EGFRvIII Chimeric Antigen Receptor (CAR) Gene-modified T Cells for Patients With Newly-Diagnosed GBM During Lymphopenia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 3
- 试验地点
- 2
- 主要终点
- Maximally Tolerated Dose
研究概览
简要总结
Please note that enrollment on this study terminated early due to the end of grant funding.
Newly diagnosed WHO grade IV malignant glioma subjects who are eligible were enrolled following surgery to remove their brain tumor. They then underwent a leukapheresis to harvest cells for the generation of the study drug, Epidermal Growth Factor variant III Chimeric Antigen Receptor (EGFRvIII CAR) T cells prior to beginning standard of care (SOC) radiation therapy (RT) with temozolomide (TMZ). Once SOC RT with TMZ was completed, subjects returned for the post-RT brain imaging assessment, and, if stable, started post-RT TMZ cycles. Patients received up to 3 cycles of dose-intensified TMZ prior to receiving the EGFRvIII CAR T cells, which was infused in dose escalation cohorts. Following a one-month delay between cycles, the subject resumed post-RT cycles of TMZ and were monitored with blood work and brain imaging as per SOC.
An expanded cohort of 12 subjects was originally planned for once the maximally tolerated dose (MTD) was reached in the dose escalation cohorts, in order to obtain a more precise estimate of the probability of unacceptable toxicity and to track the EGFRvIII CAR T cells using 111 Indium (111In) labeling. Computed Tomography (CT) was planned on days 1, 2, and 3 post-infusion to determine intracerebral (IC) localization.
详细描述
Please note that enrollment on this study terminated early due to the end of grant funding.
Following consent, subjects were enrolled onto dose-escalation cohorts. Patients will underwent leukapheresis to harvest Peripheral Blood Mononuclear Cells (PBMCs) for the generation of EGFRvIII CAR T cells prior to beginning RT and concurrent TMZ. T cells were isolated from the patient's PBMCs and transduced to express the CAR. Briefly, PBMCs were stimulated with Muromonab-cluster of differentiation 3 (CD3) (OKT3), an anti-CD3 monoclonal antibody (mAb), and transduced on RetroNectin® coated plates. Transduced cells were expanded in interleukin-2 (IL-2) for 14 days.
Patients then completed standard of care RT and concurrent TMZ. Patients who remained eligible after standard of care radiation and TMZ received up to 3 cycles of TMZ at 50-100 mg/m^2/day for 21 days of 28 day cycles, which is the standard dose-intensified (DI) TMZ regimen. If the CAR-specific T cells did not meet release criteria, the patient was withdrawn before CAR treatment and replaced.
At least 48 hours after the last dose of DI TMZ, the total dose of EGFRvIII CAR T cells were delivered intravenously. If sufficient CAR-specific T cells could not be generated to meet the targeted assigned dose within the dose-escalation portion of the study, the patient was have been treated at a lower pre-defined dose level using available CAR-specific T cells and replaced in the assigned higher dose. The administered dose would have been the highest defined dose level for which there are sufficient CAR-specific T cells available. Within the expanded cohort, if sufficient CAR-specific T cells could not be generated to meet the MTD dose, all available T cells would be administered.
Following the infusion of EGFRvIII CARs, blood samples for immune monitoring were drawn 1, 5, and 10 days after the infusion, then 1, 3, and 6 months, then yearly until progression (or death or lost to contact). The return visits for immune monitoring at 3 months, 6 months, and yearly coincided with SOC clinic visits. Blood was also taken for Replication Competent Retrovirus (RCR) Polymerase Chain Reaction (PCR) per the Food and Drug Administration (FDA) at 3, 6, and 12 months during SOC clinic visits. Lastly, blood for evaluation of cytokine release syndrome (CRS) was drawn prior to cell infusion, 1 and 4 hours after infusion, and on days 1, 2, 5, 10, and at one month. Measurements for CRS included IL-2, IL-6, Tumor Necrosis Factor alpha (TNFα), interferon (IFN) gamma, Granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein (CRP).
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
- •Age 18-80 years of age
- •Histopathologically proven newly-diagnosed, supratentorial glioblastoma or gliosarcoma (World Health Organization [WHO] Grade IV)
- •Karnofsky Performance Status (KPS) score ≥ 70
- •The presence of the target antigen, EGFRvIII, must be identified on tumor tissue by immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR).
- •Hematology:
- •Absolute Neutrophil Count (ANC) ≥ 1000/mm^3 without the support of filgrastim
- •Platelet count ≥ 100,000/mm^3
- •Hemoglobin ≥ 8.0 g/dl (eligibility level for hemoglobin may be reached with transfusion)
- •Alanine Amino Transferase (ALT)/Aspartate Amino Transferase (AST) ≤ 2.5 times the upper limit of normal
- •Creatinine ≤ 1.6 mg/dl
- •Total bilirubin ≤ 1.5 mg/dl
排除标准
- •Patients who are pregnant, breast-feeding, or unwilling to practice an effective method of birth control
- •Patients with known potentially anaphylactic allergic reactions to Gadolinium-Diethylene Triamine Pentaacetic Acid (gd-DTPA)
- •Patients who cannot undergo Magnetic Resonance Imaging (MRI) or Single Photon Emission-Computed Tomography (SPECT) due to obesity or to having certain metal in their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods, or plates)
- •Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord, or with evidence of leptomeningeal disease
- •Active infection requiring treatment or an unexplained febrile (> 101.5 F) illness
- •Known autoimmune disease, immunosuppressive disease or human immunodeficiency virus (HIV) infection (i.e., known HIV or Hepatitis C)
- •Patients with unstable or severe intercurrent medical conditions such as severe heart or lung disease
- •Patients with previous history of radiosurgery, brachytherapy, gliadel implantation, or radiolabeled monoclonal antibodies
- •Prior antitumor therapy for glioma (other than steroids)
- •Allergic to TMZ
结局指标
主要结局
Maximally Tolerated Dose
时间窗: 12-18 months
Within this "3+3" phase I study, the primary objective is to determine the MTD of a single IV infusion of EGFRvIII CAR T cells in patients with newly-diagnosed WHO grade IV malignant glioma. Four dose levels were to be considered based on transduced cells/kg: #1: 4.5 x 10\^6/kg, #2: 1.5 x 10\^7/kg, #3: 4.5 x 10\^7/kg, and #4: 1.5 x 10\^8/kg. The MTD is the highest dose level at which ≤1 of 3-6 patients experience dose-limiting toxicity during the 4 weeks after CAR infusion.
次要结局
- Number of Patients Who Experienced a Dose-limiting Toxicity (DLT)(12-18 months)
研究者
Daniel Landi
Assistant Professor of Pediatrics and Neurosurgery
Duke University