Phase II Study of Metastatic Melanoma With Lymphodepleting Conditioning and Infusion of Anti-MART-1 F5 TCR-Gene-Engineered Lymphocytes

Melanoma Clinical Trial

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

Clinical Trial Summary

Background:

• Human peripheral blood lymphocytes have been engineered to express a T-cell receptor (TCR) that recognizes a blood type,HLA-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).

• Patient's 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 patient's 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.

Clinical Trial 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-A*0201 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-A*0201 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-A*0201 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 10(9) 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 10(8) to 5 times 10(8) 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 (720,000 IU/kg 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% (p0=0.05) in favor of a modest 20% PR (partial response) + CR (complete response) rate (p1=0.20). ;

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma
• Skin Cancer
• Skin Neoplasms

• NCT number: NCT00509288
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 2
• Start date: June 2007
• Completion date: July 2012