Ignite Creation Date:
2024-05-05 @ 6:34 PM
Last Modification Date:
2024-10-26 @ 9:35 AM
Study NCT ID:
NCT00509288
Status:
COMPLETED
Last Update Posted:
2012-12-28
First Post:
2007-07-30
Brief Title:
Phase II Study of Metastatic Melanoma With Lymphodepleting Conditioning and Infusion of Anti-MART-1 F5 TCR-Gene-Engineered Lymphocytes
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 F5 TCR-Gene Engineered Lymphocytes
Status:
COMPLETED
Status Verified Date:
2012-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background
Human peripheral blood lymphocytes have been engineered to express a T-cell receptor TCR that recognizes a blood typeHLA-A 0201 human leukocyte antigen derived from the gp100 protein A retroviral vector was constructed that can deliver the T-cell receptor TCR to cells
Patients cells will be converted into cells able to recognize and fight melanoma tumors
Objectives
To determine whether TCR-engineered lymphocytes 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
Patients leukocyte antigen type is 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 anti-MART-1 protein is 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 patients immune cells do not interfere with the treatment
Treatment with anti-melanoma antigen recognized by T-cells MART-1 Patients receive an intravenous IV infusion of the treated cells containing anti-MART-1 protein followed by infusions of a drug called IL-2 aldesleukin 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 CT computed tomography 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
Human peripheral blood lymphocytes have been engineered to express a T-cell receptor TCR that recognizes a blood typeHLA-A 0201 human leukocyte antigen derived from the gp100 protein A retroviral vector was constructed that can deliver the T-cell receptor TCR to cells
Patients cells will be converted into cells able to recognize and fight melanoma tumors
Objectives
To determine whether TCR-engineered lymphocytes 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
Patients leukocyte antigen type is 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 anti-MART-1 protein is 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 patients immune cells do not interfere with the treatment
Treatment with anti-melanoma antigen recognized by T-cells MART-1 Patients receive an intravenous IV infusion of the treated cells containing anti-MART-1 protein followed by infusions of a drug called IL-2 aldesleukin 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 CT computed tomography 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
Detailed Description:
Background
We have engineered human TIL tumor infiltrating lymphocytes and peripheral blood lymphocytes PBLs to express an anti-MART-1 T-cell receptor that recognizes an HLA-A0201 restricted epitope derived from the TIL clone DMF5
We constructed a single retroviral vector that contains both alpha and beta chains and can mediate genetic transfer of this TCR with high efficiency without the need to perform any selection
In co-cultures with HLA-A0201 positive melanoma anti-MART-1 F5 TCR transduced T cells secreted significant amount of interferon IFN-gamma but no significant secretion was observed in control co-cultures with cell lines
The anti-MART-1 F5 TCR transduced T-cells could efficiently kill HLA-A0201 positive tumors There was little or no recognition of normal fibroblasts cells
This TCR is over 10 times more reactive with melanoma cells than the MART-1 TCR that mediated tumor regression in two patients with metastatic melanoma
Objectives
Primary objectives
-Determine if the administration of anti-MART-1 F5 TCR -engineered peripheral blood lymphocytes PBL or tumor infiltrating lymphocytes TIL and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic melanoma
Secondary objectives
Determine the in vivo survival of TCR gene-engineered cells
Determine the toxicity profile of this treatment regimen
Eligibility
Patients who are HLA-A 0201 positive and 18 years of age or older must have
metastatic melanoma
previously received and have been a non-responder to or recurred after aldesleukin
normal values for basic laboratory values
Patients may not have
concurrent major medical illnesses
any form of primary or secondary immunodeficiency
severe hypersensitivity to any of the agents used in this study
contraindications for high dose aldesleukin administration
Design
If TIL can be obtained and grown but are non-reactive patients will be assigned to receive TIL transduced with the anti-MART-1 F5 TCR retroviral vector If TIL cannot be obtained PBMC will be obtained by leukapheresis approximately 5 X 109 cells and cultured in the presence of anti-CD3 OKT3 and aldesleukin and transduced with the anti-MART-1 F5 TCR retroviral vector If TIL cells are reactive to autologous tumor or major histocompatibility complex MHC-matched tumor cells or PBL cannot be grown patients will not be treated on this protocol
Transduction is initiated by exposure of approximately 108 to 5 times 108 cells to retroviral vector supernatant containing the anti-MART-1 F5 TCR genes These transduced cells will be expanded and tested for their anti-tumor activity
Once engineered lymphocytes are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive TCR gene transduced cells plus IV aldesleukin 720000 IUkg q8h for a maximum of 15 doses
Patients will undergo complete evaluation of tumor with physical examination CT of the chest abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met
The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled into each of two cohorts If 0 or 1 of the 21 patients per cohort experiences a clinical response then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled in that cohort have a clinical response then accrual to that cohort will continue until a total of 41 evaluable patients have been enrolled in that cohort
The objective will be to determine in two cohorts if the combination of high dose aldesleukin lymphocyte depleting chemotherapy and anti-MART-1 F5 TCR-gene engineered lymphocytes TIL and PBL is able to be associated with a clinical response rate that can rule out 5 p0005 in favor of a modest 20 PR partial response CR complete response rate p1020
We have engineered human TIL tumor infiltrating lymphocytes and peripheral blood lymphocytes PBLs to express an anti-MART-1 T-cell receptor that recognizes an HLA-A0201 restricted epitope derived from the TIL clone DMF5
We constructed a single retroviral vector that contains both alpha and beta chains and can mediate genetic transfer of this TCR with high efficiency without the need to perform any selection
In co-cultures with HLA-A0201 positive melanoma anti-MART-1 F5 TCR transduced T cells secreted significant amount of interferon IFN-gamma but no significant secretion was observed in control co-cultures with cell lines
The anti-MART-1 F5 TCR transduced T-cells could efficiently kill HLA-A0201 positive tumors There was little or no recognition of normal fibroblasts cells
This TCR is over 10 times more reactive with melanoma cells than the MART-1 TCR that mediated tumor regression in two patients with metastatic melanoma
Objectives
Primary objectives
-Determine if the administration of anti-MART-1 F5 TCR -engineered peripheral blood lymphocytes PBL or tumor infiltrating lymphocytes TIL and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic melanoma
Secondary objectives
Determine the in vivo survival of TCR gene-engineered cells
Determine the toxicity profile of this treatment regimen
Eligibility
Patients who are HLA-A 0201 positive and 18 years of age or older must have
metastatic melanoma
previously received and have been a non-responder to or recurred after aldesleukin
normal values for basic laboratory values
Patients may not have
concurrent major medical illnesses
any form of primary or secondary immunodeficiency
severe hypersensitivity to any of the agents used in this study
contraindications for high dose aldesleukin administration
Design
If TIL can be obtained and grown but are non-reactive patients will be assigned to receive TIL transduced with the anti-MART-1 F5 TCR retroviral vector If TIL cannot be obtained PBMC will be obtained by leukapheresis approximately 5 X 109 cells and cultured in the presence of anti-CD3 OKT3 and aldesleukin and transduced with the anti-MART-1 F5 TCR retroviral vector If TIL cells are reactive to autologous tumor or major histocompatibility complex MHC-matched tumor cells or PBL cannot be grown patients will not be treated on this protocol
Transduction is initiated by exposure of approximately 108 to 5 times 108 cells to retroviral vector supernatant containing the anti-MART-1 F5 TCR genes These transduced cells will be expanded and tested for their anti-tumor activity
Once engineered lymphocytes are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive TCR gene transduced cells plus IV aldesleukin 720000 IUkg q8h for a maximum of 15 doses
Patients will undergo complete evaluation of tumor with physical examination CT of the chest abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met
The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled into each of two cohorts If 0 or 1 of the 21 patients per cohort experiences a clinical response then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled in that cohort have a clinical response then accrual to that cohort will continue until a total of 41 evaluable patients have been enrolled in that cohort
The objective will be to determine in two cohorts if the combination of high dose aldesleukin lymphocyte depleting chemotherapy and anti-MART-1 F5 TCR-gene engineered lymphocytes TIL and PBL is able to be associated with a clinical response rate that can rule out 5 p0005 in favor of a modest 20 PR partial response CR complete response rate p1020
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 07-C-0175 | None | None | None |