Phase I Clinical Trial of Anti-CD3 × Anti-EGFR Bispecific-armed T Cells (EGFR BATs) and Low-Intensity Focused Ultrasound (LIFU) Blood-brain Barrier Opening in Patients With MGMT Unmethylated Glioblastoma (GBM)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- The safety of this treatment will be evaluated through the number of participants experiencing Grade ≥3 dose-limiting toxicities (DLTs).
研究概览
简要总结
This is a phase 1 study for patients with newly diagnosed MGMT unmethylated IDH wild-type glioblastoma utilizing autologous activated T-cells armed with bispecific antibody (EGFR-BATs) that recognize the tumor. The investigators hypothesized that the combination of infusions of EGFR BATs and low-intensity focused ultrasound would induce blood-brain barrier opening and increase the permeability of the adoptive immunotherapy. The investigators will radiolabel the EGFR BATs with 89Zr-oxine for subsequent PET imaging to determine the trafficking and uptake of this approach. There is a concern that several infusions of EGFR BATs before BBB opening could change the immune tumor microenvironment that would not allow a permissive BBB after LIFU. Therefore, Arm A will have two LIFU with BBB opening after the 4th and the 8th infusion, and Arm B will have three LIFU with BBB opening after the 1st, 4th, and 8th infusions. This study will determine the safety and feasibility of the combination of low-intensity focused ultrasound (LIFU) with microbubbles BBB opening and EGFR BATs and the access of the adoptive cell immunotherapy to the tumor microenvironment to inform future studies.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed supratentorial glioblastoma or gliosarcoma IDH wildtype and MGMT unmethylated that express EGFR (score ≥ 1 by IHC)) and confirmed by UVA pathology review.
- •Age ≥ 18 and ≤ 70 years at the time of signing informed consent.
- •Karnofsky Performance Status (KPS) ≥
- •Be willing and able to provide written informed consent for the trial.
- •Females of childbearing potential, and males, must be willing to use an effective method of contraception.
- •Maximal surgical debulking of the tumor was performed where residual contrast enhancement is 2 cm3 or less on immediate post-operative MRI. Intraoperative post-resection MRI is acceptable.
- •Able to communicate during the LIFU BBB opening procedure.
- •BBB opening target(s) must lie in non-eloquent area(s).
- •The brain tumor to be treated must be in the treatment envelope of the NaviFUS system with a minimum distance of 30 mm from the inner skull table.
- •Females of childbearing potential should have a negative serum pregnancy test. Males who are partners of females of childbearing potential must agree to use an acceptable method of contraception throughout the study and for 1 month following completion of the EGFR BATs infusions.
- •Demonstrate adequate organ function as defined in Table
- •All screening labs should be performed within 10 days before leukapheresis.
排除标准
- •Patients with a diagnosis of another malignancy within 2 years of being on-study. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or any type of in situ cancer. Patients must not be on any treatment for another malignancy.
- •Patients undergoing only biopsy (partial resection or greater is required).
- •Patients with cerebellar or brainstem tumors.
- •Patients with evidence of leptomeningeal dissemination or subependymal spread on initial MRI.
- •Patients with extracranial metastases.
- •Patients with evidence of acute intracranial hemorrhage.
- •Known hypersensitivity to cetuximab or another EGFR antibody.
- •Known sensitivity to gadolinium-based contrast agents.
- •Known sensitivity to Lumason® ultrasound contrast agent.
- •Alpha 1,3 Galactose IgE ("alpha gal") test result outside of the reference range (indicating likely hypersensitivity to cetuximab).
- •Patients with claustrophobia.
- •Clips, shunts, or other non-MRI compatible metallic implanted objects in the skull or the brain.
- •Evidence of active bleeding or bleeding diathesis.
- •Unable to discontinue use of anticoagulant therapy as per local standard.
- •Scalp atrophy or scars in the expected location of the ultrasound transducer.
- •Cardiac Status: Patients will be ineligible for treatment on this protocol if (before protocol entry):
- •There is a history of a recent (within one year) myocardial infarction or stroke.
- •There is a current or prior history of angina/coronary symptoms requiring medications and/or a history of depressed left ventricular function (LVEF < 45%).
- •Patient has a pacemaker.
- •There is clinical evidence of congestive heart failure requiring medical management.
- •Has Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- •Has received a live vaccine within 30 days of leukapheresis.
- •Has received any treatment for GBM besides surgery.
- •Females must not be pregnant or breastfeeding.
- •Ongoing immunosuppressive therapy except for corticosteroids
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- •A patient may be excluded if, in the opinion of the treating investigator, the patient is not capable of being compliant.
研究组 & 干预措施
Arm A
Arm A will have Low-Intensity Focused Ultrasound (LIFU) after infusions 4 and 8.
干预措施: anti-EGFR bispecific-armed T cells (Drug)
Arm A
Arm A will have Low-Intensity Focused Ultrasound (LIFU) after infusions 4 and 8.
干预措施: Low-Intensity Focused Ultrasound (Device)
Arm B
Arm B will have Low-Intensity Focused Ultrasound (LIFU) after infusions 1, 4 and 8.
干预措施: anti-EGFR bispecific-armed T cells (Drug)
Arm B
Arm B will have Low-Intensity Focused Ultrasound (LIFU) after infusions 1, 4 and 8.
干预措施: Low-Intensity Focused Ultrasound (Device)
结局指标
主要结局
The safety of this treatment will be evaluated through the number of participants experiencing Grade ≥3 dose-limiting toxicities (DLTs).
时间窗: 8 weeks
The safety will be evaluated by determining the number of participants who experience Grade ≥3 DLTs according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 during EGFR BAT and LIFU BBB opening after RT/TMZ. The scale displays Grades 1 through 5 and refers to the severity of the AE. A higher grade (e.g., 5) represents a worse outcome.
The feasibility of this treatment will be determined by the proportion of participants achieving ≥75% of the recommended EGFR BATs dose
时间窗: 8 weeks
The feasibility of this treatment will be determined by calculating the proportion of participants achieving ≥75% (60 x 10\^9 EGFR BATs) of the recommended Phase II EGFR BAT dose.
Incidence and severity of treatment-emergent adverse events (AEs) based on physical examination, vital signs, laboratory parameters, serum chemistry and hematology
时间窗: 8 weeks
Safety will be quantified using AE counts and severity grading per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Physical examinations, vital signs, and laboratory studies will be recorded.
Brain uptake of 89Zr-oxine-labeled EGFR BATs measured by PET standardized uptake values (SUV) with and without LIFU BBB opening
时间窗: 8 weeks
Three PET imaging scans will be taken to quantify trafficking of labeled EGFR BATs into the GBM microenvironment. PET signal (SUV) will be compared across time points and between LIFU BBB-opened and non-opened regions.
次要结局
- Change from baseline in peripheral immune response markers (CTL cytotoxicity)(8 weeks)
- Change from baseline in peripheral immune response markers (IFN-γ ELISpot Counts)(8 weeks)
- Change from baseline in peripheral immune response markers (Th1/Th2 serum cytokine concentrations)(8 weeks)
- PET-based quantification of 89Zr-oxine-labeled EGFR BAT trafficking across the BBB and into the GBM microenvironment after infusions and Low Intensity Focused Ultrasound (LIFU).(8 weeks)
- PET-based quantification of 89Zr-oxine-labeled EGFR BAT trafficking across the BBB and into the GBM microenvironment with versus without Low Intensity Focused Ultrasound (LIFU).(8 weeks)
- Quantitative levels of circulating tumor DNA (ctDNA)(8 weeks)
- Quantitative levels of antibodies against tumor-associated antigens (IgG anti-EGFR and IgG anti-HER2)(8 weeks)
- Progression-free survival (PFS) measured using modified Response Assessment in Neuro-Oncology (RANO) criteria.(From date of surgery to date of first documented progression, assessed up to 104 weeks.)
- Overall survival (OS)(From date of surgery to date of documented death, assessed up to 104 weeks.)
- Correlation between immune response measures and clinical outcomes(From baseline until 1-year post-treatment completion)
- Objective response rate (ORR) per modified Response Assessment in Neuro-Oncology (RANO) criteria(From baseline until 1-year post-treatment completion)
- Incidence and severity of adverse events (AEs) and laboratory abnormalities(From baseline through 30-days post-treatment completion)
研究者
Camilo E. Fadul, MD
Joan and Ronald Butcher, Professor of Neurology
University of Virginia