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:

- We have engineered human PBLs to express a T-cell receptor (TCR) that recognizes HLAA*0201 restricted epitopes derived from the gp100 or the MART-1 melanoma antigen.

- We constructed single retroviral vectors that contain both Alpha and Beta TCR chains and can mediate genetic transfer of this TCR with high efficiency (greater than 30 percent) without the need to perform any selection.

- In co-cultures with HLA-A*0201 positive melanomas these TCR transduced T cells secreted significant amount of IFN-y but no significant secretion was observed in control co-cultures.

- gp100:154-162 TCR or MART-1:27-35 TCR transduced T-cells could efficiently kill HLAA*0201 positive tumors. There was little or no recognition of normal fibroblasts.

- Adoptive transfer of either of these TCR transferred gene modified PBL following a nonmyeloblative lymphodepleting regimen could mediate tumor regression in from 13-30 percent of patients with metastatic melanoma though no complete responses were seen.

Objectives:

Primary objectives:

- Determine if the administration of both the anti-gp100:154-162 TCR-engineered and anti- MART-1:27-35 TCR-engineered peripheral blood lymphocytes (PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide to patients following a chemoradiation lymphodepleting preparative regimen will result in complete tumor regression in patients with metastatic melanoma.

- Determine whether the administration of the specific vaccine (the gp100:154-162 peptide or the MART-1:26-35(27L) peptide) can increase the persistence of the specific transferred cells (anti-gp100:154-162 TCR PBL or the anti-MART-1:27-35 TCR PBL), respectively.

Secondary objectives:

- Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are HLA-A*0201 positive and 18 years of age or older must have:

- metastatic melanoma with measurable disease

- been previously treated with IL-2 for melanoma;

- normal values for basic laboratory values.

Patients may not have:

- concurrent major medical illnesses;

- any form of primary or secondary immunodeficiency;

- severe hypersensitivity to any of the agents used in this study;

- contraindications for high dose aldesleukin administration.

Design:

- PBMC will be obtained by leukapheresis (approximately 5 times 10(9) cells) and cultured in the presence of anti-CD3 (OKT3) and aldesleukin and separate aliquots will be transduced with the anti-gp100:154-162 TCR and the anti-MART-1:27-35 TCR retroviral vector.

- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) cells to supernatant containing the retroviral vectors. These gp100 and MART-1 TCR transduced cells will be separately expanded and tested for their anti-tumor activity.

- Once engineered lymphocytes are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis, patients will receive a chemoradiation lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine and 600 cGy total body irradiation followed by intravenous infusion of ex vivo tumor reactive, gp100 and MART-1 TCR gene-transduced cells plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses).

- Patients will be randomized to receive either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide emulsified in incomplete Freund's adjuvant.

- Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met.

- The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled into each of two cohorts. If none of the 21 patients per cohort experiences a complete clinical response, then no further patients will be enrolled but if 1 or more of the first 21 evaluable patients enrolled in that cohort have a complete clinical response, then accrual to that cohort will continue until a total of 41 evaluable patients have been enrolled in that cohort.

- The objective will be to determine in two cohorts if the combination of high dose aldesleukin, lymphocyte depletion , TCR-gene engineered lymphocytes and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide is able to be associated with complete clinical responses, and whether peptide vaccine can increase persistence of the transferred cells.

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 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:

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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