Phase I Study of Cellular ImmunoTx Using Memory Enriched T Cells Lentivirally Transduced to Express an IL13Rα2-Specific, Hinge-Optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Pts With Rec/Ref MaligGlioma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 65
- 试验地点
- 2
- 主要终点
- Number of Participants With Grade 3 or Higher Toxicity Related to CAR T Cells
研究概览
简要总结
This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. Assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded autologous memory-enriched T cells (Arms 1, 2, 3, or 4 = Tcm or Arm 5 = Tn/mem) that are genetically modified using a self-inactivating (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13Ra2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as a truncated CD19 (CD19t) for participants with recurrent/refractory malignant glioma in one of the following ways: (1) directly into the tumor (intratumoral), (2) into the tumor cavity (intracavitary), (3) into the lateral ventricles (intraventricular), or (4) into both the tumor/tumor cavity (intratumoral) and into the lateral ventricles (intraventricular) (dual delivery).
II. Determine maximum tolerated dose schedule (MTD)/maximum feasible dose schedule (MFD) and a recommended phase II dosing plan (RP2D) for each arm based on dose limiting toxicities (DLTs) and the full toxicity profile.
SECONDARY OBJECTIVES:
I. In research participants who receive the full schedule of three CAR+ T cell doses:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •SCREENING INCLUSION CRITERIA
- •Participant has a prior histologically-confirmed diagnosis of a grade III or IV glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now has radiographic progression consistent with a grade III or IV malignant glioma (MG) after completing standard therapy
- •Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of the initial radiation therapy
- •Karnofsky performance status (KPS) >= 60%
- •Life expectancy > 4 weeks
- •Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
- •City of Hope (COH) Clinical Pathology confirms IL13R alpha 2+ tumor expression by immunohistochemistry (>= 20%, 1+)
- •All research participants must have the ability to understand and the willingness to sign a written informed consent
- •ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION
- •Research participant must not require more than 2 mg three times daily (TID) of dexamethasone on the day of PBMC collection.
- •Research participant must have appropriate venous access
- •At least 2 weeks must have elapsed since the research participant received his/her last dose of prior chemotherapy or radiation
- •ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT
- •Creatinine < 1.6 mg/dL
- •White blood cell (WBC) > 2,000/dl or
- •Absolute neutrophil count (ANC) > 1,000
- •Platelets >= 100,000/dl
- •International normalized ratio (INR) < 1.3
- •Bilirubin < 1.5 mg/dL
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limits of normal
- •An interval of at least 12 weeks must have elapsed since the completion of initial radiation therapy
- •Wash-out requirements (standard or investigational):
- •At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen
- •At least 23 days since the completion of Temodar and/or 4 weeks for any other non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most recent treatment was with a targeted agent only, and s/he has recovered from any toxicity of this targeted agent, then a waiting period of only 2 weeks is needed from the last dose and the start of study treatment, with the exception of bevacizumab where a wash out period of at least 4 weeks is required before starting study treatment
- •ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH CAR T CELL INFUSION
- •Research participant has a released cryopreserved T cell product
- •Research participant does not require supplemental oxygen to keep saturation greater than 95% and/or does not have presence of any radiographic abnormalities on chest x-ray that are progressive
- •Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias
- •Research participant does not have a fever exceeding 38.5° Celsius (C); there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to T cell infusion and/or there aren't any indications of meningitis
- •Research participant serum total bilirubin does not exceed 2 x normal limit
- •Research participant transaminases does not exceed 2 x normal limit
- •Research participant serum creatinine =< 1.8 mg/dL
- •Research participant does not have uncontrolled seizure activity following surgery prior to starting the first T cell dose
- •Research participant platelet count must be >= 100,000; however, if platelet level is between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is given and the post transfusion platelet count is >= 100,000
- •Research participants must not require more than 2 mg TID of dexamethasone during T cell therapy
排除标准
- •SCREENING EXCLUSION CRITERIA
- •Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks
- •Research participant requires pressor support and/or has symptomatic cardiac arrhythmias
- •Research participant requires dialysis
- •Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy
- •Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study; a legal guardian may substitute for the research participant
- •Research participants with any non-malignant intercurrent illness which is either poorly controlled with currently available treatment, or which is of such severity that the investigators deem it unwise to enter the research participant on protocol shall be ineligible
- •Research participants with any other active malignancies
- •Research participants being treated for severe infection or who are recovering from major surgery are ineligible until recovery is deemed complete by the investigator
- •Research participants with any uncontrolled illness including ongoing or active infection; research participants with known active hepatitis B or C infection; research participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections
- •Research participants who have confirmed human immunodeficiency virus (HIV) within 4 weeks of screening
研究组 & 干预措施
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb])
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb]
干预措施: Laboratory Biomarker Analysis (Other)
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb])
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb]
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb])
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb]
干预措施: Magnetic Resonance Spectroscopic Imaging (Procedure)
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb])
Arm 1 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb]
干预措施: Quality-of-Life Assessment (Other)
Arm 2 (Tcm-derived CAR T cells, ICTb/r)
Arm 2 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb] or Intracavitary a/f resection [ICTr])
干预措施: Laboratory Biomarker Analysis (Other)
Arm 2 (Tcm-derived CAR T cells, ICTb/r)
Arm 2 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb] or Intracavitary a/f resection [ICTr])
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 2 (Tcm-derived CAR T cells, ICTb/r)
Arm 2 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb] or Intracavitary a/f resection [ICTr])
干预措施: Magnetic Resonance Spectroscopic Imaging (Procedure)
Arm 2 (Tcm-derived CAR T cells, ICTb/r)
Arm 2 (Tcm-derived CAR T cells, Intratumoral a/f biopsy [ICTb] or Intracavitary a/f resection [ICTr])
干预措施: Quality-of-Life Assessment (Other)
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
干预措施: Laboratory Biomarker Analysis (Other)
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
干预措施: Magnetic Resonance Spectroscopic Imaging (Procedure)
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
Arm 3 (Tcm-derived CAR T cells, Intraventricular [ICV])
干预措施: Quality-of-Life Assessment (Other)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Laboratory Biomarker Analysis (Other)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Magnetic Resonance Spectroscopic Imaging (Procedure)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Quality-of-Life Assessment (Other)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Magnetic Resonance Spectroscopic Imaging (Procedure)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 4 (Tcm-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Quality-of-Life Assessment (Other)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Laboratory Biomarker Analysis (Other)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
Arm 5 (Tn/mem-derived CAR T cells, Dual delivery: both ICTb/r AND ICV)
干预措施: Magnetic Resonance Imaging (Procedure)
结局指标
主要结局
Number of Participants With Grade 3 or Higher Toxicity Related to CAR T Cells
时间窗: An average of 11 months
Grade 3 or higher toxicity profile for adverse events probably or definitely related to CAR T cells as assessed by the NCI CTCAE version 4.0.
Number of Participants Experiencing a Dose Limiting Toxicity (DLT)
时间窗: Up to 1 week following the last course, up to a total of 4 weeks (not including optional courses 4-6)
Toxicities will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT is defined as events attributable to T-cell infusion (probable or definite) with a few expected events that resolve within a specified time and occurring from the time of initial CAR T cell infusion through 1 week following the last infusion cycle (not including optional cycles) unless otherwise specified in this definition: 1. Two grade 3 toxicities at the same dose with the exception of those grade 3 toxicities listed below. 2. Any grade 3 Cytokine release syndrome (CRS) toxicity lasting more than 72 hours without intervention 3. Any grade 3 or higher allergic reaction 4. Any grade 3 or higher autoimmune reaction 5. Any grade 4 toxicity
次要结局
- Number of Participants With Active Response Determined by Response Assessment in Neuro-Oncology (RANO) Criteria(Between 4 and 8 weeks post 1st CAR T infusion)
- Number of Participants Alive at 6 Months(From surgery to death from any cause or six months, whichever occurred first)