Protocol Number: 07-C-0174

Title:

Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-gp100:154-162 TCR-Gene Engineered Lymphocytes

Number:

07-C-0174

Summary:

Background:

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

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

a. Metastatic melanoma with measurable disease.

b. Previously received high dose IL-2 and have been either non-responders (progressive disease) or have recurred.

c. Positive for gp100 by IHC.

d. Greater than or equal to 18 years of age.

e. Willing to sign a durable power of attorney.

f. Able to understand and sign the Informed Consent Document.

g. Clinical performance status of ECOG 0 or 1.

h Life expectancy of greater than three months.

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

j. Must be HLA-A 0201 positive

k. Serology:

a) 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.)

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

l. Hematology:

a) Absolute neutrophil count greater than 1000/mm(3).

b) WBC (greater than 3000/ mm(3)).

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

d) Hemoglobin greater than 8.0 g/dl.

m. Chemistry:

a) Serum ALT/AST less than or equal to 2.5 times the upper limit of normal.

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

c) Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

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

o. 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 1 or less (except for toxicities such as alopecia or vitiligo).

p. Six weeks must have elapsed since prior anti-CTLA4 antibody therapy to allow antibody levels to decline, and patients who have previously received must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

a. Patients with reactive TIL (IFN- gamma release greater than 200 pg/mL) available based on overnight co-culture assay with autologous tumor or MHC-matched tumor cells.

b. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

c. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

d. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).

e. 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.)

f. Systemic steroid therapy.

g. History of severe immediate hypersensitivity reaction to any of the agents used in this study.

h. History of coronary revascularization.

i. Documented LVEF of less than 45 percent in patients with:

a. Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2 degree or 3 degree heart block.

b. Age greater than or equal to 60 years old.

j. Documented FEV1 greater than or equal to 60 percent predicted for patients with:

a. A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years).

b. Symptoms of respiratory distress.

Special Instructions:

Currently Not Provided

Keywords:

Refractory

Gene Therapy

HLA-A2 Positive

Stage IV Melanoma

Recruitment Keyword(s):

Melanoma

Skin Cancer

Malignant Melanoma

Condition(s):

Skin Cancer

Melanoma

Investigational Drug(s):

PG13-154-EcII AIB (anti-gp100: 154-162 TCR) PBL

PG13-154-EcII AIB (anti-gp100: 154-162 TCR) TIL

Investigational Device(s):

None

Intervention(s):

Drug: PG13-154-EcII AIB (anti-gp100: 154-162 TCR) PBL

Drug: Aldesleukin

Drug: PG13-154-EcII AIB (anti-gp100: 154-162 TCR) TIL

Supporting Site:

National Cancer Institute

Contact(s):

Recruitment Center - SB
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Building 10, Room 2-1730, Bethesda, Maryland 20892, United States
Phone: (866) 820-4505
Fax: (301) 451-1927
Electronic Address: ncisbirc@mail.nih.gov

Citation(s):

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.

Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, Appella E, Rosenberg SA. 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.

Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E, Yannelli JR, Adema GJ, Miki T, Rosenberg SA. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458-62.

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