A Phase I-II Study of the Treatment of Metastatic Cancer That Expresses MAGE-A3 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3 HLA-A*01 Restricted TCR-Gene Engineered Lymphocytes and Aldesleukin
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Number of Treatment Related Adverse Events Related to T-Cell Receptor (TCR) Gene-Engineered Cells
研究概览
简要总结
Background:
The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patients white blood cells with a retrovirus that has the gene for anti-MAGE-A3 incorporated in the retrovirus.
Objective:
The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-MAGE A3 cells) cause tumors to shrink and to be certain the treatment is safe
Eligibility:
- Adults age 18-66 with cancer expressing the MAGE-A3 molecule.
Design:
- Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
- Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti MAGE-A3 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}
- Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti MAGE-A3 cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.
详细描述
Background:
- We have constructed a single retroviral vector that contains both alpha and beta chains of a T cell receptor (TCR) that recognizes the human leukocyte antigen serotype within HLA-A "A" serotype group (HLA-A 01) restricted MAGE-A3 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.
- In co-cultures with human leukocyte antigen serotype within HLA-A A serotype group (HLA-A 01) and MAGE-A3 double positive tumors, the anti-MAGE-A3- A 01 restricted (anti-MAGE-A3-01) TCR transduced T cells secreted significant amounts of Interferon (IFN)- >= with high specificity.
Objectives:
Primary objectives:
- Determine a safe dose of administration of autologous T cells transduced with an anti- MAGE-A3 HLA-A 01-restricted TCR (MAGE-A3-01) TCR and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen.
- Determine if this approach will result in objective tumor regression in patients with metastatic cancer expressing MAGE-A3.
- Determine the toxicity profile of this treatment regimen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 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
Phase 1 - Dose Escalation/De-Escalation
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Aldesleukin (Drug)
Phase 1 - Dose Escalation/De-Escalation
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Fludarabine (Drug)
Phase 1 - Dose Escalation/De-Escalation
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Phase 1 - Dose Escalation/De-Escalation
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR) (Biological)
Phase II - Maximum Tolerated Dose
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Aldesleukin (Drug)
Phase II - Maximum Tolerated Dose
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Fludarabine (Drug)
Phase II - Maximum Tolerated Dose
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Phase II - Maximum Tolerated Dose
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
干预措施: Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR) (Biological)
结局指标
主要结局
Number of Treatment Related Adverse Events Related to T-Cell Receptor (TCR) Gene-Engineered Cells
时间窗: Date treatment consent signed to end of treatment, approximately 30 days
Aggregate of all Grade ≥3 adverse events and their frequency possibly, probably or definitely related to the research. Adverse Events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Grade 3 is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (ADL). Grade 4 is life-threatening consequences; urgent intervention indicated. Grade 5 is death related to adverse event.
Number of Participants With Serious and Non-Serious Adverse Events
时间窗: Date treatment consent signed to date off study, approximately 53 days for the Anti-MAGE-A3 A1 TCR PBL 1x10^9 Cells + Interleukin-2 (IL-2) Arm/Group, and 1 year and 4 months for the Anti-MAGE-A3 A1 TCR PBL 1x10^8 Cells + Interleukin-2 (IL-2) Arm/Group.
Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Number of Patients With Objective Tumor Regression
时间窗: 6 and 12 weeks after cell infusion on up to 2 years
Objective tumor regression is defined as the number of participants with a complete or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Maximum Tolerated Cell Dose (MTD)
时间窗: Within 30 days of study cell infusion, before progression to next-higher dose level
Highest dose at which less than or equal to 1 of 6 patients experienced a dose limiting toxicity (DLT) or the highest dose level studied if DLTs are not observed at any of the dose levels. DLT is defined as follows: Grade 3-5 allergic reactions related to the study cell infusion. Grade 3 and greater autoimmune reactions. Grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying malignancy and occurring within 30 days of study cell infusion and does not resolve within 72 hours. Treatment-related death within 8 weeks of the study cell infusion.
次要结局
- In Vivo Survival of T-Cell Receptor (TCR) Cells(Up to 3 years after study cell infusion)
- Number of Participants With Dose-Limiting Toxicity (DLT)(Within 30 days of study cell infusion)
研究者
Steven Rosenberg, M.D.
Principal Investigator
National Cancer Institute (NCI)