A Phase 1/2, Open-Label, Nonrandomized, Biomarker-Guided Study of Locoregional Allogeneic Dual-Target Mesothelin (MSLN) / Fibroblast Activation Protein (FAP) Chimeric Antigen Receptor Natural Killer Cells in Adults With Unresectable, Recurrent, or Refractory Pleural or Peritoneal Mesothelioma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicities (DLTs) after first CAR-NK infusion
研究概览
简要总结
This example study evaluates locoregional allogeneic dual-target mesothelin/FAP CAR-NK cells in adults with unresectable, recurrent, or refractory pleural or peritoneal mesothelioma.
Eligible participants must have central confirmation of MSLN-positive tumor cells and FAP-positive tumorassociated stroma. The phase 1 portion defines the recommended phase 2 dose and schedule, and the phase 2 expansion explores preliminary antitumor activity, persistence, and biomarker response in pleural and peritoneal disease cohorts.
详细描述
Mesothelioma remains a difficult serosal malignancy with limited curative options in recurrent or refractory disease. Mesothelin (MSLN) is a well-established tumor-associated antigen in malignant pleural mesothelioma and other serosal tumors, while fibroblast activation protein (FAP) is relevant in the dense, immunosuppressive stromal compartment that can limit immune-cell trafficking and persistence. For this example, MSLN is retained as the anchor target and FAP is selected as the preferred second target after assessment.
Screening includes central pathology review using archival or fresh tissue and, where available, complementary liquid-biopsy profiling. Participants enter this dual-target study only if both MSLN and FAP meet pre-specified positivity thresholds. If only one actionable target is confirmed, the participant should be considered for a companion single-target protocol rather than this draft dual target protocol.
The study is designed as an open-label, biomarker-guided phase 1/2 trial with two nonrandomized parallel cohorts defined by disease site: pleural mesothelioma and peritoneal mesothelioma.
Part 1uses staggered locoregional dose escalation to determine the recommended phase 2 dose and schedule.
Part 2 expands each cohort at the selected dose. Participants receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide before CAR-NK infusion. Delivery is intrapleural for pleural mesothelioma and intraperitoneal for peritoneal mesothelioma. A repeat infusion may be permitted between Day 21 and Day 35 if there is no dose-limiting toxicity and no radiographic progression.
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
盲法说明
No masking is used because this is a first-in-disease-site early-phase cell-therapy study with route-specific locoregional administration, dose-escalation decisions, and intensive safety monitoring that require real-time knowledge of treatment assignment.
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
- •Age 18 to 75 years at the time of consent.
- •Histologically confirmed malignant pleural mesothelioma or malignant peritoneal mesothelioma; unresectable, recurrent, metastatic, or refractory disease.
- •Prior receipt of at least one standard systemic regimen for mesothelioma, or documented ineligibility, intolerance, or refusal of standard therapy considered reasonable by the investigator.
- •Central biomarker confirmation of MSLN-positive tumor cells and FAP-positive tumorassociated stroma at protocol-defined thresholds.
- •At least one measurable or evaluable lesion by cohort-appropriate imaging criteria.
- •ECOG performance status 0 to
- •Adequate bone marrow, renal, hepatic, coagulation, cardiac, and pulmonary function to undergo lymphodepletion and locoregional cell infusion.
- •Safe procedural access for intrapleural or intraperitoneal administration, as applicable.
- •Recovery to Grade 1 or better from prior anticancer therapy toxicities, except alopecia, stable neuropathy, or controlled endocrine replacement.
- •Life expectancy of at least 12 weeks.
- •Negative pregnancy test for participants of childbearing potential and agreement to use protocoldefined contraception.
- •Ability to understand and sign informed consent
排除标准
- •Active or untreated CNS metastases, leptomeningeal disease, or uncontrolled seizures.
- •Uncontrolled bacterial, fungal, viral, or mycobacterial infection, including empyema, active pleural space infection, peritonitis, or uncontrolled HBV, HCV, or HIV infection.
- •Autoimmune disease requiring systemic immunosuppression within 14 days before lymphodepletion, or prednisone equivalent greater than 10 mg/day.
- •Clinically significant cardiovascular disease, uncontrolled arrhythmia, unstable angina, recent myocardial infarction, or other condition judged to increase infusion risk.
- •Severe interstitial lung disease, baseline oxygen requirement, or other pulmonary compromise making pleural therapy unsafe.
- •Bowel perforation risk, uncontrolled bowel obstruction, uncontrolled ascites, or any abdominal condition that makes intraperitoneal infusion unsafe in the peritoneal cohort.
- •Prior gene-modified cell therapy directed against MSLN or FAP within the protocol washout period, or active graft-versus-host disease after prior transplant.
- •Need for concurrent systemic anticancer therapy other than protocol-permitted supportive care.
- •Pregnancy or breastfeeding.
- •Any medical, psychiatric, social, or logistical condition that, in the investigator's judgment, could compromise safety, compliance, or interpretability of study results.
研究组 & 干预措施
Pleural Mesothelioma Cohort
Participants with malignant pleural mesothelioma receive lymphodepleting chemotherapy followed by locoregional intrapleural infusion of the dual-target allogeneic CAR-NK product.
干预措施: EB-MF-CAR-NK-01 (Biological)
Peritoneal Mesothelioma Cohort
Participants with malignant peritoneal mesothelioma receive the same conditioning backbone and product platform, but the CAR-NK cells are delivered by locoregional intraperitoneal administration.
干预措施: EB-MF-CAR-NK-01 (Biological)
Pleural Mesothelioma Cohort
Participants with malignant pleural mesothelioma receive lymphodepleting chemotherapy followed by locoregional intrapleural infusion of the dual-target allogeneic CAR-NK product.
干预措施: Fludarabine (Drug)
Peritoneal Mesothelioma Cohort
Participants with malignant peritoneal mesothelioma receive the same conditioning backbone and product platform, but the CAR-NK cells are delivered by locoregional intraperitoneal administration.
干预措施: Fludarabine (Drug)
Pleural Mesothelioma Cohort
Participants with malignant pleural mesothelioma receive lymphodepleting chemotherapy followed by locoregional intrapleural infusion of the dual-target allogeneic CAR-NK product.
干预措施: Cyclophosphamide (Drug)
Peritoneal Mesothelioma Cohort
Participants with malignant peritoneal mesothelioma receive the same conditioning backbone and product platform, but the CAR-NK cells are delivered by locoregional intraperitoneal administration.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs) after first CAR-NK infusion
时间窗: 28 days
ncidence and severity of treatment-emergent adverse events (TEAEs)
时间窗: 12 months
ncidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), cytokine release syndrome, neurotoxicity, pleuritis/peritonitis, infusion reactions, and on-target/off-tumor toxicities graded by CTCAE v5.0 and ASTCT crit
Determination of recommended phase 2 dose and schedule (RP2D/RP2S)
时间窗: 6 months
次要结局
- Duration of response (DOR)(24 months)
- Progression-free survival (PFS)(24 months)
- Objective response rate (ORR) by modified RECIST for the pleural cohort and RECIST 1.1 for the peritoneal cohort(12 months)
- Disease control rate (DCR) at 12 weeks(12 weeks)
- Overall survival (OS)(24 months)