Phase II Study in Patients With Metastatic Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of MART-1 Reactive Peripheral Blood Lymphocytes (PBL) With or Without High Dose Aldesleukin
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Clinical Tumor Response
研究概览
简要总结
Background:
- Some cancer treatments collect a patient s own blood cells to use as specialized cancer-fighting cells. Collected white blood cells known as PBL (peripheral blood lymphocytes) can use to isolate special cells that can fight tumors. Before treatment with PBL, chemotherapy is given to destroy existing white blood cells so that the new cells can survive and attack the tumors. After PBL treatment, aldesleukin is given to help the new cells grow. Researchers want to see if special white blood cells that recognize a specific protein that is present in melanoma cells (melanoma antigen recognized by T cells (MART)) can cause tumors to shrink. These white blood cells will be tested with and without aldesleukin.
Objectives:
- To test the safety and effectiveness of white blood cells that target MART in the treatment of melanoma.
- To test white blood cells that target MART with and without aldesleukin.
Eligibility:
- Individuals at least 18 years of age who have melanoma that has not responded to standard treatments.
Design:
- Participants will be screened with a medical history and physical exam. Blood and urine samples will be taken. Imaging studies such as x-rays or magnetic resonance imaging scans will be performed.
- Participants will provide white blood cells through leukapheresis. Researchers will attempt to isolate white blood cells that recognize MART
- Seven days before the start of treatment, participants will have chemotherapy.
- After the last dose of chemotherapy, participants will receive the MART reactive PBL cells. Filgrastim doses will also be given to help white blood cell counts return to normal. Participants will have frequent blood tests.
- Participants who are able to have aldesleukin treatment will start within 24 hours after receiving the MART reactive PBL cells. Treatment will continue for up to 5 days.
- Participants may have an optional tumor or lymph node biopsy to study the effects of treatment.
- If the tumor continues to grow after MART PBL treatment, participants may have one more round of cell collection and treatment.
- Participants will have followup visits for up to 6 months after receiving the MART reactive PBL treatment.
详细描述
Background:
- TIL transfer studies in patients with metastatic melanoma following lymphodepletion have resulted in 50 percent objective response rates with a 10-15 percent rate of complete responses. Despite these important clinical findings, adoptive cell transfer has not become widely available for patient treatment. Significant obstacles to this therapy are the need for invasive surgery and the inability of some patients to tolerate high dose aldesleukin. Further, the specific characteristics of the T cells that are responsible for the therapeutic effect of tumor infiltrating lymphocyte (TIL) are unknown, thus, resulting in significant treatment variability.
- Pre-clinical and correlative clinical studies of adoptive immunotherapy have suggested putative favorable characteristics for transferred lymphocytes, such as, high avidity for the target antigen, limited in vitro stimulation, and high expression of CD27+. However, these characteristics have not been prospectively evaluated in human clinical trials.
- We have developed a novel non invasive T cell isolation strategy using the heteroclitic MART-1:26-35(27L) peptide for in vitro sensitization of human PBL and high throughput quantitative polymerase chain reaction (qPCR) screening to rapidly isolate antigen specific cluster of differentiation 8 (CD8) + T cells from the cluster of differentiation 4 (CD4) + T cell depleted peripheral blood repertoire. These isolated T cells possess the above mentioned favorable characteristics and recognize the native MART-1:27-35 epitope, an abundantly expressed melanoma antigen presented by human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2) on the tumor surface.
- The current proposed transfer of these select MART-1:27-35 reactive lymphocytes in conjunction with a lymphodepleting preparative regimen with or without high dose aldesleukin would represent a novel therapeutic option for patients with advanced melanoma and provide a desperately needed option for patients who are not medically eligible for aldesleukin treatment.
Objectives:
- To determine whether MART-1:27-35 reactive lymphocytes infused with or without the administration of high-dose aldesleukin may result in clinical tumor regression in patients with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative regimen.
- To evaluate the safety of the treatment in patients receiving the non-myeloablative conditioning regimen and cell transfer with or without the administration of high-dose aldesleukin
- To determine the survival in patients, of infused cells following the administration of the non-myeloablative regimen, using analysis of the sequence of the variable region of the T cell receptor or flow cytometry (fluorescence activated cell sorting (FACS)).
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
High Dose (HD) Aldesleukin
Pts receiving high dose aldesleukin: Cyclophosphamide 60 mg/kg intravenous (IV) for days -7 and -6, Fludarabine 25 mg/m^2 IV for days -5 to -1, plus melanoma antigen recognized by T cells (MART)-127-35 reactive CD8+ peripheral blood lymphocytes (PBL) up to 3x10^11 IV over 20-30 minutes on day 0, plus aldesleukin 720,000 IU/kg IV over 15 minutes, every 8 hrs for up to 5 days.
干预措施: Fludarabine (Drug)
High Dose (HD) Aldesleukin
Pts receiving high dose aldesleukin: Cyclophosphamide 60 mg/kg intravenous (IV) for days -7 and -6, Fludarabine 25 mg/m^2 IV for days -5 to -1, plus melanoma antigen recognized by T cells (MART)-127-35 reactive CD8+ peripheral blood lymphocytes (PBL) up to 3x10^11 IV over 20-30 minutes on day 0, plus aldesleukin 720,000 IU/kg IV over 15 minutes, every 8 hrs for up to 5 days.
干预措施: Cyclophosphamide (Drug)
High Dose (HD) Aldesleukin
Pts receiving high dose aldesleukin: Cyclophosphamide 60 mg/kg intravenous (IV) for days -7 and -6, Fludarabine 25 mg/m^2 IV for days -5 to -1, plus melanoma antigen recognized by T cells (MART)-127-35 reactive CD8+ peripheral blood lymphocytes (PBL) up to 3x10^11 IV over 20-30 minutes on day 0, plus aldesleukin 720,000 IU/kg IV over 15 minutes, every 8 hrs for up to 5 days.
干预措施: Aldesleukin (Drug)
High Dose (HD) Aldesleukin
Pts receiving high dose aldesleukin: Cyclophosphamide 60 mg/kg intravenous (IV) for days -7 and -6, Fludarabine 25 mg/m^2 IV for days -5 to -1, plus melanoma antigen recognized by T cells (MART)-127-35 reactive CD8+ peripheral blood lymphocytes (PBL) up to 3x10^11 IV over 20-30 minutes on day 0, plus aldesleukin 720,000 IU/kg IV over 15 minutes, every 8 hrs for up to 5 days.
干预措施: MART-1 Reactive CD8+ PBL (Drug)
Peripheral Blood Lymphocytes (PBL)
Cyclophosphamide 60 mg/kg intravenous (IV ) for days -7 and -6, Fludarabine 25 mg/m^2 IV for days -5 to -1, plus MART-127-35 reactive CD8+ PBL up to 3x10^11 IV over 20-30 minutes on day 0
干预措施: Fludarabine (Drug)
Peripheral Blood Lymphocytes (PBL)
Cyclophosphamide 60 mg/kg intravenous (IV ) for days -7 and -6, Fludarabine 25 mg/m^2 IV for days -5 to -1, plus MART-127-35 reactive CD8+ PBL up to 3x10^11 IV over 20-30 minutes on day 0
干预措施: Cyclophosphamide (Drug)
Peripheral Blood Lymphocytes (PBL)
Cyclophosphamide 60 mg/kg intravenous (IV ) for days -7 and -6, Fludarabine 25 mg/m^2 IV for days -5 to -1, plus MART-127-35 reactive CD8+ PBL up to 3x10^11 IV over 20-30 minutes on day 0
干预措施: MART-1 Reactive CD8+ PBL (Drug)
结局指标
主要结局
Clinical Tumor Response
时间窗: One year
Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Partial response (PR) is at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum diameters while on study.
Number of Participants With Adverse Events
时间窗: 10 months
Here is the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module.
次要结局
未报告次要终点
研究者
Udai Kammula, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)