Exploration of the Dynamic Changes and Mechanisms of the Immune Microenvironment in Advanced Colorectal Cancer Treated With IBI363 Combination Therapy
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Primary Efficacy Analysis
研究概览
简要总结
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.
详细描述
Exploration of the Dynamic Changes and Mechanisms of the Immune Microenvironment in Advanced Colorectal Cancer Treated with IBI363 Combination Therapy Study Protocol Version No.: 1.0.0 Version Date: December 2, 2024 I. Study Background 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.
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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.
- •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.
排除标准
- •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.
- •Congestive heart failure requiring ongoing treatment.
- •Left ventricular ejection fraction (LVEF) <50%.
- •New York Heart Association (NYHA) Class III or IV cardiovascular disease.
- •Acute coronary syndrome (e.g., myocardial infarction, unstable angina), coronary angioplasty, or stent placement within 6 months before the first study drug administration.
- •Stroke or transient ischemic attack within 6 months before the first study drug administration.
- •Known active seizures.
- •Interstitial lung disease (ILD), pulmonary fibrosis, pneumoconiosis, drug-induced pneumonitis, radiation pneumonitis requiring steroid treatment, or severe pulmonary dysfunction/restrictive lung disease.
- •History of allergic diathesis, asthma, or atopic dermatitis.
- •Recurrent or symptomatic pleural, pericardial, or peritoneal effusions requiring repeated drainage.
- •Active autoimmune diseases requiring systemic therapy within 2 years before the first study drug administration (except for replacement therapies such as thyroid hormone, insulin, or corticosteroids for adrenal or pituitary insufficiency).
- •History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
- •Known or suspected hypersensitivity to the study drug or any excipients.
- •History of significant immune checkpoint inhibitor-related toxicity requiring permanent discontinuation.
- •Unresolved Grade >1 toxicity from previous antitumor treatments, except for:
- •Persistent Grade 2 alopecia, peripheral neuropathy, or hypomagnesemia.
- •Stable, controlled toxicities (e.g., hypothyroidism managed with hormone replacement or hypertension controlled to <160/100 mmHg with antihypertensive therapy).
- •Incomplete recovery from surgery or major surgery within 4 weeks prior to the first study drug administration.
- •Active, uncontrolled bleeding or known bleeding disorders.
- •Significant gastrointestinal diseases within 6 months before the first study drug administration, including but not limited to:
- •History of inflammatory bowel disease (IBD).
- •≥Grade 2 diarrhea within 2 weeks before the first study drug administration.
- •Radiation enteritis.
- •Uncontrolled tumor-related pain or symptomatic hypercalcemia.
- •Known HIV infection, active hepatitis B (HBV), hepatitis C (HCV), or active tuberculosis:
- •HBV-positive patients must undergo HBV DNA testing. Patients are eligible if HBV DNA is ≤2.5 × 10³ copies/mL or ≤500 IU/mL.
- •HBsAg-positive patients must receive antiviral therapy during the study to prevent reactivation.
- •Patients with HBcAb(+), HBsAg(-), HBs(-), and HBV DNA(-) do not require antiviral prophylaxis but must be closely monitored for reactivation.
- •HCV-seropositive patients with negative or undetectable HCV RNA are eligible.
- •Patients who have completed HCV treatment and achieved an undetectable viral load are eligible.
- •Severe/uncontrolled infections requiring IV antibiotics within 2 weeks before the first study drug administration or unexplained fever (>38°C).
- •Diagnosis of another malignancy within the past 5 years, except for curatively treated basal/squamous cell carcinoma, carcinoma in situ, localized prostate cancer, or papillary thyroid carcinoma.
- •Prohibited medications and therapies, including but not limited to:
- •IL-2/IL-15 cytokines (except for their use in adoptive cell therapy or immune modulation in immunocompromised patients).
- •Chemotherapy or small-molecule targeted therapy within 2 weeks (or 5 half-lives) before first study drug administration, unless no delayed toxicity is expected. Exceptions:
- •Nitrosoureas and mitomycin C require a 6-week washout period.
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结局指标
主要结局
Primary Efficacy Analysis
时间窗: 2027-12-31
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.
次要结局
未报告次要终点
研究者
jianming xu
Leading Site Principal Investigator
The Affiliated Hospital of the Chinese Academy of Military Medical Sciences