Protocol Number: 09-C-0051

Title:

Phase II Study of Metastatic Melanoma Using a Chemoradiation Lymphodepleting Conditioning Regimen Followed by Infusion of Anti-Mart-1 and Anti-gp100 TCR-Gene Engineered Lymphocytes and Peptide Vaccines

Number:

09-C-0051

Summary:

Background:

- MART-1 and gp100 are two genes found in melanoma cells. An experimental procedure developed for treating patients with advanced melanoma uses these genes and a type of virus to make special cells called anti-MART-1 and anti-gp100 cells, which are designed to destroy the patient's tumor. The cells are created in the laboratory using the patient's own tumor cells or blood cells.

- The procedure also uses one of two vaccines-the anti-MART-1 peptide or the anti-gp100 peptide-to stimulate cells in the immune system that may increase the effectiveness of the anti-MART-1 and anti-gp100 cells. Both vaccines are made from a virus that is modified to carry a copy of the MART-1 gene or gp100 gene. The virus cannot cause disease in humans.

Objectives:

- To evaluate the safety and effectiveness of anti-MART-1 and anti-gp100 cells and peptide vaccines for treating patients with advanced melanoma.

Eligibility:

- Patients 18 years of age with metastatic melanoma for whom standard treatments, including interleukin-2 (IL-2) therapy to boost immune response, have not been effective.

Design:

- Participants have an initial evaluation with complete medical history, as well as scans, x-rays, and other tests as directed by researchers. Most of the treatments for this study will be given on an inpatient basis.

- Before the treatment begins, participants will undergo leukapheresis (removal of selected blood cells) to obtain cells for preparing the anti-MART-1 and anti-gp100 cells, and for later stem cell transplantation.

- Preinfusion treatment: 5 days of chemotherapy and 2 days of total-body irradiation to prepare the immune system for receiving the anti-MART-1 and anti-gp100 cells.

- Infusion of cells, followed by IL-2 treatment to improve immune response. IL-2 is given as a 15-minute infusion through a vein every 8 hours for a maximum of 15 doses (over 5 days).

- After the cell infusion, participants will be divided into two groups and will receive either the gp100 peptide or MART-1 vaccine, given once a week for 3 weeks. Participants will also have stem cell transplantation (from previously collected stem cells) to promote cell survival.

- Periodic follow-up clinic visits after hospital discharge for physical examination, review of treatment side effects, laboratory tests and scans every 1 to 6 months.

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 IL-2 and have been either non-responders (progressive disease) or have recurred.

c. Positive for gp100 and MART-1 (at least 1 plus and greater than 5 percent) as assessed by IHC in the CLIA approved test in the Laboratory of Pathology, CCR, NCI, NIH.

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 from the time of enrollment on this study and for up to 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 anti-CTLA4 antibody must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

a. 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.

b. 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.

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

d. Systemic steroid therapy.

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

f. History of coronary revascularization

g. 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

h. Documented FEV1 less 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:

Metastatic Melanoma

Tumor Regression

Safety

Immunotherapy

Recruitment Keyword(s):

None

Condition(s):

Melanoma

Skin Cancer

Investigational Drug(s):

MART-1: 26-35(27L) Peptide

Montanide ISA 51 VG

gp100:154-162 Peptide

PG 13/Faf2aB C 162D1 (anti- MART-1 F5 TCR)

PG13-154-Ecll AIB (anti-gp100:154-162 TCR)

Investigational Device(s):

None

Intervention(s):

Drug: MART-1: 26-35(27L) Peptide

Drug: Montanide ISA 51 VG

Drug: gp100:154-162 Peptide

Drug: PG 13/Faf2aB C 162D1 (anti- MART-1 F5 TCR)

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

Procedure: Radiation

Drug: Aldesleukin

Drug: Fludarabine

Drug: Cyclophosphamide

Gene Transfer: Anti-gp 100:154 TCR PBL

Gene Transfer: Anti-MART-1 F5 TCR PBL

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, 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.

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.

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