A Phase II Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 158
- 试验地点
- 1
- 主要终点
- Clinical Response
研究概览
简要总结
Background:
- Most therapeutic therapies for metastatic melanoma have focused on the ability of T-cell lymphocytes to kill cells of tumors.
- An adaptive cell transfer therapy has been pioneered, in which cells are grown for a short time in the laboratory. The way they are grown may have a better effect in a patient's body than do other cells that are cultured for a longer time.
Objectives:
- To determine whether tumor-infiltrating lymphocytes (TIL) can be put in cells removed from patients' tumors or blood and then reinfused, with the purpose of shrinking tumors.
- To evaluate safety and effectiveness of the treatment.
Eligibility:
- Patients 18 years of age or older with metastatic cancer melanoma (cancer that has spread beyond the original site).
- Patient's leukocyte antigen type is human leukocyte antigens (HLA-A) 0201.
Design:
-Patients undergo the following procedures:
- Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory, and the TIL cells (called young TIL cells) are inserted into the cells using an inactivated (harmless) virus in a process called retroviral transduction. Cells collected in the second leukapheresis procedure are used to evaluate the effectiveness of the study treatment.
- Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) over 1 hour for 2 days to suppress the immune system so that the patient's immune cells do not interfere with the treatment.
- Treatment with young TIL cells. Patients receive an IV infusion of the treated cells, followed by infusions the drug aldesleukin-2 (IL-2), which helps boost the effectiveness of the treated white cells.
- Patients are given support medications to prevent complications such as infections.
- Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue).
- Patients are evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans, 4 to 6 weeks after treatment and then once a month for 3 to 4 months to determine the response to treatment.
- Patients have blood tests at 3, 6, and 12 months and then annually for 5 years.
详细描述
Background:
- Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to an autologous patient with high dose (HD) IL-2 following a non-myeloablative (NMA) but lymphodepleting chemotherapy preparative regimen.
- Clinical investigations and preclinical animal models have demonstrated that less time in culture, longer telomeres, and a less differentiated lymphocyte phenotype are associated with TIL that are capable of mediating objective clinical responses and persisting long term in the host.
- Previous methods for generating TIL require screening for anti-tumor specificity using gamma-interferon (IFN) production by the TIL. However, in vitro screening depends on autologous tumor reagents that are often unavailable; and gamma-IFN release in vitro may not be the best correlate to in vivo efficacy. Additionally, this method necessitates long in vitro culture times (44 days), and therefore reduces the clonal heterogeneity of TIL cultures, and results in TIL cultures with shorter telomere lengths and phenotypes that are skewed toward a more differentiated phenotype.
- In Surgery Branch pre-clinical experiments, we evaluated a method for rapidly generating young TIL from melanoma tumors with optimal phenotypic characteristics.
Objectives:
- In cohort 1, to determine the ability of autologous TIL cells infused after minimal in vitro culture in conjunction with high dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative regimen to mediate tumor regression in patients with metastatic melanoma.
- In cohort 2, to determine the ability of autologous cluster of differentiation 4 (CD4+) cell depleted TIL cells infused after minimal in vitro culture in conjunction with high dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative regimen to mediate tumor regression in patients with metastatic melanoma.
- In cohort 3, to determine the ability of autologous CD4+ cell depleted TIL cells infused after minimal in vitro culture in conjunction with high dose aldesleukin following chemoradiation lymphoid depleting regimen to mediate complete tumor regression in patients with metastatic melanoma.
- In a prospective randomized fashion, to compare the ability of autologous TIL cells (cohort 4) and autologous CD4plus cell depleted TIL cells (cohort regimen, to mediate tumor regression, progression free survival, and overall survival in patients with metastatic melanoma.
- Evaluate the toxicity of these treatment regimens.
- Determine the rate of repopulation of the young TIL cells in treated patients and establish in vitro correlates of TIL cultures that mediate objective response and in vivo persistence.
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Cohort 1 - NMA, TIL, aldesleukin
Cohort 1 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), & high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 1 = unselected TIL
干预措施: aldesleukin (Biological)
Cohort 1 - NMA, TIL, aldesleukin
Cohort 1 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), & high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 1 = unselected TIL
干预措施: therapeutic autologous lymphocytes (Biological)
Cohort 1 - NMA, TIL, aldesleukin
Cohort 1 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), & high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 1 = unselected TIL
干预措施: Cyclophosphamide (Drug)
Cohort 1 - NMA, TIL, aldesleukin
Cohort 1 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), & high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 1 = unselected TIL
干预措施: Fludarabine phosphate (Drug)
Cohort 2 - NMA, CD4+ TIL, aldesleukin
Cohort 2 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 2 = CD4+ depleted (selected) TIL
干预措施: aldesleukin (Biological)
Cohort 2 - NMA, CD4+ TIL, aldesleukin
Cohort 2 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 2 = CD4+ depleted (selected) TIL
干预措施: therapeutic autologous lymphocytes (Biological)
Cohort 2 - NMA, CD4+ TIL, aldesleukin
Cohort 2 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 2 = CD4+ depleted (selected) TIL
干预措施: Cyclophosphamide (Drug)
Cohort 2 - NMA, CD4+ TIL, aldesleukin
Cohort 2 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 2 = CD4+ depleted (selected) TIL
干预措施: Fludarabine phosphate (Drug)
Cohort 3 - NMA, total body irradiation
Cohort 3 - Nonmyeloablative (NMA), total body irradiation (TBI):
Nonmyeloablative chemotherapeutic conditioning regimen and 2 gray units (Gy) of total body irradiation followed by cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL 2Gy (gray units) of total body irradiation (TBI) twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute using a linear accelerator in Radiation Oncology Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 3 = CD4 + depleted (selected) TIL + 600Gy radiation
干预措施: aldesleukin (Biological)
Cohort 3 - NMA, total body irradiation
Cohort 3 - Nonmyeloablative (NMA), total body irradiation (TBI):
Nonmyeloablative chemotherapeutic conditioning regimen and 2 gray units (Gy) of total body irradiation followed by cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL 2Gy (gray units) of total body irradiation (TBI) twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute using a linear accelerator in Radiation Oncology Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 3 = CD4 + depleted (selected) TIL + 600Gy radiation
干预措施: therapeutic autologous lymphocytes (Biological)
Cohort 3 - NMA, total body irradiation
Cohort 3 - Nonmyeloablative (NMA), total body irradiation (TBI):
Nonmyeloablative chemotherapeutic conditioning regimen and 2 gray units (Gy) of total body irradiation followed by cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL 2Gy (gray units) of total body irradiation (TBI) twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute using a linear accelerator in Radiation Oncology Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 3 = CD4 + depleted (selected) TIL + 600Gy radiation
干预措施: Cyclophosphamide (Drug)
Cohort 3 - NMA, total body irradiation
Cohort 3 - Nonmyeloablative (NMA), total body irradiation (TBI):
Nonmyeloablative chemotherapeutic conditioning regimen and 2 gray units (Gy) of total body irradiation followed by cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL 2Gy (gray units) of total body irradiation (TBI) twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute using a linear accelerator in Radiation Oncology Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 3 = CD4 + depleted (selected) TIL + 600Gy radiation
干预措施: Fludarabine phosphate (Drug)
Cohort 3 - NMA, total body irradiation
Cohort 3 - Nonmyeloablative (NMA), total body irradiation (TBI):
Nonmyeloablative chemotherapeutic conditioning regimen and 2 gray units (Gy) of total body irradiation followed by cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL 2Gy (gray units) of total body irradiation (TBI) twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute using a linear accelerator in Radiation Oncology Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 3 = CD4 + depleted (selected) TIL + 600Gy radiation
干预措施: Total body irradiation (Radiation)
Cohort 4 - NMA, young TIL, aldesleukin
Cohort 4 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 4 = unselected TIL - it is the SAME as cohort 1
干预措施: aldesleukin (Biological)
Cohort 4 - NMA, young TIL, aldesleukin
Cohort 4 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 4 = unselected TIL - it is the SAME as cohort 1
干预措施: therapeutic autologous lymphocytes (Biological)
Cohort 4 - NMA, young TIL, aldesleukin
Cohort 4 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 4 = unselected TIL - it is the SAME as cohort 1
干预措施: Cyclophosphamide (Drug)
Cohort 4 - NMA, young TIL, aldesleukin
Cohort 4 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose (HD) aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 4 = unselected TIL - it is the SAME as cohort 1
干预措施: Fludarabine phosphate (Drug)
Cohort 5 - NMA, CD4+TIL, HD aldesleukin
Cohort 5 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) tumor infiltrating lymphocytes (TIL), high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 5 = CD4 + depleted TIL - it is the SAME as cohort 2
干预措施: aldesleukin (Biological)
Cohort 5 - NMA, CD4+TIL, HD aldesleukin
Cohort 5 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) tumor infiltrating lymphocytes (TIL), high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 5 = CD4 + depleted TIL - it is the SAME as cohort 2
干预措施: therapeutic autologous lymphocytes (Biological)
Cohort 5 - NMA, CD4+TIL, HD aldesleukin
Cohort 5 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) tumor infiltrating lymphocytes (TIL), high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 5 = CD4 + depleted TIL - it is the SAME as cohort 2
干预措施: Cyclophosphamide (Drug)
Cohort 5 - NMA, CD4+TIL, HD aldesleukin
Cohort 5 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) tumor infiltrating lymphocytes (TIL), high dose (HD) aldesleukin:
Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose aldesleukin.
Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.
Cohort 5 = CD4 + depleted TIL - it is the SAME as cohort 2
干预措施: Fludarabine phosphate (Drug)
结局指标
主要结局
Clinical Response
时间窗: every 1-3 months until disease progression. Total length of time -8/7/2007 to 9/27/2012
Clinical response is defined as complete response (CR)- a disappearance of all target lesions, partial response (PR) - at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD)- at least a 20% increase in the sum of the LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
Toxicity
时间窗: 5 years
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
次要结局
未报告次要终点
研究者
Steven Rosenberg, M.D.
Dr. Steven Rosenberg
National Institutes of Health Clinical Center (CC)