A Phase I, Open-label, Single-arm, Dose-escalation and Expansion Study of Dual-targeting VEGFR1 and PD-L1 CAR-T Cells in Patients With Pleural, Peritoneal, or Leptomeningeal Metastases From Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- AEs and SAEs
研究概览
简要总结
This is a Phase I, open-label, single-arm, dose-escalation and expansion study designed to evaluate the safety, tolerability, and preliminary antitumor activity of dual-targeting VEGFR1/PD-L1 chimeric antigen receptor (CAR) T-cells in patients with solid tumors presenting with pleural, peritoneal, or leptomeningeal metastases.
Despite advances in systemic therapies, patients with serosal cavity and leptomeningeal dissemination face extremely poor prognoses and limited treatment options due to the unique immunosuppressive tumor microenvironment and the physical barrier of these anatomical sites. Preclinical evidence suggests that simultaneous blockade of VEGFR1-mediated angiogenesis and PD-L1-mediated immune checkpoint signaling via a bispecific CAR-T construct may synergistically overcome local immunosuppression and enhance tumor eradication in these sanctuary sites.
The study consists of two phases: a dose-escalation phase utilizing a standard 3+3 design and backfilling design to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of locoregionally administered CAR-T cells, followed by a dose-expansion phase to further assess safety and preliminary efficacy at the RP2D.
Eligible patients will receive a single infusion of VEGFR1/PD-L1 dual-CAR T-cells via intrapleural, intraperitoneal, or intrathecal routes, depending on the primary site of metastasis. The primary endpoints are the incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs) graded by CTCAE v5.0. Secondary endpoints include objective response rate (ORR) , progression-free survival (PFS), overall survival (OS), and assessment of CAR-T cell persistence and cytokine profiles in peripheral blood and local effusion fluids.
详细描述
The study comprises two independent cohorts based on metastatic site and route of administration:
Cohort 1 - Pleural or Peritoneal Metastases (Intracavitary Administration):
This cohort enrolls patients with solid tumors who have developed pleural or peritoneal metastases and have failed standard-of-care therapies. A standard 3+3 dose-escalation design is applied with three dose levels: 2×10⁶, 5.0×10⁶, and 1.0×10⁷ CAR-T cells/kg. Cells are administered via intrapleural or intraperitoneal injection based on the predominant metastatic site.
Cohort 2 - Leptomeningeal Metastases (Intrathecal Administration):
This cohort enrolls patients with cytologically or radiologically confirmed leptomeningeal metastases from solid tumors who have failed prior standard therapies. A dose-escalation with backfill cohort strategy is employed, with three prespecified dose levels (DL): DL1 at 7.5×10⁶ CAR-T cells, DL2 at 1.5×10⁷ CAR-T cells, and DL3 at 3.0×10⁷ CAR-T cells, all administered via intrathecal injection. The escalation method differs by dose level: DL1 follows an accelerated titration design (single participant), while DL2 and DL3 follow the standard 3+3 design. Backfill cohorts will be initiated only after the DL2 main cohort has completed the DLT observation period and the DL3 main cohort has enrolled 3 participants who have entered the DLT window. Thereafter, newly enrolled patients will be randomly allocated (for dose assignment only) to either the DL2 or DL3 backfill cohorts, with 3 additional participants per level. The final recommended phase II dose (RP2D) for leptomeningeal metastases will be comprehensively determined using pooled safety and tolerability data from both the main escalation and backfill cohorts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion Criteria
- •Male or female participants aged 18 to 75 years. Participants older than 75 years may be enrolled at the investigator's discretion based on overall health status.
- •Females of childbearing potential must have a negative serum or urine pregnancy test. Females who have undergone surgical sterilization or have been postmenopausal for at least 2 years are considered not of childbearing potential.
- •Histologically or cytologically confirmed advanced solid tumors with evidence of serosal cavity metastasis (pleural/peritoneal) and/or leptomeningeal metastasis, who have failed standard-of-care therapies.For leptomeningeal metastasis: patients must have received at least 3 intrathecal chemotherapy infusions with persistent positive CSF cytology and neurological symptoms, OR have re-positivity of CSF cytology after prior clearance.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-
- •Life expectancy > 3 months.
- •Adequate organ and bone marrow function:
- •Absolute neutrophil count ≥ 1.5 × 10⁹/L Platelets ≥ 90 × 10⁹/L Absolute lymphocyte count ≥ 1.0 × 10⁸/L Hemoglobin ≥ 9.0 g/dL ALT/AST ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases) Total bilirubin ≤ 1.5 × ULN Creatinine < 1.5 × ULN AND creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula). Creatinine clearance assessment is required only when creatinine ≥ 1.5 × ULN.
- •Cardiac ejection fraction ≥ 50%. Patients with minimal or moderate pericardial effusion may be enrolled at the investigator's discretion.
- •No other severe concurrent diseases (e.g., active autoimmune diseases, immunodeficiency).
- •Chemotherapy must be discontinued for at least 3 weeks prior to CAR-T cell infusion.
- •Sexually active participants of childbearing potential must agree to use highly effective contraceptive methods from screening through 1 year after CAR-T cell infusion.
- •Voluntary participation with written informed consent obtained prior to any study-specific procedures.
- •Recovery from prior antitumor therapy to ≤ Grade 1 (CTCAE v5.0), except for alopecia, hormone-replacement-controlled hypothyroidism, Grade 2 peripheral neuropathy, vitiligo, well-controlled diabetes, or other chronic toxicities deemed by the investigator to be stable and not interfering with study conduct.
排除标准
- •Known hypersensitivity to cytokines.
- •Active infection requiring systemic anti-infective therapy.
- •Acute or chronic graft-versus-host disease (GVHD).
- •History of malignancies other than the target indication within 5 years prior to screening, with the exception of adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast after curative resection.
- •Active hepatitis B or C, or HIV infection. HBsAg-positive patients may be enrolled if HBV DNA is below the lower limit of normal (LLN) per institutional standard; HCV antibody-positive patients may be enrolled if HCV RNA is below LLN per institutional standard. Carriers require antiviral therapy as clinically indicated and periodic quantitative nucleic acid testing during the study.
- •Prior immunotherapy-related adverse event of Grade ≥ 3, or any other concurrent disease, metabolic dysfunction, physical examination finding, or laboratory abnormality that would reasonably preclude use of the investigational product, confound study results, or place the participant at undue risk.
- •Clinically significant cardiovascular disease, including but not limited to:Congestive heart failure (NYHA Class > 2);Unstable angina;Myocardial infarction within the past 3 months;Supraventricular or ventricular arrhythmia requiring treatment or intervention;Poorly controlled Grade 2-3 hypertension
- •Known psychiatric disorders, alcoholism, drug abuse, or substance dependence that may interfere with study compliance.
- •Active autoimmune disease, history of autoimmune disease, or condition requiring systemic corticosteroids (> 10 mg/day prednisone or equivalent) or immunosuppressive therapy (e.g., post-organ transplantation). Inhaled corticosteroids are permitted.
- •Unstable pulmonary embolism, deep vein thrombosis, or other major arterial/venous thromboembolic events within 6 months prior to enrollment. Patients on anticoagulation therapy must be on a stable dose prior to enrollment.
- •Pregnant or lactating women, or women planning pregnancy during the treatment period or within 1 year after CAR-T cell infusion.Women of childbearing potential unwilling to use highly effective contraception during the treatment period and for 1 year after CAR-T cell infusion. A negative serum or urine pregnancy test (within 48 hours prior to treatment) is required for women of childbearing potential.
- •Any condition that, in the investigator's opinion, precludes the participant from providing written informed consent or complying with study procedures.
- •Any other condition deemed by the investigator as inappropriate for study participation.
研究组 & 干预措施
VEGFR1/PD-L1 Dual-Targeting CAR-T Cell Therapy
Participants receive a single infusion of autologous VEGFR1/PD-L1 dual-targeting chimeric antigen receptor (CAR) T-cells via locoregional administration (intrapleural, intraperitoneal, or intrathecal) depending on the metastatic site. The dose is escalated according to the assigned cohort's protocol.
干预措施: Dual-targeting VEGFR1/PD-L1 CAR-T cells (Biological)
结局指标
主要结局
AEs and SAEs
时间窗: 6 months after infusion
Safety
Dose-limiting toxicity (DLT)
时间窗: 21 days
Tolerability evaluation
Recommended phase II dose (RP2D).
时间窗: Approximately 2 years.
Efficacy dose
次要结局
- Objective Remission Rate (ORR).(From date of first CAR-T cell infusion until the date of first documented disease progression or death,up to 5 years.)
- Progression-Free Survival (PFS ).(From date of first CAR-T cell infusion until the date of first documented disease progression or death，assessed up to 5 years.)
- Duration Of Control Rate (DCR).(From date of first CAR-T cell infusion until the date of first documented disease progression or death，assessed up to 5 years.)
- Duration Of Response (DOR).(From date of first CAR-T cell infusion until the date of first documented disease progression or death，assessed up to 5 years.)
- Overall-Survival (OS).(From date of CAR-T cell infusion until date of death from any cause, assessed up to 5 years)
- CSF Tumor Cell Clearance Rate(Up to 5 years)
- Duration of CSF Clearance(Up to 5 years)
- Neurological Symptom and Intracranial Pressure Improvement Rate(Up to 5 years)
- CAR-T cell numbers.(24 months.)
研究者
Yongsheng Wang
Deputy Director of the Cancer Center of West China Hospital
West China Hospital