NCT02654821Unknown1 期
Multicenter Phase I/IIa Study Using T-cell Receptor Gene Therapy in Metastatic Melanoma
适应症
试验速览
- 阶段
- 1 期
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- Safety of the TCR treatment (according to CTCAE 4.0)
研究概览
简要总结
Patients with stage IV melanoma (also eye melanoma) will be treated with TCR transduced cells.
详细描述
In this multicenter phase I/IIa trial 25 patients will be treated with non-myeloablative chemotherapy followed by adoptive transfer of autologous TCR transduced T cells, to study the feasibility, safety and efficacy of this treatment.
Patients will receive a non-myeloablative lymphocyte-depleting preparative regimen consisting of cyclophosphamide (60 or 30 mg/kg/day x 2 days i.v.) and fludarabine (25 mg/m2/day i.v. x 5 days). Following this regimen, patients will receive one single intravenous adoptive transfer of transduced T cells starting with the first dose level.
- Dose level 1: 5x10^7 transduced T cells, cyclophosphamide 60 mg/kg/day
- Dose level 1a: 1,0x10^8 transduced T cells, cyclophosphamide 30 mg/kg/day
- Dose level 2: 2,5x10^8 transduced T cells, cyclophosphamide 60 mg/kg/day
- Dose level 3: maximum 1x10^9 transduced T cells (depending on production yield). At time points 4, 8, and 12 weeks and every 3 months thereafter patients will be evaluated for response to treatment. After 3 patients have been treated in each dose level, but not before 8 weeks after the last patient has been infused with transduced T cells, the DSMB will be informed about the observed toxicity and efficacy within this cohort and decide, based on this information, whether the trial will be continued to the next dose level or will continue in the current dose level. The study will continue as the first stage (2-stage Simon), until a total of 16 patients have been enrolled and treated: if less than 2 responses are observed, the trial will be stopped and the conclusion will be that TCR lacks efficacy. Otherwise, the trial will continue its second stage. In addition, safety data after these first 16 patients will be evaluated by the DSMB. Any unexpected or serious (grade 3/4 or higher) toxicities during the trial, will be reported immediately to the DSMB and CCMO. Second stage: overall 25 patients will be enrolled (including the first stage): if the total number of responses for the two stages combined is less than 5, the trial will be stopped as soon as this is evident and the conclusion will be that TCR lacks efficacy.
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 must be ≥ 18 years of age.
- •Patients must have inoperable stage IIIc or stage IV melanoma (AJCC), including ocular or mucosal melanoma, progressing after standard of care therapy, if available.
- •Patients must be HLA-A*0201 positive.
- •The primary tumor and/or metastasis have to be positive for MART-1 (>10% of tumor cells).
- •Patients with measurable disease (RECIST 1.1)
- •Patients must have a clinical performance status of ECOG 0 or
- •Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen.
- •Patients must be able to understand and sign the Informed Consent document. Specific lab values
排除标准
- •Life expectancy of less than three months.
- •Requirement for systemic steroid therapy.
- •Patients who have a history of CNS metastases.
- •Patients with malignant pleural effusion or ascites.
- •Any immunosuppressive chemotherapy or systemic steroid therapy within the last 3 weeks.
- •Patients who have: history of coronary revascularization, documented LVEF of less than 45%, clinically significant atrial and/or ventricular arrhythmias including but not limited to atrial fibrillation, ventricular tachycardia, 2° or 3° heart block, documented FEV1 less than or equal to 60% predicted for patients with a history of cigarette smoking (greater than 20 pack/year within the past 2 years) and with symptoms of respiratory distress
- •All patients' toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less.
- •Women who are pregnant or breastfeeding, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. A negative pregnancy test before inclusion in the trial is required for all women of child bearing potential.
- •Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune disease requiring anti-TNF treatment.
结局指标
主要结局
Safety of the TCR treatment (according to CTCAE 4.0)
时间窗: Baseline until release from the hospital, about 4 weeks.
Safety of the TCR treatment will be measured by noting the toxicity (according to CTCAE 4.0) that the patient experiences while on treatment.
Objective response rate according to RECIST 1.1.
时间窗: Baseline until progressive disease, median 6 months.
The objective response rate will be measured by RECIST 1.1.
次要结局
- Overall survival(Assessed up to 12 months)
- Systemic release of inflammatory cytokines after administration of transduced T cells compared to baseline(Baseline until progressive disease, median 6 months.)
- Efficacy of induction of tumor specific T cell responses as measured by the persistence of Melan-A/MART1 specific T cells in peripheral blood samples(Baseline until progressive disease, median 6 months.)
- 1-year progression free survival (PFS)(Baseline until 1 year after treatment.)
研究者
研究点 (2)
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