluable for efficacy, with three participants in the 100-300 μg/kg QW dose group achieving a best tumor response of partial response (PR). In the dose-expansion phase, 76 participants were evaluable for efficacy, with six participants in the 100-1000 μg/kg QW dose group achieving PR. It is well established that the immune system can eliminate tumor cells through the cancer-immunity cycle. However, this process is not sustained, as tumors can gradually shape the tumor immune microenvironment (TIME) into an immunosuppressive state to counteract host immunity. The balance between pro-tumor and anti-tumor inflammatory mediators may determine tumor progression (Figure 1). Anti-tumor immune cells primarily include effector T cells (such as cytotoxic CD8+ T cells and effector CD4+ T cells), natural killer (NK) cells, dendritic cells (DCs), and M1-polarized macrophages. Pro-tumor immune cells mainly consist of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), M2-polarized macrophages, N2-polarized neutrophils, and type 2 innate lymphoid cells (ILC2s). Tumors have evolved various mechanisms to evade immune surveillance, such as defective antigen presentation, upregulation of negative immune regulatory pathways, and recruitment of pro-tumor immune cells. As a result, the function of anti-tumor immune cells is suppressed, and the anti-tumor immune response is difficult to sustain. The goal of immunotherapy is to restore the cytotoxic function of anti-tumor immune cells, particularly cytotoxic T lymphocytes (CTLs), against tumors. Therefore, investigating the function and mechanisms of different immune components within the TIME will help improve immunotherapy response rates and facilitate the development of novel immunotherapeutic strategies. Figure 1.Tumor-associated immune cells in the tumor microenvironment With the rapid development and iteration of omics technologies such as multiplex immunohistochemistry (mIHC), single-cell transcriptome sequencing (scRNA-seq), and spatial transcriptome sequencing (stRNA-seq), we can now investigate individual cells or specific cellular subpopulations at a higher resolution. This study aims to enroll patients with advanced MSS/pMMR colorectal cancer (CRC) and perform single-cell transcriptome sequencing on baseline and follow-up tissue samples. The objective is to dynamically map the spatial heterogeneity and evolutionary landscape of the tumor immune microenvironment (TIME) throughout the disease course, from initial diagnosis to disease progression. By analyzing TIME at different time points, we seek to elucidate the potential mechanisms of action of IBI363 in colorectal cancer. Furthermore, we will leverage spatiotemporal transcriptomic analyses to validate cell subpopulation interactions in situ within the tumor microenvironment.

Conditions

Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Primary Efficacy Analysis

  The primary efficacy endpoint is the Objective Response Rate (ORR). Descriptive statistics will summarize the Best Overall Response (BOR) across cohorts and treatment arms. The number and proportion of responders (CR+PR) will be provided, and the 95% CI for ORR will be estimated using the Clopper-Pearson method. The ORR difference between groups A and B within each cohort will be summarized using descriptive statistics, and the 95% CI will be calculated using the normal approximation method.

  2027-12-31

Study Arms (1)

advanced microsatellite-stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC)

Other: tissue biopsy

Interventions

tissue biopsy OTHER

By performing single-cell sequencing on tumor tissues at baseline and post-treatment (cycle 2) across all patients, we will conduct pseudotime trajectory analysis to study the differentiation dynamics of cellular populations.

advanced microsatellite-stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This study plans to enroll 50 patients with advanced microsatellite-stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC) who receive combination therapy with the immunotherapeutic agent IBI363 and bevacizumab plus chemotherapy. Tumor tissues will be collected at different time points during treatment (baseline and after every two treatment cycles for efficacy evaluation) through tissue biopsy (including core needle biopsy or endoscopic forceps biopsy).

You may qualify if:

• The participant must sign a written informed consent form (ICF) and be able to comply with the protocol-specified visit schedule and related procedures.
• Age ≥18 years and ≤75 years, with no gender restrictions.
• Histologically or cytologically confirmed diagnosis of advanced malignant tumors, meeting the following cohort-specific criteria:
• Cohort 2:
• Patients with histopathologically confirmed advanced colorectal cancer (CRC).
• Locally confirmed as mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L) or microsatellite stable (MSS) based on standard testing.
• Cohort 9:
• Patients with histopathologically confirmed advanced colorectal cancer (CRC).
• Locally confirmed as mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L) or microsatellite stable (MSS) (if applicable testing results are available).
• Baseline imaging must indicate the absence of active liver metastases. Note: Patients with previously treated liver metastases (including surgical resection, microwave or radiofrequency ablation, or stereotactic radiotherapy, but excluding transarterial chemoembolization) are eligible if they received definitive treatment at least 6 months prior to study enrollment and subsequent imaging confirms the absence of liver metastases.

You may not qualify if:

• \- 1. Pregnant or breastfeeding women, or women planning to become pregnant before, during, or within 6 months after the last administration of the study drug.
• \. Active or untreated central nervous system (CNS) metastases, confirmed by imaging during screening or previous evaluations (e.g., brain or leptomeningeal metastases).
• Patients with asymptomatic brain metastases may participate.
• Patients who have received treatment for brain metastases and have been symptomatically stable for ≥2 weeks without evidence of new or enlarging lesions may also be eligible, provided they meet all of the following:
• Presence of measurable extracranial disease.
• No metastases in the meninges, midbrain, pons, medulla, or spinal cord, and no multiple cerebellar metastases.
• No compression of the cerebral aqueduct, third or fourth ventricle, or spinal cord.
• Discontinuation of steroid therapy at least 14 days prior to the first dose of study drug.
• \. Active thrombosis, deep vein thrombosis (DVT), or pulmonary embolism within 4 weeks prior to the first administration of the study drug, unless adequately treated and considered stable by the investigator.
• \. Clinically significant cardiovascular or cerebrovascular diseases, including but not limited to:
• Ventricular arrhythmias or other uncontrolled cardiac arrhythmias requiring medical intervention (e.g., antiarrhythmic therapy).
• Severe conduction disorders (e.g., third-degree atrioventricular block).
• QTc interval (corrected by Fridericia's formula) ≥480 ms.
• Uncontrolled arterial hypertension despite standard treatment (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg).
• History of myocarditis.

Sponsors & Collaborators

• jianming xu: lead

Study Sites (1)

Chinese PLA General Hospital, Beijing

Beijing, China

RECRUITING

Central Study Contacts

jianming Xu

CONTACT

13910866712; jianmingxu2014@163.com

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Leading Site Principal Investigator

Study Record Dates

• First Submitted: April 21, 2025
• First Posted: April 27, 2025
• Study Start: December 2, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: April 27, 2025

Record last verified: 2025-04

Locations

CN (1)