Anti-MART-1 F5 Cells Plus ALVAC MART-1 Vaccine to Treat Advanced Melanoma

Study Overview
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Brief Summary
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Background: Melanoma antigen recognized by T-cells (MART)-1 is a protein present in melanoma cells. An experimental procedure developed for treating patients with melanoma uses the anti-MART-1 F5 gene and a type of virus to make special cells called anti-MART-1 F5 cells that are designed to destroy the patient's tumor. These cells are created in the laboratory using the patient's own tumor cells or blood cells. The treatment procedure also uses a vaccine called plaque purified canarypox vector (ALVAC) MART-1, made from a virus that ordinarily infects canaries and is modified to carry a copy of the MART-1 gene. The virus cannot reproduce in mammals, so it cannot cause disease in humans. When the vaccine is injected into a patient, it stimulates cells in the immune system that may increase the efficiency of the anti-MART-1 F5 cells. Objectives: -To evaluate the safety and effectiveness of anti-MART-1 F5 and the ALVAC vaccine in treating patients with advanced melanoma. Eligibility: -Patients 18 years of age with metastatic melanoma for whom standard treatments have not been effective. Design: Patients undergo scans, x-rays and other tests and leukapheresis to obtain white cells for laboratory treatment. Patients have 7 days of chemotherapy to prepare the immune system for receiving the anti-MART-1 F5. Patients receive the ALVAC vaccine, anti-MART-1 F5 cells and interleukin-2 (IL-2) (an approved treatment for advanced melanoma). The anti-MART-1 F5 cells are given as an infusion through a vein. The vaccine is given as injections just before the infusion of anti-MART-1 F5 cells and again 2 weeks later. IL-2 is given as a 15-minute infusion every 8 hours for up to 5 days after the cell infusion for a maximum of 15 doses. After hospital discharge, patients return to the clinic for periodic follow-up with a physical examination, review of treatment side effects, laboratory tests and scans every 1 to 6 months.

Detailed Description
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Background: We have engineered human PBLs to express an anti-MART-1 T-cell receptor that recognizes an human leukocyte antigens (HLA-A) 0201 restricted epitope derived from the tumor infiltrating lymphocytes (TIL) clone DMF5. We constructed a single retroviral vector that contains both alpha and infinity chains and can mediate genetic transfer of this T cell receptor (TCR) with high efficiency without the need to perform any selection. In co-cultures with HLA-A 0201 positive melanoma, anti-MART-1 F5 TCR transduced T cells secreted significant amount of interferon (IFN)-(but no significant secretion was observed in control co-cultures with cell lines. The anti-MART-1 F5 TCR transduced peripheral blood lymphocytes (PBL) could efficiently kill HLA-A 0201 positive tumors. There was little or no recognition of normal fibroblasts cells. This TCR is over 10 times more reactive with melanoma cells than the MART-1 TCR that mediated tumor regression in two patients with metastatic melanoma. In this trial we would like to test our hypothesis that the addition of an anti-tumor ALVAC vaccine will result in clinical tumor regression and persistence of the transferred cells (as is the case in murine models). Objectives: Primary objectives: -Determine if the administration of anti-MART-1 F5 TCR -engineered peripheral blood lymphocytes, ALVAC anti-tumor immunization, and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic melanoma. Secondary objectives: Determine the in vivo survival of TCR gene-engineered cells. 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; previously received and have been a non-responder to or recurred after aldesleukin; 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: peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5 times 10^9 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. Transduction is initiated by exposure of approximately 10^8 to 5 X 10^8 cells to retroviral vector supernatant containing the anti-MART-1 F5 TCR genes. These transduced cells will be expanded and tested for their anti-tumor activity. Once engineered PBMC are demonstrated to be biologically active according to the strict-criteria outlined in the Certificate of Analysis, patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive, TCR gene-transduced PBMC plus intravenous (IV) aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses). Approximately 2 hours prior to cell infusion, patients will be immunized with ALVAC virus expressing the tumor antigen. ALVAC immunization will be repeated at 2 weeks. Patients will undergo complete evaluation of tumor with physical examination, computed tomography (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. If 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled. The objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, ALVAC immunization and anti-MART-1 F5 TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5 percent (p0=0.05) in favor of a modest 20 percent partial response (PR) plus complete response (CR) rate (p1=0.20).

Official Title
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Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 F5 TCR-Gene Engineered Lymphocytes and ALVAC Virus Immunization

Conditions
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Metastatic Melanoma, Skin Cancer

Intervention / Treatment
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* Biological: autologous anti-MART-1 F5 T-cell receptor gene-engineered peripheral blood lymphocytes
* Biological: ALVAC MART-1 Vaccine
* Biological: aldesleukin
* Drug: cyclophosphamide
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Metastatic melanoma with measurable disease. Previously received high dose interleukin-2 (IL-2) and have been either non-responders (progressive disease) or have recurred. Positive for MART-1 by immunohistochemistry (IHC) which will be reviewed by the Laboratory of Pathology at National Cancer Institute (NCI). Tumor infiltrating lymphocytes (TIL) cells not available for treatment on other Surgery Branch protocols. Greater than or equal to 18 years of age. Willing to sign a durable power of attorney. Able to understand and sign the Informed Consent Document. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1. Life expectancy of greater than three months. Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen. Patients must be human leukocyte antigens (HLA-A) 0201 positive. Serology: Seronegative for human immunodeficiency virus (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.) Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. Hematology: Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim. White blood cell (WBC) (greater than 3000/mm^3. Platelet count greater than 100,000/mm^3. Hemoglobin greater than 8.0 g/dl. Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal. Serum creatinine less than or equal to 1.6 mg/dl. 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. 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). Six weeks must have elapsed since prior MDX-010 therapy to allow antibody levels to decline. Patients who have previously received MDX-010 or ticilimumab must have a normal colonoscopy with normal colonic biopsies. EXCLUSION CRITERIA: 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. 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. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). Ongoing 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). Systemic steroid therapy. History of severe immediate hypersensitivity reaction to any of the agents used in this study. History of coronary revascularization or ischemic symptoms. Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45 percent. Documented LVEF of less than or equal to 45 percent tested in patients with: Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block. Age greater than or equal to 60 years old. Documented forced expiratory volume in 1 second (FEV1) less than or equal to 60 percent predicted tested in patients with: A prolonged history of cigarette smoking (20 pk/yrs of smoking). Symptoms of respiratory dysfunction.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALVAC plus anti-MART-1 F5 TCR PBL + HD IL-2<br>ALVAC plus anti-MART-1 F5 T cell receptor (TCR ) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin 2 (IL-2): ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14. Aldesleukin - 720,000 IU/kg intravenously over 15 minutes every 8 hours (+/- 1 hour) for up to 5 days. | Biological: autologous anti-MART-1 F5 T-cell receptor gene-engineered peripheral blood lymphocytes<br>* ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 CCID50 (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14.<br>Biological: ALVAC MART-1 Vaccine<br>* ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 CCID50 (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14.<br>Biological: aldesleukin<br>* Aldesleukin - 720,000 IU/kg intravenous over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses)<br>* Other names: Recombinant human interleukin 2;Drug: cyclophosphamide<br>* 60 mg/kg day x 2 days intravenous in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg day x 2 days over 1 hour<br>* Other names: Cytoxan;Drug: fludarabine phosphate<br>* 25 mg/m^2 day intravenous piggy back over 30 minutes for 5 days<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Metastatic Melanoma Who Develop Clinical Tumor Regression (CR or PR) | Clinical tumor response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 criteria. Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is a 30% decrease in lesions taking as reference the baseline sum longest diameter (LD). For details about the RECIST criteria see the protocol link module. | 4-6 weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With in Vivo Survival of T-cell Receptor (TCR) Gene-engineered Cells | T cell receptor (TCR) and vector presence will be quantitated in peripheral blood mononuclear cells (PBMC) samples using established polymerase chain reaction (PCR) techniques. This will provide data to estimate the in vivo survival of lymphocytes derived from the infused cells. | 1 month | 
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module. | 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Metastatic Melanoma, Vaccination, Tumor Regression, Skin Cancer