Protocol Number: 04-C-0181

Title:

Treatment of Patients with Metastatic Melanoma by Lymphodepleting Conditioning Followed by Infusion of TCR-Gene Engineered Lymphocytes and Subsequent Peptide Immunization

Number:

04-C-0181

Summary:

This study will use genetically engineered lymphocytes (white blood cells) and an experimental vaccine to treat advanced melanoma. Tumor-fighting lymphocytes taken from the patient's blood or tumor are grown in the laboratory and treated with an anti-melanoma protein for later re-infusion into the patient. The protein is inserted into the cells with a virus that has been inactivated so that it cannot cause illness.

Patients 18 years of age and older with metastatic melanoma that does not improve with standard therapy or treatment with high-dose IL-2 and who have tissue type HLA-A*0201 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.

Participants undergo the following procedures:

- Tumor biopsy: A small piece of tumor is obtained either with a needle or by a small cut in the tumor to collect lymphocytes with good tumor-fighting ability for treatment with the anti-melanoma protein. Alternatively, the cells may be collected by leukapheresis, in which blood is withdrawn through a needle in an arm vein and directed through a catheter into a cell-separating machine. The lymphocytes are removed and the rest of the blood is returned to the body through the same needle.

- G-CSF injections: This growth factor is injected under the skin every day for 5 days before leukapheresis (see below) to stimulate white blood cell production.

- Leukapheresis: Leukapheresis is performed to collect and store blood that may be needed in the rare event that the patient's blood components do not recover after chemotherapy.

- Catheter placement: When the patient is admitted to the Clinical Center for treatment, a catheter (plastic tube) is placed in a vein in the patient's neck or arm for giving chemotherapy and other medicines, infusing the lymphocytes, and collecting blood samples.

- Chemotherapy: A week before the lymphocyte infusion, patients receive a 1-hour infusion of cyclophosphamide for 2 days and then a 15- to 30-minute infusion of fludarabine for 5 days to suppress the immune system and thereby prevent rejection of the infused lymphocytes.

- Vaccine and lymphocyte delivery: Patients receive vaccine shots in the thigh to boost the immune response to the tumor. The vaccine contains a peptide (piece of a protein) produced by melanoma tumors. Two injections every day for five days beginning the morning of the cell infusion and then once a week for three more injections. The lymphocytes are infused through the catheter over 30 minutes the day after the last dose of chemotherapy.

- IL-2: Patients receive IL-2 infusions every 8 hours for up to 5 days after the cell infusion to help keep the cells alive.

Between 4 and 6 weeks after completing the full treatment regimen, patients return to NIH for about 2 days for evaluation. Patients whose tumor has shrunk or remained stable may repeat the treatment one time. Those whose tumors continued to grow are taken off the study and admitted to another protocol or are returned to the care of their local physician. Patients have blood tests done at 1, 3, 6, and 12 months after the infusion and then yearly to look for changes in the virus used to insert the anti-melanoma protein and for changes in the genetically modified lymphocytes.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

CELL HARVEST INCLUSION CRITERIA:

a. Patients must have metastatic melanoma.

b. Age greater than or equal to 18 years.

c. Clinical performance status of ECOG 0 or 1.

d. Life expectancy of greater than three months.

e. Seronegative for HIV antibody.

f. Seronegative for hepatitis B antigen.

g. Seropositive for EBV.

CELL INFUSION INCLUSION CRITERIA:

a. Patients must have measurable metastatic melanoma that is refractory to standard therapy including high dose IL-2 therapy.

b. Patients must be HLA-A*0201.

c. Patients may not have brain metastases.

d. Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.

e. Clinical performance status of ECOG 0, 1 at the time of chemotherapy induction.

f. Absolute neutrophil count greater than 1000/mm3.

g. Platelet count greater than 100,000/mm3.

h. Hemoglobin greater than 8.0 g/dl.

i. Serum ALT/AST less than three times the upper limit of normal.

j. Serum creatinine less than or equal to 1.6 mg/dl.

k. Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

l. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 2 or less. Six weeks must have elapsed since prior MDX-010 therapy to allow antibody levels to decline.

m. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.

n. Life expectancy of greater than three months.

o. No systemic steroid therapy required.

p. Seronegative for HIV antibody.

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

r. Seropositive for EBV.

s. No 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.

t. No form of primary (such as autoimmune colitis or Crohn's Disease) or secondary immunodeficiency (due to chemotherapy or radiation therapy). Must have recovered immune competence after chemotherapy or radiation therapy as evidenced by normal lymphocyte counts (greater than 500/mm3), normal WBC (greater than 3000/mm3) or absence of opportunistic infections.

u. No history of severe immediate hypersensitivity reaction to any of the agents used in this study.

v. Must sign a durable power of attorney.

w. Patients who have progressive disease while receiving prior immunization to melanoma antigens or who have received prior anti-CTLA-4 antibody, or prior cellular therapy, with or without myeloablation, as long as all toxicities are resolved to grade 2 or less and do not require systemic steroids (except vitiligo) are eligible for this protocol.

x. Patients must understand and sign the Informed Consent Document.

y. Patients will be excluded if they have a history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) less than 45 percent on a cardiac stress test (stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test).

z. Similarly, patients who are 50 years old with a LVEF less than 45 percent, will be excluded.

aa. 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 FEV1 less than 60 percent predicted will be excluded.

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

EXCLUSION CRITERIA:

CELL HARVEST EXCLUSION CRITERIA:

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

Special Instructions: Currently Not Provided

Keywords:

gp100

MART-1

HLA-A0201

Clinical Response

Toxicity

Recruitment Keywords:

Metastatic Melanoma

Melanoma

Conditions:

Melanoma

Investigational Drug(s):

GCsamAPB (anti-gp 100 TCR) retroviral vector-transduced autologous tumor-infiltr

GCsamAPB (anti-gp100 TCR) retroviral vector transduced autologous peripheral blo

GP100: 209-217 (210M)

IL-2

Montanide

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. Progress in human tumour immunology and immunotherapy. Nature. 2001 May 17;411(6835):380-4.

Topalian SL, Rosenberg SA. Tumor-infiltrating lymphocytes: evidence for specific immune reactions against growing cancers in mice and humans. Important Adv Oncol. 1990;:19-41.

Schwartzentruber DJ, Topalian SL, Mancini M, Rosenberg SA. Specific release of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IFN-gamma by human tumor-infiltrating lymphocytes after autologous tumor stimulation. J Immunol. 1991 May 15;146(10):3674-81.

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