Protocol Number: 04-C-0251

Title:

Treatment of Patients with Metastatic Melanoma by Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 TCR-Gene Engineered Lymphocytes and Subsequent Peptide Immunization

Number:

04-C-0251

Summary:

This study will examine the safety and effectiveness of gene therapy for creating special tumor-fighting cells to treat patients with metastatic melanoma (melanoma that has spread beyond the primary tumor site). An anti-melanoma gene is inserted into immune cells collected from the patient's blood or tumor and the gene-modified cells are grown in culture and then given back to the patient.

Patients 18 years of age and older with metastatic melanoma who have been treated with the growth factor interleukin-2 (IL-2) and have progressive disease without spread to the brain may be eligible for this study. Patients must have tissue type HLA-A*0201. Candidates are screened with a physical examination, eye examination, electrocardiogram (EKG), blood and urine tests, scans, and x-rays to evaluate the tumor. Some patients may have a cardiac stress test or lung function test. Participants undergo the following procedures:

- Tumor biopsy and cell culture: A small area of skin is numbed and a piece of tumor is removed with a needle or a small incision. The tumor cells are grown in the laboratory for about 40 days. If the cells do not grow well, blood is collected through leukapheresis (see below) to try to grow lymphoctyes.

- MART-1 gene insertion into cells: While the cells are growing in culture, anti-melanoma protein genes called MART-1 are inserted into them using a virus that has been made incapable of causing infection.

- G-CSF administration and leukapheresis: G-CSF injections are given under the skin once a day for 5 days, followed by leukapheresis. G-CSF is a hormone that causes white cells to increase in number, allowing more cells to be collected through leukapheresis. For leukapheresis, whole blood is drawn from a needle in an arm vein and circulated through a machine that separates it into its components. The white cells are removed and the plasma and red cells are given back to the patient through a vein in the other arm.

- Chemotherapy: Patients receive two immune-suppressing drugs, cyclophosphamide and fludarabine, through a catheter (flexible plastic tube) in a vein in the arm, upper chest, or neck. The cyclophosphamide is given over 1 hour for 2 days; then the fludarabine is given for 30 minutes for 5 days. The drugs are not intended to treat the tumor, but to see if the immune suppression improves the functioning of the gene-modified white cells.

- After chemotherapy, patients receive two injections of a vaccine to increase the immune response to the tumor. The vaccine consists of pieces of the same MART-1 protein that the cultured cells were modified to react with, along with an adjuvant called Montanide ISA-51 to boost the immune response to the protein. The injections are given the morning of the cell infusion (see below), then every day for a total of 5 days, and then weekly for 3 more weeks.

- Cell infusion: The gene-modified cells are given through the catheter over 30 minutes the day after the last dose of chemotherapy. Within 24 hours after the cell infusion, high-dose IL-2 is given as a 15-minute infusion every 8 hours for up to 5 days. Patients are monitored closely for side effects and are given medicines as needed to treat and prevent as many side effects as possible.

Patients may be asked to undergo a tumor or lymph node biopsy after treatment to look at the effects of treatment on the tumor immune cells. Patients whose tumor remains stable or shrinks may have one additional treatment. Patients return to NIH for a 2-day follow-up evaluation 4-6 weeks after each treatment and annually for 5 years. After that, they are sent a health questionnaire for the next 10 years.

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:

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. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)

f. Seronegative for hepatitis B antigen.

g. Seropositive for EBV.

CELL HARVEST EXCLUSION CRITERIA:

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

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/mm(3).

g. Platelet count greater than 100,000/mm(3).

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. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)

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/mm(3)), normal WBC (greater than 3000/mm(3)) or absence of opportunistic infections. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)

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, including vector transduction, 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. Since IL-2 is administered following cell infusion:

1. 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)

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

3. 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) less than 60% predicted will be excluded; and

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

Special Instructions: Currently Not Provided

Keywords:

Maximum Tolerated Dose

In Vivo Survival

Toxicity Profile

Clinical Response

Adoptive Cell Therapy

Recruitment Keywords:

Metastatic Melanoma

Conditions:

Investigational Drug(s):

GCsamAPB(anti-MART-1 TCR) retroviral vector-transduced autologous tumor infiltra

GCsamAPB (anti-MART-1 TCR) retroviral vector-transduced autologous peripheral bl

MART-1: 26-35(27L)

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. Review.

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.

Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA. 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.

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