Dual-Target MSLN/FAP CAR-NK Cells for Pleural and Peritoneal Mesothelioma

Официальное название

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

Обзор

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.

Подробное описание

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.

Key objectives are to characterize safety, define the recommended dose and schedule, estimate preliminary antitumor activity, and study pharmacodynamic effects including CAR-NK persistence in blood and serosal fluid, changes in soluble mesothelin-related peptide (SMRP), ctDNA dynamics, and cytokine modulation within pleural or peritoneal compartments.

Вмешательства

• Биопрепарат EB-MF-CAR-NK-01
  Example investigational product: donor-derived allogeneic NK cells engineered to recognize both MSLN-positive tumor cells and FAPpositive stromal elements, manufactured under GMP
• Препарат Fludarabine
  Lymphodepleting chemotherapy administered before CAR-NK infusion
• Препарат Cyclophosphamide
  Lymphodepleting chemotherapy administered before CAR-NK infusion.

Первичные конечные точки

• Incidence of dose-limiting toxicities (DLTs) after first CAR-NK infusion [Срок оценки: 28 days]
• ncidence and severity of treatment-emergent adverse events (TEAEs) [Срок оценки: 12 months]
• Determination of recommended phase 2 dose and schedule (RP2D/RP2S) [Срок оценки: 6 months]

Вторичные конечные точки (5)

• Objective response rate (ORR) by modified RECIST for the pleural cohort and RECIST 1.1 for the peritoneal cohort [Срок оценки: 12 months]
• Disease control rate (DCR) at 12 weeks [Срок оценки: 12 weeks]
• Duration of response (DOR) [Срок оценки: 24 months]
• Progression-free survival (PFS) [Срок оценки: 24 months]
• Overall survival (OS) [Срок оценки: 24 months]

Критерии участия

Критерии включения

• 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 1.
• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking University Shenzhen Hospital — Шэньчжэнь

Идентификаторы

NCT: NCT07510815 · EB-CARNK-CRC-102

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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