Phase 1 Open-label Study Evaluating the Safety of CART-EGFR-IL13Rα2 Cells in Patients With Newly Diagnosed, EGFR-Amplified, MGMT-unmethylated Glioblastoma Following Completion of Initial Radiotherapy
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0
研究概览
简要总结
This is an open-label phase 1 study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy of autologous T cells co-expressing two CARs targeting the cryptic EGFR epitope 806 and IL13Ra2 (referred to as "CART-EGFR-IL13Ra2 cells") in patients with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma, without evidence of disease recurrence/progression following completion of initial radiotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Step #1 Inclusion Criteria:
- •Signed informed consent form
- •Male or females age ≥ 18 years.
- •Patients with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma (as defined by WHO 2021 Classification for CNS Tumors, including that the tumor must be IDH wildtype). The tumor must also have histopathologic evidence of glioblastoma (i.e., presence of microvascular proliferation and/or necrosis).
- •Patients must have undergone maximal safe resection of the tumor as per routine cancer care. Patients who have had a biopsy only are not eligible.
- •Tumor tissue positive for wild-type EGFR amplification by Neogenomics Laboratories
- •Karnofsky Performance Status ≥ 60%
- •Patient scheduled to receive 60 Gy of radiotherapy. Either photon or proton therapy is acceptable.
排除标准
- •Active hepatitis B or hepatitis C infection
- •Class III/IV cardiovascular disability according to the New York Heart Association Classification.
- •Tumors with enhancing disease involving the thalamus, brain stem or spinal cord.
- •Tumors with an MGMT promoter methylation result of hypermethylated, methylated, low positive methylated, or indeterminate.
- •Multifocal disease if ≥ 1 focus of tumor has not undergone maximal safe resection
- •Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study.
- •History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
- •Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
- •Anticipated treatment plan that involves bevacizumab, any other systemic anti-neoplastic therapy, and/or tumor-treating fields as part of 1st line therapy.
- •Step #2 Inclusion Criteria:
- •Patient completed full course of radiotherapy to 60 Gy.
- •No overt evidence of disease recurrence/progression post-radiotherapy confirmed by RANO 2.0 criteria.
- •Karnofsky Performance Status ≥ 60%
- •Adequate organ function defined as:
- •Serum creatinine ≤ 1.5x ULN or estimated creatinine clearance ≥ 30 mL/min and not on dialysis
- •ALT/AST ≤ 3 x ILN
- •Total bilirubin ≤ 2.0 mg/dl, except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome (≤ 3.0 mg/Dl)
- •Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA
- •Must have minimum level of pulmonary reserve defined as > 92% on room air
- •Step #2 Exclusion Criteria:
- •Any active, uncontrolled infection.
- •Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study.
- •Clinical or neurological decline related to disease and/or radiotherapy that, in the opinion of the physician-investigator, would preclude participation in this study.
- •Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.
- •Receipt of prior bevacizumab therapy for their newly diagnosed glioblastoma.
- •Receipt of temozolomide for their newly diagnosed glioblastoma.
- •Anticipated post-radiotherapy maintenance treatment that includes tumor treating fields, bevacizumab, or any other anti-neoplastic therapies.
- •Enrollment in any other clinical trial for the treatment of their newly diagnosed glioblastoma.
研究组 & 干预措施
Cohort B (Repeat Cycles Following Lymphodepletion)
CART-EGFR-IL13Ra2 cells will be administered via intracerebroventricular delivery in q6 week cycles of treatment, following lymphodepletion with fludarabine, cyclophosphamide, and rituximab.
干预措施: Fludarabine + Cyclophosphamide combination (Drug)
Cohort A (Single Fixed Dose)
All subjects will receive a single fixed dose of CART-EGFR-IL13Ra2 cells on Day 0 via intracerebroventricular delivery.
干预措施: CART-EGFR-IL13Ra2 cells (Drug)
Cohort B (Repeat Cycles Following Lymphodepletion)
CART-EGFR-IL13Ra2 cells will be administered via intracerebroventricular delivery in q6 week cycles of treatment, following lymphodepletion with fludarabine, cyclophosphamide, and rituximab.
干预措施: CART-EGFR-IL13Ra2 cells (Drug)
Cohort B (Repeat Cycles Following Lymphodepletion)
CART-EGFR-IL13Ra2 cells will be administered via intracerebroventricular delivery in q6 week cycles of treatment, following lymphodepletion with fludarabine, cyclophosphamide, and rituximab.
干预措施: Rituximab or Rituximab biosimilar (Biological)
结局指标
主要结局
Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0
时间窗: Up to 15 years following CART-EGFR-IL13Ra2 administration
Type, frequency, severity, and attribution of adverse events
Occurrence of treatment-limiting toxicities (TLTs)
时间窗: 28 days post-CAR T cell administration
次要结局
- Proportion of enrolled subjects who receive study treatment as planned(28 days following initial treatment with CART-EGFR-IL13Ra2 cells)
- Proportion of eligible subjects who receive study treatment as planned(28 days following initial treatment with CART-EGFR-IL13Ra2 cells)
- Frequency of manufacturing failures(3 months)
- Progression-free Survival (PFS)(Up to 15 years following CART-EGFR-IL13Ra2 administration)
- Overall Survival (OS)(Up to 15 years following initial CART-EGFR-IL13Ra2 administration)
- Objective Response Rate (ORR)(Up to 12 months following CART-EGFR-IL13Ra2 administration)
- Duration of response (DOR)(Up to 15 years following initial CART-EGFR-IL13Ra2 administration)