A Phase I, Dose-Escalation Trial of Anti-GARP Chimeric Antigen Receptor-T Cell Therapy in Patients With Recurrent High-Grade Glioma Treated at a Single Medical Center
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Dose limiting toxicities
研究概览
简要总结
This phase I trial tests the safety, side effects, and best dose of anti-glycoprotein-A repetitions predominant (GARP) chimeric antigen receptor (CAR) T cell therapy and how well it works in treating patients with grade III or IV gliomas that have come back after a period of improvement (recurrent). 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, such as GARP, 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 tumors. Giving anti-GARP CAR T cell therapy may be safe, tolerable, and/or effective in treating patients with recurrent grade III or IV gliomas.
详细描述
PRIMARY OBJECTIVE:
I. To assess the safety and feasibility of a CAR T targeting GARP for glioma by defining rate, frequency, and severity of dose limiting toxicities (DLT) following intracavity administration to patients with recurrent glioma, to determine recommended phase II dose (RP2D).
SECONDARY OBJECTIVES:
I. To describe the adverse event profile of anti-GARP CAR T cell therapy. II. To describe the cytokine levels and immunophenotype in cerebrospinal fluid (CSF) during and following anti-GARP CAR T cell therapy.
III. To describe the duration of anti-GARP CAR T cell persistence and phenotype in CSF.
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
- •Patients are ≥ 18 years old
- •Capacity to understand and willingness to provide written informed consent
- •Diagnosis or clinical suspicion of recurrent malignant glioma, including:
- •History of high-grade glioma (World Health Organization [WHO] grade III or IV), or
- •Prior, histologically-confirmed diagnosis of grade II glioma with new radiographic findings consistent with a high-grade glioma
- •Imaging and/or histopathological confirmation of recurrent disease, or verification of "high risk" histology confirmed by a biopsy with measurable disease by the Radiologic Assessment in Neuro-Oncology (RANO) criteria
- •Patient has unifocal disease in one hemisphere and is supratentorial. Lesion and edema can not be located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex) or within 2 gyri of motor strip.
- •If on steroids such as dexamethasone, must be on a low dose (≤ 4mg per day) at the time of treatment, and not at an ascending dosage schedule at time of enrollment/leukapheresis
- •Prior to apheresis and treatment 1 a 2- week washout should be observed
- •Subjects must not have received bevacizumab therapy and are not planned to start such therapy
- •Karnofsky performance score (KPS) ≥ 60
- •Subject is a surgical candidate for surgery for malignant glioma with the intent of resecting >80-90% of the tumor as the ideal treatment option
- •White blood cells (WBC) > 4,000 cells/uL
- •Hemoglobin (Hgb) > 7 gm/dL
- •Platelets (Plt) > 100/dL
- •Serum creatinine ≤ 1.5 x institutional upper limit of normal
- •Liver function tests within 1.5 x institutional upper limit of normal
- •Women of reproductive potential must have a negative pregnancy test within 7 days of study start. All patients of reproductive potential must use a physician-approved contraceptive and refrain from sperm donation for at least two weeks prior, during, and six months after final T cell infusion. Women must refrain from breastfeeding for six months after final T cell infusion
- •Sufficient venous access, to be confirmed prior to apheresis
- •Life expectancy of greater than 12 weeks
- •PI clinical judgement of patients who will likely complete the trial and are able to maintain stable neurologic symptoms during intervention period
排除标准
- •Patients who have a history of malignancy other than the glioma under investigation in this study, except patients with the following malignancies/treatment characteristics, who are eligible at the investigator's discretion:
- •Patients with a history of malignancy that has been treated with curative intent at least 2 years prior to screening and with no evidence of relapse, if no concurrent anti-cancer therapy (except hormonal therapy) is being given
- •Patients with a history of malignancy with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer
- •Patients who have prostate cancer with no evidence of metastatic disease and are not on active therapy, except anti-androgen therapy
- •History of autoimmune disease, or other diseases require long-term administration of high-dose steroids [> 10 mgs/day] or immunosuppressive therapies
- •Research participants who received steroids must have either received their last dose of steroids 7 days or more prior to apheresis or have dosage tapered to < 2mg/kg/day
- •Patients being treated concurrently (within 14 days prior to study enrollment) with any other investigational agent
- •Examples of other investigational agents that would be exclusionary include supportive care agents
- •Patients receiving anti-cancer agents such as chemotherapy (e.g., temozolomide) must stop treatment 14 days prior to undergoing apheresis and remain off therapy throughout the duration of CAR T therapeutic intervention
- •Patients with active fungal, bacterial, viral, or other infection that requires intravenous antimicrobials
- •Prophylactic antimicrobials are allowed
- •Patients with active invasive fungal infection should be excluded even if the treatment is oral antimicrobials
- •History of allergy to study products/diluents/emulsions
- •Recent history (within last 3 months) of uncontrolled seizures
研究组 & 干预措施
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Anti-GARP Chimeric Antigen Receptor-T Cells (Biological)
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Chest Radiography (Procedure)
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Echocardiography Test (Procedure)
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Multigated Acquisition Scan (Procedure)
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Pheresis (Procedure)
Treatment (anti-GARP CAR T cell)
Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo ECHO or MUGA at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and MRI throughout the study.
干预措施: Surgical Procedure (Procedure)
结局指标
主要结局
Dose limiting toxicities
时间窗: Up to 30 days after the first dose
The rate, frequency and severity will be defined using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. Will be summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
次要结局
- Incidence of adverse events(Up to 30 days after last dose of study drug)
- Cytokine levels and immunophenotype in cerebrospinal fluid (CSF)(During and following therapy, assessed up to 15 years)
- Duration of anti-glycoprotein-A repetitions predominant (GARP) chimeric antigen receptor (CAR) T cell persistence and phenotype in CSF(Up to 15 years)
- Objective response rate (ORR)(Up to 15 years)
- Progression-free survival (PFS)(From initiation of therapy to the time of progression or death, assessed up to 15 years)
- Overall survival (OS)(From initiation of therapy to death, assessed up to 15 years)
- Correlation of GARP expression levels with outcomes(At pre- and post-treatment, assessed up to 24 months)
- Frequency and phenotype of anti-GARP CAR T cells in tumor tissue(At progression, assessed up to 15 years)
研究者
James Elder
Principal Investigator
Ohio State University Comprehensive Cancer Center