Prospective Randomized Controlled Trial of Immunodynamics-Guided Optimization of Individualized Immunochemotherapy Infusion Timing in Driver Gene-Negative Advanced Non-Small Cell Lung Cancer
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 246
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
The goal of this clinical trial is to evaluate whether individualized sequencing of immunotherapy and chemotherapy based on immune dynamics can improve treatment outcomes in adults with advanced non-small cell lung cancer (NSCLC) without driver gene mutations. This study will also assess the safety and feasibility of different infusion strategies.
The main questions it aims to answer are:
Does optimizing the timing of PD-1 inhibitor infusion relative to chemotherapy improve the objective response rate (ORR)?
Does individualized infusion sequencing enhance progression-free survival (PFS) compared to standard or fixed-delay administration?
What safety concerns or immune-related adverse events occur with different infusion timing strategies?
Researchers will compare three treatment strategies:
Group A (Standard Concurrent Group): Immunotherapy and chemotherapy administered on the same day (D1).
Group B (Fixed Delay Group): Chemotherapy on D1, followed by PD-1 inhibitor infusion on Day 3.
Group C (Individualized Delay Group): Chemotherapy on D1, and PD-1 inhibitor infusion scheduled on D2-D6 based on daily immune monitoring.
Participants will:
Receive a PD-1 inhibitor (e.g., sintilimab, pembrolizumab, camrelizumab) combined with platinum-based chemotherapy.
Attend clinic visits for regular immune monitoring, imaging assessments, and safety checks during each treatment cycle.
Undergo blood tests to evaluate immune biomarkers (e.g., CD8⁺PD-1⁺ T cells, MDSC, Treg、IFN-γ、NLR、ALC、CRP) to guide individualized treatment decisions.
详细描述
Detailed Description
This study is a prospective, randomized, open-label, multicenter exploratory clinical trial designed to evaluate the efficacy and safety of immunodynamics-guided optimization of chemoimmunotherapy scheduling in patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. The trial specifically investigates whether individualized scheduling of PD-1 inhibitor infusion, guided by dynamic immune monitoring, can improve antitumor activity compared with standard synchronous or fixed-delay administration.
Rationale and Background
For patients with metastatic NSCLC lacking EGFR, ALK, or other approved targetable alterations, chemoimmunotherapy has become the standard first-line treatment. However, clinical outcomes remain heterogeneous, and not all patients benefit equally. Preclinical and translational evidence suggests that the timing of immune checkpoint blockade relative to chemotherapy exposure may significantly influence immune response, tumor microenvironment remodeling, and overall treatment efficacy. Immunodynamics-the dynamic assessment of immune status during therapy-offers a novel approach to guide individualized administration of immunotherapy, potentially enhancing efficacy while maintaining safety.
Study Objectives
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria:
- •Voluntarily agree to participate, sign the informed consent form (ICF), and be able to comply with the study procedures.
- •Age ≥18 years and ≤75 years at enrollment, both male and female participants are eligible.
- •Histologically or cytologically confirmed stage IV non-small cell lung cancer (NSCLC) based on the AJCC 8th edition; if mixed histology exists, classification must be based on the predominant histologic component. Presence of small-cell histology excludes eligibility.
- •Negative for actionable driver mutations: no EGFR mutations, ALK rearrangements, or ROS1 fusions. For other targetable alterations (e.g., BRAF V600E, NTRK1/2/3 fusions, MET exon 14 skipping, RET rearrangements), patients are excluded if FDA- or NMPA-approved targeted therapies are available.
- •Note: Genetic testing can be conducted locally or via a central laboratory. Pre-existing valid reports are acceptable.
- •Estimated life expectancy ≥3 months. At least one measurable lesion per RECIST v1.1 confirmed by IRC; irradiated lesions are not considered measurable unless unequivocal progression is demonstrated.
- •ECOG performance status of 0 or
- •No prior systemic therapy for advanced/metastatic NSCLC, except adjuvant or neoadjuvant chemotherapy if the last dose was ≥6 months before recurrence.
- •Adequate organ and bone marrow function within 14 days prior to randomization:
- •ANC ≥ 1.5 × 10⁹/L Platelets ≥ 100 × 10⁹/L Hemoglobin ≥ 90 g/L Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula) Total bilirubin ≤ 1.5 × ULN (≤3 × ULN for Gilbert's syndrome) AST/ALT ≤ 2.5 × ULN (≤5 × ULN if liver metastases) INR and APTT ≤ 1.5 × ULN unless on therapeutic anticoagulation LVEF ≥ 50% by echocardiography or MUGA Female patients of childbearing potential must test negative for pregnancy within 14 days before enrollment and agree to use effective contraception from ICF signing until 180 days after the last dose. Male participants must also agree to effective contraception during the same period.
排除标准
- •Participants meeting any of the following are excluded:
- •Prior thoracic radiotherapy >30 Gy within 6 months before first dose. Palliative radiotherapy within 7 days before first dose. Requirement for concurrent anti-tumor therapy during the study. Uncontrolled or symptomatic pleural, pericardial, or peritoneal effusions requiring repeated drainage.
- •Brainstem, leptomeningeal, spinal cord metastases, or cord compression.
- •Active CNS metastases or carcinomatous meningitis. Treated, stable brain metastases are allowed if:
- •Clinically stable ≥2 weeks, No evidence of progression, Off corticosteroids ≥3 days prior to treatment initiation. Previous treatment with immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4, etc.), immune agonists, or cellular immunotherapies.
- •Use of traditional Chinese medicines or immunomodulatory drugs with anti-cancer activity within 2 weeks before first dose.
- •Systemic corticosteroids (>10 mg prednisone equivalent/day) or other immunosuppressants within 2 weeks prior to first dose.
- •Uncontrolled systemic infection, unexplained fever >38.5°C, or IV antibiotic use >7 days within 2 weeks prior to first dose.
- •History of other malignancies within the past 5 years, except adequately treated cervical carcinoma in situ, basal/squamous cell skin cancer, localized thyroid papillary carcinoma, prostate cancer in remission, or DCIS after curative surgery.
- •Active or history of autoimmune disease, including but not limited to: autoimmune hepatitis, interstitial lung disease, uveitis, colitis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, or hypothyroidism.
- •Controlled hypothyroidism with hormone replacement is eligible. Vitiligo, alopecia, type 1 diabetes, resolved childhood asthma, or mild psoriasis without systemic therapy are allowed.
- •Clinically significant pulmonary diseases: e.g., steroid-requiring pneumonitis, drug-induced pneumonitis, or moderate-to-severe COPD.
- •Major surgery within 4 weeks prior to first dose or unresolved surgical wounds.
- •Significant cardiovascular diseases, including:
- •MI, unstable angina, stroke, or TIA within 6 months Arterial thromboembolism within 6 months DVT, PE, or severe thrombosis within 3 months Uncontrolled hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg) Myocarditis or NYHA III-IV heart failure History of allogeneic HSCT or organ transplantation (except corneal).
- •≥ Grade 2 peripheral neuropathy per CTCAE v5.
- •Active tuberculosis or suspected TB not ruled out. Positive HIV antibody; active syphilis or untreated positive non-treponemal antibody; uncontrolled HBV/HCV infection per protocol definition.
- •Live vaccine administration within 30 days before first dose or planned during study.
- •History of severe hypersensitivity to monoclonal antibodies, PD-1 agents, pemetrexed, carboplatin, or premedications.
- •Concurrent participation in another interventional clinical trial or use of other investigational products/devices within 4 weeks prior to first dose.
- •History of drug/alcohol abuse or uncontrolled psychiatric disorders interfering with compliance.
- •Any other condition judged by the investigator as inappropriate for study participation.
研究组 & 干预措施
Arm 2: Fixed Delay Group
Patients receive standard chemotherapy on Day 1 of each 21-day cycle. The PD-1 inhibitor is administered with a fixed delay, on Day 4 (3 days after chemotherapy). Combination treatment is given for 4 cycles, followed by PD-1 inhibitor maintenance until disease progression, unacceptable toxicity
干预措施: Arm 2：Fixed Delay Group (Drug)
Arm 1: Standard Synchronous Group
Patients receive standard chemotherapy and PD-1 inhibitor concurrently on Day 1 of each 21-day cycle. After 4 cycles of combination therapy, patients continue PD-1 inhibitor maintenance until progression
干预措施: Arm 1： Standard Synchronous Group (Drug)
Arm 3: Individualized Delay Group
Patients receive chemotherapy on Day 1 of each 21-day cycle. From Day 2 to Day 5, peripheral blood immunodynamic markers (e.g., CD8⁺PD-1⁺ T cells, MDSCs, Tregs, cytokines) are monitored daily. The PD-1 inhibitor is administered at the optimal time when predefined immunodynamic criteria are met, or on Day 6 if criteria are not met. After 4 cycles of combination therapy, patients continue PD-1 inhibitor maintenance until progression
干预措施: Arm 3： Individualized Delay Group (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: From baseline until disease progression, death, or completion of treatment, whichever occurs first, up to approximately 36 months.
The proportion of participants who achieve a complete response (CR) or partial response (PR) based on RECIST v1.1 criteria, as assessed by investigators. Imaging assessments will be performed every 6-8 weeks during treatment, and responses will be confirmed at least 4 weeks after initial documentation.
次要结局
- PFS(From baseline until documented disease progression or death, up to approximately 36 months.)
- Overall Survival (OS)(From baseline until death from any cause, up to approximately 48 months.)
- Incidence of Immune-Related Adverse Events (irAEs)(From baseline through 90 days after the last dose of study treatment, up to approximately 36 months.)
- Incidence of Treatment-Related Adverse Events (TRAEs)(From baseline through 90 days after the last dose of study treatment, up to approximately 36 months.)
研究者
Liang bin
Clinical Investigator
First Affiliated Hospital of Wenzhou Medical University