A Phase 1 Trial to Evaluate the Safety of EGFR/IL13Rα2 Pool-CAR T Cells in Patients With Recurrent or Progressive High-Grade Glioma (HGG)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Incidence of adverse events
研究概览
简要总结
This phase I trial studies the side effects and best dose of EGFR/IL13Rα2 pool-chimeric antigen receptor (CAR) T cells when given through a thin, flexible tube into the brain (locoregional administration) in treating patients with high-grade gliomas that have come back after a period of improvement (recurrent) or that are growing, spreading, or getting worse (progressive). EGFR/IL13Rα2 pool-CAR T cells are a type of CAR T cell therapy. CAR T cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's tumor cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers.
详细描述
PRIMARY OBJECTIVE:
I. Assess the safety and determine the maximum tolerated dose (MTD) of locoregional administration of autologous anti-EGFR/anti-IL13Rα2 CAR T-cells (EGFR/IL13Rα2 pool-CAR T cell) therapy.
SECONDARY OBJECTIVES:
I. In participants who receive at least 50% of the assigned cell dose for each cycle (1-4) and at least 70% of the total cumulative dose:
- Estimate disease control rate (DCR: complete response [CR] + partial response [PR] +stable disease [SD]);
- Estimate overall response rate (ORR: CR+PR);
- Estimate time to progression (TTP);
- Estimate median overall survival, and;
- Estimate overall survival (OS) at 12-months.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Main Inclusion Criteria
- •Documented informed consent of the participant and/or legally authorized representative.
- •Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with Study PI approval.
- •Age 18 years and older.
- •KPS ≥ 70%, ECOG ≤ 2 (Appendix A).
- •Life expectancy ≥ 4 weeks.
- •Participant has a prior histologically confirmed diagnosis of a glioblastoma (IDH-wildtype) or grade 4 IDH-mutant astrocytoma, or has a prior histologically confirmed diagnosis of a grade 2 or 3 astrocytoma and now has radiographic progression consistent with grade 4 IDH-mutant astrocytoma.
- •Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy (such as temozolomide with or without Optune device), and ≥ 12 weeks after completion of front-line radiation therapy.
- •COH Clinical Pathology assessment at the initial tumor presentation or recurrent disease (reference Appendix B):
- •IL13Rα2+ expression by IHC > 20, and
- •EGFR gene-altered by NGS or FISH analysis
- •No known contraindications to leukapheresis, steroids, imaging studies, or tocilizumab.
- •WBC > 2000 /dl (or ANC ≥ 1,000/mm3)
- •Platelets ≥ 75,000/mm3
- •Hemoglobin > 9g/dL
- •Total bilirubin ≤ 1.5x ULN
- •AST ≤ 2.5x ULN
- •ALT ≤ 2.5x ULN
- •Serum creatinine ≤1.6 mg/dL
- •O2 saturation ≥ 95% on room air.
- •Seronegative for HIV Ag/Ab combo, HCV, and active HBV
- •Women of childbearing potential (WOCBP): negative urine or serum pregnancy test.
- •Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of CAR T cells.
排除标准
- •Owing to higher frequency of wound-related complications, participants who require active bevacizumab therapy at the time of enrollment are excluded.
- •Participant has not yet recovered from toxicities of prior therapy.
- •Participant has received any live vaccine within 30 days prior to enrollment.
- •Uncontrolled seizure activity and/or clinically evident progressive encephalopathy.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent.
- •Clinically significant uncontrolled illness.
- •Active autoimmune disease requiring systemic immunosuppressive therapy
- •Active infection requiring IV antibiotics (for example, minor scalp infection is not exclusion).
- •Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection.
- •Other active malignancy.
- •Females only: Pregnant or breastfeeding.
- •Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures.
- •Prospective participants who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).
研究组 & 干预措施
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Leukapheresis (Procedure)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Echocardiography Test (Procedure)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: FDG-Positron Emission Tomography (Procedure)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Intracranial Catheter Placement (Procedure)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Autologous Anti-EGFR/Anti-IL13Ralpha2 CAR T-cells (Biological)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Biopsy Procedure (Procedure)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (EGFR/IL13Rα2 pool-CAR T cell therapy)
Patients undergo leukapheresis followed by surgical resection, biopsy, and ICT and/or ICV catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per PI and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo ECHO during screening, as well as FDG-PET, MRI, and blood, TCF, and CSF sample collection throughout the study.
干预措施: Resection (Procedure)
结局指标
主要结局
Incidence of adverse events
时间窗: Up to 15 years
Toxicity will be assessed using the Common Terminology Criteria for Adverse Events version 5.0, Cytokine Release Syndrome/Neurotoxicity grading by the American Society for Transplantation and Cellular Therapy Consensus Criteria, Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome grading system, and Tumor Inflammation-Associated Neurotoxicity grading system.
Maximum tolerated dose (MTD)
时间窗: Up to 5 years
The MTD will be determined based on dose limiting toxicities (DLTs), toxicities observed in later cycles (5+), and the activity data. Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence intervals \[CI\]) will be estimated for participants experiencing DLTs at the MTD schedule. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, attributions, and arm.
次要结局
- Time to progression(From surgery/biopsy to last contact or relapse/progression date, assessed up to 15 years)
- Disease response(Up to 15 years)
- Overall survival (OS)(From surgery/biopsy to last contact or death (from any cause), assessed up to 15 years)
- EGFR/IL13Rα2 pool-CAR T cell product feasibility - leukapheresis and manufacturing processes(Up to 5 years)