Protocol Number: 04-C-0104

Title:

Treatment of Patients With Metastatic Melanoma Using a Nonmyeloablative but Lymphocyte Depleting Regimen Followed by the Administration of In Vitro Sensitized Lymphocytes Reaction With ESO-1 Antigen

Number:

04-C-0104

Summary:

This study will determine whether certain lymphocytes (white blood cells) taken from a melanoma patient's blood or tumor and grown in the laboratory with a melanoma peptide (piece of protein) will fight the patient's cancer. The lymphocytes are sensitized with a peptide called ESO-1, which is made by melanoma tumors in some patients who have ESO-1 tissue type and grown in the lab. Patients will be given a chemotherapy regimen prior to cell infusion to suppress the immune system and prevent rejection of the ESO-1 treated lymphocytes. The treated cells are returned to the patient as an infusion given through an IV. Patients also receive an immunization of ESO-1 peptide in a preparation containing Montanide ISA-51, a substance that boosts the immune reaction to the peptide Additionally, patients will be given IL-2, another immune system booster.

This study consists of 2 parts, first cells will be harvested and grown in the lab. If the cells grow and react when stimulated with ESO-1, they will be given back to the patient. There will be 2 groups of patients (arms) in this study. The first group will receive ESO-1 reactive cells that were grown from peripheral blood (PB). The other group of patients will receive ESO-1 reactive cells grown from tumor cells (TIL). If the patient's cells do not grow adequately they will not be eligible to participate in this protocol.

Patients 16 years of age and older with metastatic melanoma (disease that has spread beyond the original site) that does not respond to standard treatment may be eligible for this study. Candidates are screened with a medical history and physical examination, chest x-ray, electrocardiogram, blood and urine tests, and x-rays and scans to the evaluate the extent and size of the tumor. Patients with certain heart abnormalities may also have a stress cardiac test. Because the experimental preparation is based on tissue type, only patients with tissue type ESO-1 and HLA-A*0201 may participate. Tissue type is determined by testing blood and tumor cells.

Participants undergo leukapheresis to collect quantities of lymphocytes (white blood cells) with good tumor-fighting ability. For this procedure, blood is collected through a needle in an arm vein and is directed from the vein through a plastic tube into a cell-separating machine. The white cells are removed and the rest of the blood is returned to the body through the same needle. White cells may also be collected from biopsied tumor tissue or from a tumor specimen removed during surgery. Biopsied tissue may be obtained by punch biopsy, which uses a small sharp cookie-cutter instrument, or by excisional biopsy, using a small knife. The lymphocytes are grown in the laboratory with ESO-1 peptide for later infusion into the patient.

Patients are admitted to the NIH Clinical Center for treatment. An intravenous line (plastic tube) is inserted into a vein in the patient's neck or chest to deliver chemotherapy, the ESO-1 treated lymphocytes, and other medicines, as needed, and to collect blood samples. In the hospital, patients undergo the following procedures:

- Chemotherapy (2 days of cyclophosphamide and 5 days of fludarabine) before the cell infusion. Cyclophosphamide is infused over 1 hour; fludarabine is infused over 15-30 minutes.

- ESO-1 melanoma peptide and Montanide ISA 51 injections beginning the morning of cell infusion and continuing for 5 consecutive days, then every week for 3 weeks. Patients receive two injections in the thigh of ESO-1 peptide.

- ESO-1 treated cells, interleukin-2 (IL-2), and filgrastim (G-CSF). Patients receive a 30-minute infusion of their ESO-1 treated lymphocytes. Within twenty four hours of the cell infusion patients are given IL-2 through the IV every 8 hours for up to 5 days to help keep the cells alive. In addition, injections of a growth factor called G-CSF are given every day after the cell infusions to help increase immune cell production.

Blood is drawn daily during chemotherapy and IL-2 infusions and then every 3 weeks to monitor side effects. Additional biopsies of normal skin and tumor or lymph nodes may be requested. Leukapheresis may be repeated at the end of the study. Patients return to NIH 4-5 weeks after completing treatment for evaluation. Patients whose tumors have shrunk or remained stable may undergo a second course of therapy.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

ELIGIBILITY CRITERIA:

Eligibility evaluation and registration will occur in two phases: 1. Patients who have PBMC and/or TIL obtained (Cell Harvest); and 2. Patients for whom adequate cells have been generated for infusional therapy (Cell Infusion).

INCLUSION CRITERIA - CELL HARVEST:

Patients must have metastatic melanoma.

Age greater than or equal to 16 years.

Clinical performance status of ECOG 0 or 1.

Life expectancy of greater than three months.

Seronegative for HIV antibody.

Seronegative for hepatitis B antigen and hepatitis C antibody (unless antigen negative).

EXCLUSION CRITERIA - CELL HARVEST:

Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system.

EXCLUSION CRITERIA - CELL INFUSION:

Less than four weeks has elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, or less than six weeks since prior nitrosurea therapy.

Women of child-bearing potential who are pregnant or breastfeeding.

Life expectancy of less than three months.

Systemic steroid therapy required.

Any active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

Any form of primary or secondary immunodeficiency. Must have recovered immune competence after chemotherapy or radiation therapy as evidenced by normal lymphocyte counts, normal WBC or absence of opportunistic infections.

Seropositive for HIV antibody.

Seropositive for hepatitis B or C antigen.

Seronegative for Epstein-Barr virus (EBV).

Any known hypersensitivity to any known agents on this trial.

Since IL-2 is administered following cell infusion, patients who are not eligible to receive IL-2 will be excluded:

Patients who are 50 years old or greater or who have history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmias who do not have a normal stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test) with a LVEF greater than 45%, will be excluded.; and

Patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction who do not have a normal pulmonary function test as evidenced by a FEV(1) greater than 60% predicted will be excluded; and

Patients who are not willing to complete a DPA will be excluded.

Special Instructions: Currently Not Provided

Keywords:

Clinical Response

Adoptive Cell Therapy

Immunologic Effects

IL-2

ESO-1 Reactive Cells

Recruitment Keywords:

Melanoma

Metastatic Melanoma

Conditions:

Melanoma

Neoplasm Metastasis

Investigational Drug(s):

IL-2

ESO-1:157-165 (165V)

Montanide ISA-51

ESO-1 reactive autologous perpheral blood lymphocytes

ESO-1 reactive autologous tumor infiltrating lymphocytes

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Rosenberg SA. Gene therapy for cancer. JAMA. 1992 Nov 4; 268(17): 2416-9.

Kawakami Y, et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A. 1994 Apr 26; 91(9): 3515-9.

Kawakami Y, et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1; 180(1): 347-52.

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