First-in-Human Phase I Study of TIGIT-Blocked NK510 Cells in Patients With PD-1 Refractory Advanced NSCLC
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Dose-limiting toxicity and incidence of adverse events
研究概览
简要总结
This study assesses the safety and efficacy of NK510 combined with PD-(L)1 inhibitors for relapsed/refractory advanced NSCLC, with two administration routes: intravenous infusion and intrapleural perfusion for malignant pleural effusion. Eligible patients need confirmed measurable lesions; intravenous cohort requires EGFR/ROS1/ALK negativity and disease progression after PD-(L)1 inhibitor treatment, while intrapleural cohort accepts targeted therapy-resistant patients with ≥500ml pleural effusion, and the treatment's safety, efficacy and immune microenvironment changes will be evaluated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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, male or female.
- •For dose expansion group (Group A/B/C):
- •A. EGFR mutation-negative, ROS1-negative, and ALK-negative; unresectable and non-radiotherapeutic stage III or IV, locally advanced, recurrent or metastatic NSCLC.
- •B. Disease progression after ≥4 courses of PD-(L)1 blockade ± chemotherapy.
- •For pleural perfusion group (Group D1/D2): Advanced NSCLC with malignant pleural effusion ≥500ml (confirmed by B-ultrasound or CT); patients with driver gene-positive and resistant to targeted therapy are acceptable.
- •At least one CT or MRI measurable lesion according to RECIST v1.
- •ECOG performance status 0-
- •Expected survival ≥3 months.
- •All toxicities from previous anti-tumor therapy (except alopecia and fatigue) resolved to grade 1 (CTCAE v5.0) or baseline; subjects with long-term sequelae from previous therapy (e.g., neuropathy after platinum-based therapy) are acceptable.
- •Fertile females must be non-lactating and have a negative serum pregnancy test within 1 week before enrollment; all subjects (male or female) must agree to use contraception from signing informed consent until 6 months after the last NK510 infusion.
- •Able to comply with the study protocol and follow-up procedures.
- •Voluntarily sign the informed consent form.
排除标准
- •Symptomatic central nervous system (CNS) metastasis and/or carcinomatous meningitis.
- •Active, known or suspected autoimmune diseases (excluding type 1 diabetes, hypothyroidism requiring only hormone replacement therapy, skin diseases not requiring systemic treatment [e.g., vitiligo, psoriasis, alopecia] or diseases not expected to recur without external triggers).
- •History of severe cardiovascular and cerebrovascular diseases, including but not limited to: severe cardiac arrhythmia or conduction abnormalities requiring clinical intervention (e.g., ventricular arrhythmia, grade III atrioventricular block); QTc interval >480 ms on 12-lead ECG at rest; acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other grade ≥3 cardiovascular and cerebrovascular events within 6 months before enrollment; NYHA cardiac function class ≥II or left ventricular ejection fraction (LVEF) <50%; clinically uncontrolled hypertension.
- •Blood transfusion, erythropoietin, granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor treatment within 2 weeks before enrollment.
- •Systemic treatment with corticosteroids (prednisone >10 mg/day or equivalent) or other immunosuppressive/immunomodulatory drugs (e.g., thymosin, interleukin-2, interferon) within 2 weeks before enrollment; inhalation or topical corticosteroids are allowed in subjects without active autoimmune diseases.
- •Known allergy or intolerance to PD-(L)1 blockade.
- •Meeting any of the following laboratory criteria:
- •Hematology: Neutrophils <1.5×10⁹/L; Platelets <75×10⁹/L; Hemoglobin <90 g/L.
- •Liver function: ALT >3×ULN (≥5×ULN in patients with liver metastasis); AST >3×ULN (≥5×ULN in patients with liver metastasis); TBIL >1.5×ULN or >2.5×ULN (3.0 mg/dL) in patients with Gilbert syndrome.
- •Renal function: Serum creatinine >1.5×ULN or creatinine clearance <50 mL/min.
- •Any other severe or uncontrollable medical diseases, active infections, physical examination abnormalities, laboratory test abnormalities, mental status changes or mental illnesses that increase subject risk or affect study results (assessed by investigator).
研究组 & 干预措施
Group C (high-dose group)
NK510 will be administered once a week for a total of six weeks.12×10^9 NK cells/dose.
PD-1 blockade will be administered every 1 or 3 weeks, depending on PD-1 blockade chosed by investigator..
干预措施: Tislelizumab，atezolizumab or sugemalimab (Drug)
Group C (high-dose group)
NK510 will be administered once a week for a total of six weeks.12×10^9 NK cells/dose.
PD-1 blockade will be administered every 1 or 3 weeks, depending on PD-1 blockade chosed by investigator..
干预措施: NK510 (Drug)
Group D2 (high-dose group)
Thoracic perfusion therapy will be conducted on Days 1, 5, 9 and 13, for a total of 4 infusions, with 6×10⁹ NK510 cells/dose for each time via intrapleural infusion, for 2 consecutive cycles. This is a single-treatment-cycle study.
干预措施: systemic therapy as selected by the investigator (Drug)
Group B (medium-dose group)
NK510 will be administered once a week for a total of six weeks.9×10^9 NK cells/dose.
PD-1 blockade will be administered every 1 or 3 weeks, depending on PD-1 blockade chosed by investigator..
干预措施: Tislelizumab，atezolizumab or sugemalimab (Drug)
Group A (low-dose group)
NK510 will be administered once a week for a total of six weeks.3×10^9 NK cells/dose.
PD-1 blockade will be administered every 1 or 3 weeks, depending on PD-1 blockade chosed by investigator.
干预措施: Tislelizumab，atezolizumab or sugemalimab (Drug)
Group B (medium-dose group)
NK510 will be administered once a week for a total of six weeks.9×10^9 NK cells/dose.
PD-1 blockade will be administered every 1 or 3 weeks, depending on PD-1 blockade chosed by investigator..
干预措施: NK510 (Drug)
Group D1 (low-dose group)
Thoracic perfusion therapy will be conducted on Days 1, 5, 9 and 13, for a total of 4 infusions, with 3×10⁹ NK510 cells/dose for each time via intrapleural infusion, for 2 consecutive cycles. This is a single-treatment-cycle study.
干预措施: NK510 (Drug)
Group D2 (high-dose group)
Thoracic perfusion therapy will be conducted on Days 1, 5, 9 and 13, for a total of 4 infusions, with 6×10⁹ NK510 cells/dose for each time via intrapleural infusion, for 2 consecutive cycles. This is a single-treatment-cycle study.
干预措施: NK510 (Drug)
Group D1 (low-dose group)
Thoracic perfusion therapy will be conducted on Days 1, 5, 9 and 13, for a total of 4 infusions, with 3×10⁹ NK510 cells/dose for each time via intrapleural infusion, for 2 consecutive cycles. This is a single-treatment-cycle study.
干预措施: systemic therapy as selected by the investigator (Drug)
Group A (low-dose group)
NK510 will be administered once a week for a total of six weeks.3×10^9 NK cells/dose.
PD-1 blockade will be administered every 1 or 3 weeks, depending on PD-1 blockade chosed by investigator.
干预措施: NK510 (Drug)
结局指标
主要结局
Dose-limiting toxicity and incidence of adverse events
时间窗: 6 weeks
To evaluate DLT and the incidence of AEs associated with NK510 treatment
Objective Response Rate
时间窗: 6 weeks
For intravenous groups: Proportion of subjects achieving CR and PR according to RECIST v1.1 after first NK510 administration; For pleural perfusion groups: Proportion of subjects achieving CR and PR according to WHO criteria after first NK510 intrapleural perfusion.
次要结局
- Progression-Free Survival(From the date of the first dose of NK510 until disease progression, death, or a maximum of 24 months after the first dose, whichever occurs first.)
- Puncture-Free Survival(From the date of the last treatment puncture to the date of the next puncture drainage, or up to a maximum of 24 months after the last treatment puncture, whichever occurs first.)
- Duration of Response(From the date of first documentation of objective response to disease progression, death, or a maximum of 24 months after the date of first response, whichever occurs first.)
- Disease Control Rate(From baseline tumor assessment up to the earliest of disease progression，or a maximum of 24 months after baseline.)
- Overall Survival(From the date of screening enrollment to death, or a maximum of 24 months after screening enrollment, whichever occurs first.)
- Health-Related Quality of Life(At screening, every 6 weeks during treatment, at study completion, or up to a maximum of 24 months after the first dose, whichever occurs first.)