Longitudinal Cohort Study of Immune-Related Adverse Events in Solid Tumor Patients Receiving Immune Checkpoint Inhibitors, With Deep Phenotyping and Multi-Omics Biomarker Discovery
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 940
- 试验地点
- 6
- 主要终点
- Time to Clinical Resolution of Immune-Related Adverse Events (Days)
研究概览
简要总结
Immune checkpoint inhibitors (ICIs) have transformed the treatment of solid tumors but are associated with immune-related adverse events (irAEs) that can affect virtually any organ system. While many irAEs are well recognized, neurological, neurocognitive, and psychiatric toxicities remain diagnostically challenging, potentially severe, and poorly understood, with limited predictive biomarkers.
This prospective longitudinal observational cohort study enrolls adult patients with solid tumors initiating a new course of ICI therapy. Participants undergo standardized baseline clinical assessments and biospecimen collection prior to ICI initiation, followed by longitudinal follow-up and event-driven sampling. Patients are dynamically assigned to organ-specific irAE cohorts based on the first clinically significant irAE that dictates management. Patients without grade ≥2 irAEs during follow-up serve as a comparator control cohort.
The primary objective is to characterize longitudinal immune and inflammatory biomarker trajectories associated with the development of irAEs and to identify predictive and prognostic biomarkers, with particular emphasis on neurological, neurocognitive, and psychiatric toxicities. Integrated clinical, imaging, and multi-omics data will be used to elucidate mechanisms of toxicity and inform future risk stratification and personalized management strategies.
详细描述
Immune checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 pathways have demonstrated substantial clinical benefit across multiple solid malignancies. However, their mechanism of action can also lead to immune-related adverse events (irAEs), which may involve dermatologic, gastrointestinal, hepatic, pulmonary, endocrine, musculoskeletal, cardiovascular, renal, hematologic, neurological, and psychiatric systems. Neurological and neurocognitive irAEs, in particular, are uncommon but potentially devastating and remain poorly characterized.
This study is a hybrid prospective longitudinal observational cohort designed to move beyond reactive identification of irAEs toward proactive prediction and mechanistic understanding. Adult patients with solid tumors initiating a new ICI regimen are enrolled prior to treatment initiation. Longitudinal clinical data, imaging, and biospecimens are collected at predefined intervals and at the time of suspected irAE onset when feasible.
Participants are assigned to event-defined cohorts based on the first grade ≥2 irAE that drives clinical management, including neuro-sensory, gastrointestinal/hepatic, rheumatologic/musculoskeletal, vascular/renal, hematologic, multi-organ, or control (no significant irAE) cohorts. Deep phenotyping and multi-omics analyses-including immune cell profiling, proteomics, metabolomics, and microbiome analyses-are performed to identify biomarkers associated with irAE risk, severity, and outcomes.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
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
- •Histologically confirmed solid malignancy
- •Planned initiation of a new immune checkpoint inhibitor regimen (monotherapy or combination) as standard of care or on an approved clinical trial
- •Ability to provide informed consent
- •Baseline study assessments and biospecimen collection completed prior to first ICI dose
- •Life expectancy of at least 6 months as determined by treating oncologist
- •Availability of archival tumor tissue or willingness to undergo biopsy if archival tissue is unavailable
排除标准
- •Uncontrolled medical, psychiatric, or social conditions that would interfere with study participation or data interpretation
- •Chronic systemic immunosuppression exceeding 10 mg/day prednisone equivalent within 14 days prior to enrollment (excluding inhaled, topical, or physiologic replacement doses)
- •Prior solid organ transplantation or allogeneic hematopoietic stem cell transplantation
- •Untreated, symptomatic, or progressing brain metastases (treated and stable brain metastases allowed if off systemic steroids for at least 7 days)
- •Inability or unwillingness to provide required baseline biospecimens
研究组 & 干预措施
Neuro-Sensory irAE Cohort
Participants who develop a grade ≥2 neurological, neurocognitive, psychiatric, ocular inflammatory, or peripheral nervous system immune-related adverse event.
Gastrointestinal and Hepatic irAE Cohort
Participants who develop grade ≥2 immune-mediated colitis, hepatitis, pancreatitis, or related gastrointestinal toxicities.
Rheumatology and Musculoskeletal irAE Cohort
Participants who develop grade ≥2 inflammatory arthritis, myositis, polymyalgia rheumatica-like syndromes, or related musculoskeletal toxicities.
Vascular and Renal irAE Cohort
Participants who develop grade ≥2 myocarditis, vasculitis, nephritis, or other vascular or renal immune-mediated toxicities.
Hematologic irAE Cohort
Participants who develop grade ≥2 immune-mediated cytopenias or other hematologic toxicities.
Multi-Organ irAE Cohort
Participants who develop two or more distinct grade ≥2 immune-related adverse events involving different organ systems.
Control Cohort
Participants who do not develop any grade ≥2 immune-related adverse events during the defined follow-up period.
结局指标
主要结局
Time to Clinical Resolution of Immune-Related Adverse Events (Days)
时间窗: From irAE diagnosis through up to 24 months of follow-up
Among participants who develop grade ≥2 immune-related adverse events (irAEs), the time from irAE diagnosis and initiation of organ-specific treatment (per institutional guidelines) to achievement of organ-specific clinical resolution will be recorded. Criteria for clinical resolution differ by organ system and are defined according to established consensus guidelines, as specified in the corresponding secondary outcome measures.
次要结局
- Neuro-Sensory irAE Subgroup: Proportion of Participants with Modified Rankin Scale (mRS) Score ≤2(12 weeks after irAE diagnosis)
- Neuro-Sensory irAE Subgroup:Proportion of Participants with Objective Improvement on Nerve Conduction Studies(12 weeks after irAE diagnosis)
- Psychiatric and Cognitive irAE Subgroup:Proportion of Participants with Patient Health Questionnaire-9 (PHQ-9) Score <10(8 weeks after initiation of targeted treatment)
- Psychiatric and Cognitive irAE Subgroup:Proportion of Participants with ≥0.5 Standard Deviation Improvement on ≥2 Standardized Neuropsychological Tests(12 weeks after irAE diagnosis)
- Gastrointestinal and Hepatic irAE Subgroup: Proportion of Participants with ≤3 Bowel Movements per Day and No Hematochezia(2 weeks after initiation of immunosuppressive therapy)
- Gastrointestinal and Hepatic irAE Subgroup: Proportion of Participants with Alanine Aminotransferase (ALT) ≤1.5 × Upper Limit of Normal(4 weeks after initiation of immunosuppressive therapy)
- Rheumatologic and Musculoskeletal irAE Subgroup: Proportion of Participants with Clinical Disease Activity Index (CDAI) ≤10(12 weeks after initiation of immunosuppressive therapy)
- Rheumatologic and Musculoskeletal irAE Subgroup: Proportion of Participants with ≥20% Improvement in Manual Muscle Testing (MMT-8) Score(12 weeks after irAE diagnosis)
- Renal irAE Subgroup: Proportion of Participants with Serum Creatinine Recovery to Within 1.3 × Baseline(12 weeks after irAE diagnosis)
- Hematologic irAE Subgroup: Proportion of Participants with Sustained Hematologic Response (CTCAE v5.0 Grade ≤1 for ≥4 Weeks)(Within 12 weeks after initiation of first-line immunosuppressive therapy)
- Hematologic irAE Subgroup: Proportion of Participants with Normalized Lactate Dehydrogenase and Stable Hemoglobin(2 weeks after initiation of treatment)
- Multi-Organ irAE Subgroup: Proportion of Participants without Any New or Worsening ≥Grade 3 Immune-Related Adverse Events Across Organ Systems(Within 4 weeks after initiation of combined immunosuppressive therapy)
- Multi-Organ irAE Subgroup: Proportion of Participants Requiring Intensive Care Unit Admission for Multi-Organ irAE(irAE diagnosis through resolution or up to 24 weeks)
- Control Cohort (No Grade ≥2 irAE): Duration of Immunotherapy without Grade ≥2 Immune-Related Adverse Events (Months)(From ICI initiation through 90 days after last dose)
- Control Cohort (No Grade ≥2 irAE): Proportion of Participants Completing Planned Immune Checkpoint Inhibitor Course per Protocol(From ICI initiation through 90 days after last dose)
研究者
Weidong Wang
Associate Professor, MD
Shantou University Medical College