Targeting Recurrent Glioblastoma With Anti-CD3 x Anti-EGFR Bispecific Antibody Armed T Cells: A Phase I/II Study
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Incidence of toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)
研究概览
简要总结
This phase I/II trial studies the side effects and best dose of epidermal growth factor receptor bispecific antibody (EGFRBi)-armed autologous T cells and how well it works in treating patients with glioblastoma that have come back or does not respond to treatment. EGFRBi-armed autologous T cells coated with antibodies (proteins used by the immune system to target and kill foreign objects such as cancer cells) may have great ability to seek out, attach to, and destroy glioblastoma cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) for 8 intrathecal (IT) injections (via lumbar puncture) of anti-cluster of differentiation (CD)3 × anti-EGFRBi armed activated T cells (aATC) (EGFRBi-armed autologous T cells) given twice per week for 4 weeks in a standard 3+3 dose escalation schema with 0.10, 0.50 and 1.00 × 10^9 EGFRBi-aATC per IT injection for a total of 0.8, 4.0, and 8.0 × 10^9 cells, respectively. (Phase I) II. To explore efficacy and confirm the toxicity profile of EGFRBi-aATC. (Phase II)
SECONDARY OBJECTIVES:
I. Measure immune responses in participants of the phase I/II trial by sequential monitoring of phenotype, interferon gamma (IFN-g) enzyme-linked immunoSpots (EliSpots), anti-glioblastoma (GBM) cytotoxicity of peripheral blood mononuclear cell (PBMC) (direct cytotoxicity against GBM cells) directed at GBM cell lines, T-helper 1 (Th1)/T-helper 2 (Th2) serum cytokine patterns, and anti-glioma antibodies in the cerebrospinal fluid (CSF)/serum during the "vaccinate and consolidate" process.
II. Assess survival and persistence of aATC in the CSF, and trafficking of IT-injected aATC out of the CSF into the bloodstream.
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
- •Histologically-confirmed intracranial glioblastoma or gliosarcoma (World Health Organization [WHO] grade IV) with evidence of clinical and radiographic (computed tomography [CT] or MRI brain) tumor progression (need not be biopsy proven)
- •Patients who have undergone prior resection, radiation therapy, and/or chemotherapy (except bevacizumab)
- •Karnofsky performance score >= 70 or Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1
- •Patient agrees to undergo a baseline and a follow-up 11C-alpha-methyl-L-tryptophan (AMT)-PET scan during immunotherapy (IMT)
- •No serious medical or psychiatric illness which prevents informed consent or intensive treatment is allowed
- •Non pregnant: negative serum test for pregnancy, unless male, prior hysterectomy, tubal ligation, or postmenopausal; (Note: postmenopausal is defined as age > 55 with amenorrhea for > 1 year or age < 55 years with amenorrhea for 2 years and follicle stimulating hormone (FSH) level within postmenopausal range of institutional parameters; patients requiring FSH level to determine menopausal status need not have this performed and may choose to proceed with serum pregnancy testing)
- •Required initial laboratory data (normal limits per treating institution; minor changes from the indicated laboratory guidelines will be allowed at the discretion of the treating team under special circumstances and reasons for the changes will be documented):
- •Granulocytes >= 1,000/mm^3
- •Absolute lymphocyte count >= 500/mm^3
- •Platelet count >= 50,000/ul
- •Hemoglobin >= 8 gm/dl
- •Blood urea nitrogen (BUN) =< 1.5 times normal
- •Serum creatinine < 1.8 mg/dl
- •Creatinine clearance >= 50 ml/mm (can be calculated utilizing the Cockcroft & Gault equation)
- •Bilirubin < 1.5 times upper limit of normal
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 times upper limit of normal
- •Alkaline phosphatase < 5 times upper limit of normal
- •Prothrombin time (PT) or international normalized ratio (INR) and activated partial thromboplastin time (aPTT) < 1.2 times upper limit of normal
- •Negative human immunodeficiency virus (HIV)-1/2 serology
- •Negative hepatitis B surface antigen
- •Negative hepatitis C serology
- •Left ventricular ejection fraction (LVEF) >= 45% at rest (multi gated acquisition [MUGA] or echocardiogram [ECHO])
- •Each patient must be aware of the nature of their disease and must willingly consent to treatment after being informed of alternatives, potential benefits, side effects, and risks
- •Surgery is done prior to IMT if needed for palliation, tumor debulking, pathological documentation of tumor recurrence; the patients may continue on study therapy even if they do not have measurable disease
- •No other investigational agents, immunomodulating agents, or cancer chemotherapy are permitted for the duration and 12 months following the study IMT unless there is disease progression; radiotherapy is not permitted; appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive care are to be used as necessary
排除标准
- •Resective surgery within 2 months prior to the initial pre-treatment AMT-PET scan
- •Severe increased intracranial pressure, status epilepticus, or other serious complications from the brain tumor, requiring emergency or urgent intervention
- •Patients with a history of another malignancy within 5 years of study enrollment
- •Patients with extracranial metastases
- •Evidence of active bleeding or bleeding diathesis
- •Patients will be ineligible for treatment on this protocol if (prior to protocol entry):
- •There is a history of a recent (within one year) myocardial infarction
- •There is a current or prior history of angina/coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by MUGA or ECHO)
- •There is clinical evidence of congestive heart failure requiring medical management (irrespective of MUGA or ECHO results)
结局指标
主要结局
Incidence of toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)
时间窗: Up to 7 days after the last infusion
Overall survival (OS) (Phase II)
时间窗: From study enrollment to death due to any cause, assessed up to 2 years
The median OS will be estimated with 95% confidence interval. Kaplan-Meier estimate of OS will be plotted. For quantitative measurements in immune evaluations, will calculate their means, standard deviations, medians, and examine the distributions of these data to ascertain whether normal theory methods are appropriate. Paired t-test or Wilcoxon signed-ranks test will be used for comparative analyses between each post-IMT time point versus pre-IMT.
次要结局
- Changes in cytotoxic T-lymphocyte as measured by IFN-gamma EliSpots directed at autologous tumor or GBM cell lines(Baseline to up to 1 year)
- Change in cytokines profiles(Baseline to up to 1 year)
- Changes in activated T cells(Baseline to up to 1 year)
- Changes induced by IMT(Baseline to up to 1 year)
- Human anti-mouse antibody responses(Up to 1 year)
- Peripheral blood measures(Up to 1 year)
研究者
Sandeep Mittal
Principal Investigator
Barbara Ann Karmanos Cancer Institute