Prognostic and Predictive Value of Gastrointestinal Microbiome in Metastatic Melanoma Treated With Immunotherapy
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Objective Treatment Response According to irRECIST
研究概览
简要总结
The aim of this prospective clinical study is to evaluate the prognostic and predictive significance of the gastrointestinal microbiome in patients with metastatic malignant melanoma treated with first-line immunotherapy using immune checkpoint inhibitors (PD-1 inhibitors and CTLA-4 inhibitors). Although immunotherapy has significantly improved survival outcomes, treatment response remains unpredictable and a substantial proportion of patients develop immune-related adverse events, pseudoprogression, or hyperprogression.
The gastrointestinal microbiome is an important regulator of immune homeostasis and may influence systemic immune response. This study investigates whether specific microbiome composition is associated with objective treatment response assessed according to iRECIST criteria, progression-free survival (PFS), and the occurrence of immune-related adverse events.
Patients treated at the Institute of Oncology Ljubljana between March 2022 and March 2024 were enrolled. In addition to standard-of-care immunotherapy, participants underwent protocol-defined collection of stool and peripheral blood samples at predefined time points for microbiome and immune profiling analyses.
详细描述
This prospective, non-randomized clinical study evaluates the prognostic and predictive value of the gastrointestinal microbiome in patients with metastatic malignant melanoma treated with immune checkpoint inhibitors (PD-1 inhibitors and CTLA-4 inhibitors) in the first-line setting. Although immunotherapy has improved survival in metastatic melanoma, clinical outcomes remain heterogeneous and a substantial proportion of patients experience immune-related adverse events, pseudoprogression, or hyperprogression. Identification of biomarkers that predict response and toxicity remains clinically important.
The gastrointestinal tract contains a high concentration of microbes and lymphoid tissue, and the immune system and microbiome exist in close interaction. The gastrointestinal microbiome influences systemic immune response through cytokine production and regulation of T-cell activity. Previous studies suggest that microbiome composition and diversity may be associated with overall survival (OS), progression-free survival (PFS), and treatment response in patients receiving immune checkpoint inhibitors. Antibiotic-induced dysbiosis has been associated with reduced efficacy of immunotherapy, and fecal microbiota transplantation has shown potential in overcoming resistance to PD-1 inhibitors.
The primary objective of this study is to determine whether the predominant composition of the gastrointestinal microbiome is associated with objective response to PD-1 and CTLA-4 inhibitors in patients with metastatic malignant melanoma, assessed according to iRECIST criteria. The primary hypothesis is that a specific microbiome profile is associated with treatment response and progression-free survival (PFS).
Secondary objectives include evaluation of the association between microbiome composition and immune-related adverse events, disease progression during treatment, and peripheral blood immune cell populations (CD3+, CD4+, CD8+, CD4/CD8 ratio, and macrophages).
A total of 132 patients treated with first-line immune checkpoint inhibitors at the Institute of Oncology Ljubljana between March 2022 and March 2024 were enrolled. Clinical data were collected in anonymized form and include sex, age, date of diagnosis, performance status at treatment initiation, laboratory parameters (including LDH and S100), melanoma localization, BRAF status, treatment duration, radiologic response, and immune-related adverse events.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Cytologically or histologically confirmed malignant melanoma
- •Unresectable stage IIID or stage IV disease according to AJCC (8th edition, 2018)
- •ECOG performance status 0-2
- •Indication for first-line systemic immunotherapy (nivolumab, combination ipilimumab/nivolumab, or pembrolizumab)
- •CT or PET/CT imaging performed within 4 weeks prior to first administration of immunotherapy
- •Written informed consent obtained prior to study participation
排除标准
- •Previous systemic therapy for melanoma
- •ECOG performance status 3-4
- •Contraindications to immunotherapy (e.g., known immunodeficiency, active immunosuppressive treatment, or active autoimmune disease requiring systemic therapy)
- •Presence of another active malignancy, except adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or other solid tumors with no evidence of recurrence for ≥3 years
研究组 & 干预措施
PD-1 inhibitor therapy
Patients with metastatic malignant melanoma treated in the first line with PD-1 inhibitors (pembrolizumab or nivolumab).
干预措施: PD-1 and CTLA-4 inhibitors (Drug)
Combination PD-1 and CTLA-4 inhibitor therapy
Patients with metastatic malignant melanoma treated in the first line with combined immunotherapy with PD-1 and CTLA-4 inhibitors (ipilimumab/nivolumab).
干预措施: PD-1 inhibitors (Drug)
结局指标
主要结局
Objective Treatment Response According to irRECIST
时间窗: Baseline (within 4 weeks before treatment initiation) and up to 28 weeks (+2 weeks) after treatment initiation
Treatment response evaluated radiologically using PET/CT or CT triplet and assessed according to irRECIST criteria (CR, PR, SD, PD).
次要结局
- Progression-Free Survival (PFS)(From treatment initiation up to 24 months)
- Immune-Related Adverse Events(From treatment initiation up to 24 months)