Phase I/II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Tumor Infiltrating Lymphocytes Genetically Engineered to Express IL-12
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
Background:
- One experimental treatment for certain types of cancer is cell therapy, which involves collecting lymphocytes (white blood cells) from a tumor, growing them in the laboratory in large numbers, and then modifying the cells with a gene (interleukin-12 (IL-12)) that stimulates the immune system to attack and destroy the cancer cells. Because this treatment is experimental, researchers are interested in determining the side effects and overall effectiveness of cell therapy using white blood cells modified with IL-12 as a treatment for aggressive cancer.
Objectives:
- To determine the safety and effectiveness of cell therapy using IL-12 modified tumor white blood cells to treat metastatic melanoma.
Eligibility:
- Individuals greater than or equal to 18 years of age and less than or equal to age 66 who have been diagnosed with metastatic melanoma.
Design:
- Participants will be screened with a medical history, physical examination, blood and urine tests, and imaging studies.
- Cells for treatment will be collected during tumor biopsy or surgery.
- Prior to the start of cell therapy, participants will have imaging procedures, heart and lung function tests, and blood and urine tests, as well as leukapheresis to collect additional white blood cells.
- For 5 days before the cell infusion, participants will be admitted for inpatient chemotherapy with cyclophosphamide and fludarabine to suppress the immune system in preparation for the cell therapy.
- Participants will receive the modified white blood cells as an infusion 1 to 4 days after the last dose of chemotherapy. The day after the infusion, participants will receive filgrastim to stimulate blood cell growth.
- Participants will remain as inpatients for at least 5 to 10 days to recover from the treatment, and will be followed regularly after the treatment to study side effects and general effectiveness.
- Participants who initially respond to treatment but have a relapse may have one additional treatment using the same procedure.
详细描述
Background:
- Interleukin-12 (IL-12) is an important immunostimulatory cytokine. We have constructed a retroviral vector that contains an inducible single chain IL-12 driven by an nuclear factor of activated T-cells (NFAT) responsive promoter which can be used to mediate transfer of this gene into anti-tumor lymphocytes. This construct enables the secretion of IL-12 following stimulation of the T cell receptor.
- Transduction of the IL-12 gene into mouse anti-tumor lymphocytes results in a profound increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. These cells have a profound advantage in inducing anti-tumor responses because very few cells are needed and there is no requirement for the concomitant administration of interleukin-2 (IL-2) as is the case for conventional cell transfer immunotherapies.
- Based on these murine studies we have now constructed a similar retrovirus that contains an inducible human single chain IL-12 driven by an NFAT responsive promoter. This retrovirus can be used to transduce tumor infiltrating lymphocytes (TIL) suitable for the therapy of patients with metastatic melanoma.
Objectives:
Primary objectives:
- To evaluate the safety of the administration of IL-12 engineered TIL in patients receiving a non-myeloablative conditioning regimen.
- Determine if the administration of IL-12 engineered TIL to patients following a non-myeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer.
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
- 18 Years 至 66 Years（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
Group 1 - CD8 + TIL expressing IL-12 1x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of interleukin-12 (IL-12) gene-transduced tumor infiltrating lymphocytes (TIL).
干预措施: Fludarabine (Drug)
Group 1 - CD8 + TIL expressing IL-12 1x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of interleukin-12 (IL-12) gene-transduced tumor infiltrating lymphocytes (TIL).
干预措施: Cyclophosphamide (Drug)
Group 1 - CD8 + TIL expressing IL-12 1x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of interleukin-12 (IL-12) gene-transduced tumor infiltrating lymphocytes (TIL).
干预措施: IL-12 transduced TIL (Biological)
Group 2 - CD8 + TIL expressing IL-12 3x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 2 - CD8 + TIL expressing IL-12 3x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 2 - CD8 + TIL expressing IL-12 3x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 3 - CD8 + TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 3 - CD8 + TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 3 - CD8 + TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 4- CD8+TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 4- CD8+TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 4- CD8+TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 5 - Bulk TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 5 - Bulk TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 5 - Bulk TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 6 - Bulk TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 6 - Bulk TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 6 - Bulk TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 7- Bulk TIL expressing IL-12 1x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 7- Bulk TIL expressing IL-12 1x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 7- Bulk TIL expressing IL-12 1x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 8 - Bulk TIL expressing IL-12 3x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 8 - Bulk TIL expressing IL-12 3x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 8 - Bulk TIL expressing IL-12 3x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 9 - Bulk TIL expressing IL-12 1x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 9 - Bulk TIL expressing IL-12 1x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 9 - Bulk TIL expressing IL-12 1x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 10- Bulk TIL expressing IL12 3x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 10- Bulk TIL expressing IL12 3x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 10- Bulk TIL expressing IL12 3x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)
Maximum tolerated dose (MTD). Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Fludarabine (Drug)
Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)
Maximum tolerated dose (MTD). Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: Cyclophosphamide (Drug)
Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)
Maximum tolerated dose (MTD). Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
干预措施: IL-12 transduced TIL (Biological)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: 4 years
The MTD was determined by evaluating dose limiting toxicities (DLT) of participants that received increasing doses of intravenous infusion of IL-12 gene transduced tumor infiltrating lymphocytes (TIL) (i.e., 1x10\^6, 3x10\^6, 3x10\^7, 1x10\^7, 3x10\^7, 1x10\^8, 3x10\^8, 1x10\^9, and 3x10\^9) in cohorts 1-10. Maximum tolerated cell dose is the highest dose at which \</= 1 of 6 patients experienced a DLT (i.e. grade 2 or greater allergic reaction)).
Response (Complete Response (CR) + Partial Response (PR)) to Therapy
时间窗: 4 years
Response was determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline um LD. Progressive disease (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions.
次要结局
- Number of Participants With Adverse Events(49 months and 20 days)
研究者
Steven Rosenberg, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)