Clinical trial NCT00509496
Conditions: Skin Cancer Melanoma
Keywords: Refractory Gene Therapy HLA-A2 Positive Stage IV Melanoma Melanoma Skin Cancer Malignant Melanoma
Sponsor: National Cancer Institute (NCI)
Start date: 2007-06-01; Completion date: 2012-07-01
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

* Human peripheral blood lymphocytes have been engineered to express a T-cell receptor (TCR) that recognizes a blood type, human leukocyte antigen (HLA-A\*0201) derived from the gp100 protein. A retroviral vector was constructed that can deliver the TCR to cells.
* This gene-engineered cell is over 10 times more reactive with melanoma cells than is the melanoma antigen recognized by T-cells (MART-1) TCR that resulted in tumor shrinkage for two patients with metastatic melanoma.

Objectives:

* To determine whether an anti-melanoma protein receptor 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-gp100 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-gp100. Patients receive an IV infusion of the treated cells containing anti-gp100 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 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 tumor infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBLs) to express a T-cell receptor that recognizes an HLAA 0201 restricted epitope derived from the gp100 protein.
* We constructed a single retroviral vector that contains both Alpha and Beta chains and can mediate genetic transfer of this TCR with high efficiency (greater than 30 percent) without the need to perform any selection.
* In co-cultures with HLA-A\*0201 positive melanoma gp100:154-162 TCR transduced T cells secreted significant amount of IFN-Beta (but no significant secretion was observed in control co-cultures with cell lines.
* gp100:154-162 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-gp100:154-162 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.
* Determine whether treated patients develop anti-mouse TCR antibody.

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-gp100:154-162 TCR retroviral vector. If TIL cannot be obtained, peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis (approximately 5 times 10(9) cells) and cultured in the presence of anti-CD3 (OKT3) and aldesleukin and transduced with the antigp100:154-162 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 supernatant containing the anti-gp100:154-162 TCR retroviral vector. 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 PBMC 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 (computed tomography) 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-gp100:154-162 TCR-gene engineered lymphocytes (TIL and PBL) is able to be associated with a clinical response rate that can rule out 5 percent (p0=0.05) in favor of a modest 20 percent PR (partial response) plus CR (complete response) rate (p1=0.20).

Arms: arm 1: 1. fludarabine phosphate-25 mg/m\^2/day intravenous piggy back over 30 minutes for 5 days
2. cyclophosphamide-60 mg/kg/day x 2 days intravenous
3. Anti-gp100:154-162 TCR-engineered peripheral blood lymphocyte (PBL) cell preparation - minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered TIL or PBL. The cells are infused intravenously over 20-30 minutes.
4. aldesleukin-720,000 IU/kg intravenously over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses) arm 2: 1. fludarabine phosphate-25 mg/m\^2/day intravenous piggy back over 30 minutes for 5 days
2. cyclophosphamide-60 mg/kg/day x 2 days intravenous
3. Anti-gp100:154-162 TCR-engineered tumor infiltrating lymphocytes (TIL) cell preparation- minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered TIL or PBL. The cells are infused intravenously over 20-30 minutes
4. aldesleukin-720,000 IU/kg intravenously over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses)
Interventions: intervention 1: fludarabine phosphate intervention 2: cyclophosphamide intervention 3: aldesleukin intervention 4: autologous anti-gp 100:154-162 T-cell receptor gene-engineered tumor infiltrating lymphocytes intervention 5: autologous anti-gp 100:154-162 T-cell receptor gene-engineered peripheral blood lymphocytes
Intervention descriptions: intervention 1: 25 mg/m\^2/day intravenous piggy back over 30 minutes for 5 days. intervention 2: 60 mg/kg/day x 2 days intravenous intervention 3: 720,000 IU/kg intravenously over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses). intervention 4: Patients will receive a minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered TIL .

The cells are infused intravenously over 20-30 minutes. intervention 5: Patients will receive a minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered PBL.

The cells are infused intravenously over 20-30 minutes.

Protocol documents: