Phase 1 Study of EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric Central Nervous System Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Safety: any adverse events associated with one or multiple EGFR806-specific CAR T cell product infusions will be assessed by CTCAE v5.0.
研究概览
简要总结
This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells that are lentivirally transduced to express an EGFR806 specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor cavity or the ventricular system in children and young adults with recurrent or refractory EGFR-positive CNS tumors. The primary objectives of this protocol are to evaluate the feasibility, safety, and tolerability of CNS-delivered fractionated CAR T cell infusions employing intra-patient dose escalation. Subjects with supratentorial tumors will receive sequential EGFR806-specific CAR T cells delivered into the tumor resection cavity, subjects with infratentorial tumors will receive sequential CAR T cells delivered into the fourth ventricle, and subjects with leptomeningeal disease will receive sequential CAR T cells delivered into the lateral ventricle. The secondary objectives are to assess CAR T cell distribution within the cerebrospinal fluid (CSF), the extent to which CAR T cells egress into the peripheral circulation, and EGFR expression at recurrence of initially EGFR-positive tumors. Additionally, tumor response will be evaluated by magnetic resonance imaging (MRI) and CSF cytology. The exploratory objectives are to analyze CSF specimens for biomarkers of anti-tumor CAR T cell presence and functional activity.
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
入排标准
- 年龄范围
- 1 Year 至 26 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 15 and ≤ 26 years
- •Histologically diagnosed EGFR positive Central Nervous System (CNS) tumor
- •Evidence of refractory or recurrent CNS disease for which there is no standard therapy
- •Able to tolerate apheresis or apheresis product available for use in manufacturing
- •CNS reservoir catheter, such as an Ommaya or Rickham catheter
- •Life expectancy ≥ 8 weeks
- •Lansky or Karnofsky score ≥ 60
- •If patient does not have previously obtained apheresis product, patient must have recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy and discontinue the following prior to enrollment:
- •≥ 7 days post last chemotherapy/biologic therapy administration
- •3 half lives or 30 days, whichever is shorter post last dose of anti-tumor antibody therapy
- •Must be at least 30 days from most recent cellular infusion
- •All systemically administered corticosteroid treatment therapy must be stable or decreasing within 1 week prior to enrollment with maximum dexamethasone dose of 2.5 mg/m2/day. Corticosteroid physiologic replacement therapy is allowed.
- •Adequate organ function
- •Adequate laboratory values
- •Subjects of childbearing/fathering potential must agree to use highly effective contraception
排除标准
- •Diagnosis of classic diffuse intrinsic pontine glioma (DIPG)
- •Presence of ≥ Grade 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention
- •Presence of primary immunodeficiency/bone marrow failure syndrome
- •Presence of clinical and/or radiographic evidence of impending herniation
- •Presence of active malignancy other than the primary CNS tumor under study
- •Presence of active severe infection
- •Receiving any anti-cancer agents or chemotherapy
- •Pregnant or breastfeeding
- •Subject and/or authorized legal representative unwilling to provide consent/assent for participation in the 15 year follow up period
- •Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol
研究组 & 干预措施
ARM A (Tumor Cavity Infusion)
Patients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity
干预措施: EGFR806-specific chimeric antigen receptor (CAR) T cell (Biological)
ARM B (Ventricular System Infusion)
Patients with either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the fourth ventricle or lateral ventricle, respectively
干预措施: EGFR806-specific chimeric antigen receptor (CAR) T cell (Biological)
结局指标
主要结局
Safety: any adverse events associated with one or multiple EGFR806-specific CAR T cell product infusions will be assessed by CTCAE v5.0.
时间窗: up to 6 months
The type, frequency, severity, and duration of adverse events as a result of EGFR806-specific CAR T cell infusion will be summarized
Feasibility: The number of successfully manufactured and infused EGFR806-specific CAR T cell product
时间窗: 28 days
The proportion of products successfully manufactured and infused will be measured
次要结局
- Expression of target epitope: assessment of whether EGFR expression changes in relapsed CNS tumors that were EGFR positive prior to treatment with CAR T cells via immunohistochemistry on resected tissue samples.(28 days)
- CAR T cell distribution: The number of subjects with CAR T cell persistence in the cerebrospinal fluid (CSF) and peripheral blood as measured by flow cytometry(up to 6 months)
- Disease response: Assessment of disease response of EGFR-expressing refractory or recurrent central nervous system (CNS) tumors to EGFR806 specific CAR T cell therapy delivered directly into the CNS by cytology and radiology criteria.(up to 6 months)
研究者
Colleen Annesley
Medical Director, Seattle Children's Therapeutics
Seattle Children's Hospital