Ignite Creation Date:
2025-12-24 @ 5:14 PM
Ignite Modification Date:
2026-01-01 @ 6:33 PM
Study NCT ID:
NCT00910650
Status:
COMPLETED
Last Update Posted:
2021-12-06
First Post:
2009-05-01
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Study of Gene Modified Immune Cells in Patients With Advanced Melanoma
Sponsor:
Jonsson Comprehensive Cancer Center
Organization:
Study Overview
Official Title:
Adoptive Transfer of MART-1 F5 TCR Engineered Peripheral Blood Mononuclear Cells (PBMC) After a Nonmyeloablative Conditioning Regimen, With Administration of MART-126•35-Pulsed Dendritic Cells and Interleukin-2, in Patients With Advanced Melanoma
Status:
COMPLETED
Status Verified Date:
2020-02
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:
F5
Brief Summary:
The purpose of this phase 2 study is to find the best way to give this new experimental regimen and determine if it can treat metastatic melanoma in humans. In this phase 2 study, the experimental products are given initially to a group of 8 people. If safe and found to have significant anti-tumor activity, it will be given to up to 14 other people, for a total of 22 people in this study. Physicians watch subjects carefully for any harmful side effects. Although the experimental regimen has been well tested in laboratory and animal studies, and a similar regimen has been given to a group of patients at the National Cancer Institute in Bethesda, MD, the side effects in people cannot be completely known ahead of time. This protocol is offered only to people whose condition cannot be helped by other known treatments.
The study procedures will start with the collection of white blood cells through apheresis (a procedure in which blood is drawn from a patient and separated into its components, some of which are retained, such as white blood cells, and the remainder returned by transfusion to the patient).
Subjects will be asked to undergo two aphereses, one to make the gene-modified MART-1 TCR CTLs (cytolytic T lymphocyte) and the dendritic cell vaccines, and a second one after the subject receives the gene modified cells to later study them in the blood.
On the day of the first apheresis, subjects will be admitted to the hospital and will receive chemotherapy over the next five days which decreases the risk of rejection of the transferred cells by the subject's immune system and facilitates their expansion and attack of the melanoma lesions. During this time, the gene-modified MART-1 TCR CTLs and the dendritic cells will be manufactured in the laboratory from the apheresis product and will be extensively tested to assure that they express the appropriate TCR and that they do not contain any contaminating bacteria or virus. Then the gene-modified MART-1 TCR CTLs will be given back to the subject through a vein in the arm. It will be followed by vaccination with the dendritic cells under the skin. During the next fourteen days, subjects will also receive interleukin 2 (IL-2), which is a standard treatment for patients with metastatic melanoma. During the next 2 to 3 weeks, subjects will stay in the hospital until the study investigators determine that the subject has fully recovered from all of the procedures, and it is safe for the subject to go home. Chemotherapy frequently causes a decrease in the platelet or red blood cells, and therefore subjects may require platelet and/or red blood cell transfusions.
The study procedures will start with the collection of white blood cells through apheresis (a procedure in which blood is drawn from a patient and separated into its components, some of which are retained, such as white blood cells, and the remainder returned by transfusion to the patient).
Subjects will be asked to undergo two aphereses, one to make the gene-modified MART-1 TCR CTLs (cytolytic T lymphocyte) and the dendritic cell vaccines, and a second one after the subject receives the gene modified cells to later study them in the blood.
On the day of the first apheresis, subjects will be admitted to the hospital and will receive chemotherapy over the next five days which decreases the risk of rejection of the transferred cells by the subject's immune system and facilitates their expansion and attack of the melanoma lesions. During this time, the gene-modified MART-1 TCR CTLs and the dendritic cells will be manufactured in the laboratory from the apheresis product and will be extensively tested to assure that they express the appropriate TCR and that they do not contain any contaminating bacteria or virus. Then the gene-modified MART-1 TCR CTLs will be given back to the subject through a vein in the arm. It will be followed by vaccination with the dendritic cells under the skin. During the next fourteen days, subjects will also receive interleukin 2 (IL-2), which is a standard treatment for patients with metastatic melanoma. During the next 2 to 3 weeks, subjects will stay in the hospital until the study investigators determine that the subject has fully recovered from all of the procedures, and it is safe for the subject to go home. Chemotherapy frequently causes a decrease in the platelet or red blood cells, and therefore subjects may require platelet and/or red blood cell transfusions.
Detailed Description:
This is a two-stage phase II clinical trial with the combined primary endpoints to determine the safety, feasibility and anti-tumor activity of adoptive transfer of peripheral blood mononuclear cells (PBMC) genetically engineered to express the alpha and beta chains of a high affinity T cell receptor (TCR) specific for the HLA-A\*0201-restricted MART-1 melanoma tumor antigen to patients with locally advanced or metastatic melanoma. This gene transfer will be facilitated by a retroviral vector pseudotyped with a gibbon ape leukemia virus (GaLV) envelope. The two transgenes are linked by a picornavirus 2A sequence. Their expression is driven by the retroviral long terminal repeat (LTR).
Patients with MART-1-positive locally advanced or metastatic melanoma who are HLA-A\*0201-positive, and HIV, hepatitis B and C seronegative, will receive a non-myeloablative but lymphocyte depleting chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine, and then receive the adoptive transfer of autologous PBMC transduced with the MSGV1-F5AfT2AB retroviral vector, which expresses a high affinity TCR for the MART-1 melanoma antigen (MART-1 F5 TCR). The cell dose will be up to 10\^9 autologous PBMC transduced with the MSGV1-F5AfT2AB retroviral vector. The transgenic T cells will be infused fresh on the day of harvest as done in the last three patients within this protocol, prior to which, thawed cryopreserved cells were infused. Following adoptive cell transfer, patients will receive MART-1.26-35 peptide-pulsed dendritic cell (DC) vaccines and low dose interleukin-2 (IL-2).
The MART-1 F5 TCR was provided by Dr. Stephen A. Rosenberg from the Surgery Branch, National Cancer Institute (NCI). The MART-1 F5 TCR is derived from the DMF5 tumor infiltrating lymphocyte (TIL) clone, and was selected from several MART-1-specific TCRs because of its high affinity and biological activity. This TCR delivered by the same retroviral vector is currently in clinical testing at the Surgery Branch/NCI. Both the NCI clinical trial and the trial at University of California at Los Angeles (UCLA) are based on the same retrovirus expressing the MART-1 F5 TCR used to transduce whole PBMC and re-infused to patients after a non-myeloablative but lymphodepleting chemotherapy conditioning regimen. Major differences between both clinical trials include the shorter ex vivo expansion of TCR transduced PBMC, the use of MART-126-35 peptide pulsed DC and the use of positron imaging tomography (PET) for non-invasive imaging of adoptively transferred TCR transgenic cells in the UCLA clinical trial.
The primary endpoints will be safety, feasibility and objective tumor response. The phase II clinical trial design will have two treatment stages following a Simon optimal two-stage clinical phase II clinical trial design 1. The clinical trial will have an initial stage with 8 patients followed by a second stage with up to 22 patients.
Safety will be determined in stage one, and if 3 out of 8 patients have MART-1 F5 TCR-induced dose limiting toxicities (DLT), then further accrual will not be warranted. Feasibility will be also determined in the first stage, and if 3 out of 8 patients cannot receive the intended cellular therapies, or if they result in suboptimal TCR transgenic cell in vivo persistence, further accrual will not be warranted to the protocol as currently designed. Objective tumor responses will be determined by RECIST objective response criteria with a design to rule out a 10% response rate as the null hypothesis, and a 35% response rate as the alternative hypothesis. With this statistical design, if 2 or more of 8 patients in stage one have an objective response, the study will proceed to stage two and accrue a total of 22 patients. If 5 or more patients in the overall study have a complete response (CR) or partial response (PR), which combined result in the objective response rate, the study will be declared positive.
Secondary study endpoints are transgenic T cell persistence in humans and their ability to home to MART-1 positive melanoma metastasis. Analysis will be performed by sampling of peripheral blood and tumor deposits for T cell persistence and by non-invasive metabolic imaging using PET scans.
Patients with MART-1-positive locally advanced or metastatic melanoma who are HLA-A\*0201-positive, and HIV, hepatitis B and C seronegative, will receive a non-myeloablative but lymphocyte depleting chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine, and then receive the adoptive transfer of autologous PBMC transduced with the MSGV1-F5AfT2AB retroviral vector, which expresses a high affinity TCR for the MART-1 melanoma antigen (MART-1 F5 TCR). The cell dose will be up to 10\^9 autologous PBMC transduced with the MSGV1-F5AfT2AB retroviral vector. The transgenic T cells will be infused fresh on the day of harvest as done in the last three patients within this protocol, prior to which, thawed cryopreserved cells were infused. Following adoptive cell transfer, patients will receive MART-1.26-35 peptide-pulsed dendritic cell (DC) vaccines and low dose interleukin-2 (IL-2).
The MART-1 F5 TCR was provided by Dr. Stephen A. Rosenberg from the Surgery Branch, National Cancer Institute (NCI). The MART-1 F5 TCR is derived from the DMF5 tumor infiltrating lymphocyte (TIL) clone, and was selected from several MART-1-specific TCRs because of its high affinity and biological activity. This TCR delivered by the same retroviral vector is currently in clinical testing at the Surgery Branch/NCI. Both the NCI clinical trial and the trial at University of California at Los Angeles (UCLA) are based on the same retrovirus expressing the MART-1 F5 TCR used to transduce whole PBMC and re-infused to patients after a non-myeloablative but lymphodepleting chemotherapy conditioning regimen. Major differences between both clinical trials include the shorter ex vivo expansion of TCR transduced PBMC, the use of MART-126-35 peptide pulsed DC and the use of positron imaging tomography (PET) for non-invasive imaging of adoptively transferred TCR transgenic cells in the UCLA clinical trial.
The primary endpoints will be safety, feasibility and objective tumor response. The phase II clinical trial design will have two treatment stages following a Simon optimal two-stage clinical phase II clinical trial design 1. The clinical trial will have an initial stage with 8 patients followed by a second stage with up to 22 patients.
Safety will be determined in stage one, and if 3 out of 8 patients have MART-1 F5 TCR-induced dose limiting toxicities (DLT), then further accrual will not be warranted. Feasibility will be also determined in the first stage, and if 3 out of 8 patients cannot receive the intended cellular therapies, or if they result in suboptimal TCR transgenic cell in vivo persistence, further accrual will not be warranted to the protocol as currently designed. Objective tumor responses will be determined by RECIST objective response criteria with a design to rule out a 10% response rate as the null hypothesis, and a 35% response rate as the alternative hypothesis. With this statistical design, if 2 or more of 8 patients in stage one have an objective response, the study will proceed to stage two and accrue a total of 22 patients. If 5 or more patients in the overall study have a complete response (CR) or partial response (PR), which combined result in the objective response rate, the study will be declared positive.
Secondary study endpoints are transgenic T cell persistence in humans and their ability to home to MART-1 positive melanoma metastasis. Analysis will be performed by sampling of peripheral blood and tumor deposits for T cell persistence and by non-invasive metabolic imaging using PET scans.
Study Oversight
Has Oversight DMC:
True
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?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 08-02-020 | OTHER | UCLA IRB | View |