Peptide Vaccination for Patients at High Risk for Recurrent Melanoma

Study Overview
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Brief Summary
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This study will examine the effectiveness and side effects of an experimental vaccine to prevent recurrence of melanoma. The likelihood of melanoma returning is higher in patients who have melanoma lesions deep in the skin, in patients who have had positive lymph nodes, and in patients who have had surgery for metastatic disease (cancer that has spread beyond the primary site). Melanoma tumors produce proteins called glycoprotein 100 (gp100) and melanoma-associated antigen recognized by T cells 1 (MART-1). Vaccination with specific pieces of these proteins (peptides) may boost the immune system's fight against the cancer. The vaccine injections are mixed with an oil-based substance called Montanide ISA-51, which is intended to increase the immune response to the peptide. Patients 16 years of age and older whose melanoma has been surgically removed and who are currently free of disease may be eligible for this study. Candidates will be screened with a physical examination and blood and urine tests. An electrocardiogram (EKG), x-rays and other imaging studies will be done if recent results are not available. Some candidates may require heart tests, such as a cardiac stress test or echocardiogram, or lung function tests. In addition, all candidates will be tested for human leukocyte antigen (HLA) tissue type; patients must be type human leukocyte antigens (HLA-A)*0201, the type on which this vaccine is based. Participants will be randomly assigned to receive one of four different vaccines to determine which peptides offer the best immunity. Each treatment course consists of two injections of the vaccines every 3 weeks for four times. The injections are given under the skin of the thigh. After every other treatment course (every 6 months), patients will undergo a series of x-rays and scans to look for tumor. The immunizations may continue for up to 12 months as long as the melanoma does not return. The injections are given at the National Institutes of Health (NIH) Clinical Center. Patients are monitored for 1 hour after each injection and have blood tests and a physical examination to look for treatment side effects. Patients will be followed with blood tests every 12 weeks to monitor body functions. They will also undergo leukapheresis-a procedure to collect white blood cells-before starting treatment and about 3 to 4 weeks after the fourth vaccine to evaluate how the vaccines affect the action of the immune system cells. For this procedure, blood is drawn through a needle in the arm, similar to donating blood. The blood goes through a machine that separates out the lymphocytes (white blood cells), and the rest of the blood is returned through a needle in the other arm. Some patients may undergo a biopsy-surgical removal of a small piece of tissue under local anesthetic-of normal skin and tumor or lymph node tissue to examine the effects of the vaccines on the tumor immune cells. Patients whose disease returns during the first course of vaccine therapy will have surgery to remove the tumor and will continue to receive the vaccine treatment. Patients whose tumor returns after completing one course of therapy may receive a substance called interleukin-2 (IL-2), which can boost immune function against the tumor. interleukin-2 (IL-2) is given intravenously (through a small tube placed in a vein) every 8 hours for 4 days. This regimen is repeated after 10 to 14 days. Those who respond to interleukin-2 (IL-2) will have a third course of treatment after 2 months. Patients whose disease recurs after treatment will be taken off the study and will be referred back to their referring physician or to another study, if an appropriate one is available.

Detailed Description
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Human leukocyte antigens (HLA-A)*0201 positive patients at high risk for recurrence of melanoma, or completely resected metastatic melanoma will receive immunization with peptides representing human leukocyte antigen (HLA)-restricted T cell epitopes of the melanoma antigen recognized by T-cells (MART-1) or glycoprotein 100 (gp100) melanoma antigens emulsified in Montanide ISA-51 or Montanide trademark(TM) ISA 51 vegetable grade (VG). Patients will be randomized to receive one of three different melanoma antigen recognized by T-cells (MART-1) peptides or to receive a combination of a melanoma antigen recognized by T-cells (MART-1) peptide plus a glycoprotein 100 (gp100) peptide. This study is designed to evaluate the immunologic effects of the different peptide immunizations.

Official Title
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Randomized Comparison of Peptide Immunization in Patients at High Risk for Recurrence of Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Glycoprotein 100 (GP100): 209-217 (210M)
* Drug: Interleukin-2 (IL-2)
* Drug: Montanide ISA 51
* Drug: Melanoma antigen recognized by T-cells (MART)-1: 27-35
* Drug: 27-35 (27L): melanoma antigen recognized by T-cells (MART)-1
* Drug: melanoma antigen recognized by T-cells (MART)-1: 26-35(27L)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Human leukocyte antigens (HLA-A)*0201 patients, age greater than or equal to 16 years, with lesions greater than or equal to 1.5 mm in thickness, or greater than or equal to 1 positive lymph node, or ulcerated lesions, or local recurrence, or completely resected metastatic melanoma, within 6 months of surgical resection will be considered. Patients must be clinically disease free at the time of protocol entry as documented by radiologic studies within 6 weeks of patient entry. Serum creatinine of 2.0 mg/dl or less. Total bilirubin 1.6 mg/dl or less, except for patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl. White blood cell (WBC) 3000/mm^3 or greater. Platelet count 90,000 mm^3 or greater. Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than three times normal. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients of both genders must be willing to practice effective birth control during this trial because the potential for teratogenic effects are unknown. Patients may have had prior adjuvant treatment with immunotherapy, including interferon, or may have had treatment for metastatic disease and are now no evidence of disease (NED), including chemotherapy or biotherapy, as long as 3 weeks have elapsed since prior systemic therapy. EXCLUSION CRITERIA: Patients will be excluded: who have ocular or mucosal melanoma. who are undergoing or have undergone in the past 3 weeks any systemic therapy except surgery for their cancer, and must have recovered from any adverse effects of treatment prior to entry, other than those that do not have clinical implications, e.g. vitiligo, alopecia. have active systemic infections, autoimmune disease or any known immunodeficiency disease. who require systemic steroid therapy. who are pregnant or breastfeeding. who are known to be positive for hepatitis B surface antigen (B(s)AG) or human immunodeficiency virus (HIV) antibody. who have any form of active primary or secondary immunodeficiency or who have not recovered immune competence after chemotherapy or radiation therapy. who have previously been immunized with melanoma antigen recognized by T-cells (MART)-1. who have known hypersensitivity to any of the agents used in this study. ELIGIBILITY FOR ADMINISTRATION OF Interleukin-2 (IL-2): Patients who develop progressive disease while receiving peptide alone must meet the following criteria to be eligible to receive Interleukin-2 (IL-2): Patients must have measurable metastatic melanoma. Patients may not have active major medical illnesses such as cardiac ischemia, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. Patients with recent prolonged history of cigarette smoking or symptoms of respiratory dysfunction must have a normal pulmonary function test as evidenced by a forced expiratory volume 1 (FEV 1) greater than 60% predicted. Patients with electrocardiogam (EKG) abnormalities, symptoms of cardiac ischemia or arrhythmias or age greater than 50 years will have a normal stress cardiac test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine echocardiogram or other stress test). Patients must be willing to sign a durable power of attorney (DPA). Serum creatinine of 2.0 mg/dl or less. Total bilirubin 2.0 mg/dl or less, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl. White blood cell (WBC) 3000/mm^3 or greater. Platelet count 90,000 mm^3 or greater.

Ages Eligible for Study
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Minimum Age: 7 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adj-2 MART-1: 27-35<br>melanoma antigen recognized by T-cells (MART)-1:27-35 peptide every three weeks for four cycles (Arm I). | Drug: Montanide ISA 51<br> <br> Drug: Melanoma antigen recognized by T-cells (MART)-1: 27-35<br> <br> |
| Experimental: Adj-2 HD IL-2 after MART-1: 27-35<br>High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm I (Arm IA) | Drug: Interleukin-2 (IL-2)<br>* 720,000 IU/kg as an intravenous bolus over a 15 minute period every 8 hours and continuing for up to 4 days (a maximum of 12 doses).<br>* Other names: Interleukin-2;Drug: Montanide ISA 51<br> <br> Drug: Melanoma antigen recognized by T-cells (MART)-1: 27-35<br> <br> |
| Experimental: Adj-2 27-35 (27L) MART-1 (Mod9mer) peptide Q3wks x 4<br>27-35(27L):melanoma antigen recognized by T-cells (MART)-1 peptide every three weeks for four cycles (Arm II). | Drug: Montanide ISA 51<br> <br> Drug: 27-35 (27L): melanoma antigen recognized by T-cells (MART)-1<br> <br> |
| Experimental: Adj-2 HD IL-2 after 27-35 (27L): MART-1 (Mod9mer)<br>High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm II (Arm IIA) | Drug: Interleukin-2 (IL-2)<br>* 720,000 IU/kg as an intravenous bolus over a 15 minute period every 8 hours and continuing for up to 4 days (a maximum of 12 doses).<br>* Other names: Interleukin-2;Drug: Montanide ISA 51<br> <br> Drug: 27-35 (27L): melanoma antigen recognized by T-cells (MART)-1<br> <br> |
| Experimental: Adj-2 MART-1: 26-35 (27L) (Mod10mer) peptide Q3wks x 4<br>melanoma antigen recognized by T-cells (MART)-1:26-35(27L) peptide every three weeks for four cycles (Arm III). | Drug: Montanide ISA 51<br> <br> Drug: melanoma antigen recognized by T-cells (MART)-1: 26-35(27L)<br> <br> |
| Experimental: Adj-2 HD IL-2 after MART-1: 26-35 (27L) (Mod10mer)<br>High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm III (Arm IIIA) | Drug: Interleukin-2 (IL-2)<br>* 720,000 IU/kg as an intravenous bolus over a 15 minute period every 8 hours and continuing for up to 4 days (a maximum of 12 doses).<br>* Other names: Interleukin-2;Drug: Montanide ISA 51<br> <br> Drug: melanoma antigen recognized by T-cells (MART)-1: 26-35(27L)<br> <br> |
| Experimental: Adj-2 27-35 (27L): MART-1 + gp100: 209-217 (210M) Q3wks x 4<br>27-35(27L):melanoma antigen recognized by T-cells (MART)-1 peptide plus the gp100:209-217(210M) peptide emulsified together every three weeks for four cycles (Arm IV). | Drug: Glycoprotein 100 (GP100): 209-217 (210M)<br> <br> Drug: Montanide ISA 51<br> <br> Drug: 27-35 (27L): melanoma antigen recognized by T-cells (MART)-1<br> <br> |
| Experimental: Adj-2 HD IL-2 after 27-35 (27L): MART-1 + gp209-2M<br>High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm IV (Arm IVA) | Drug: Interleukin-2 (IL-2)<br>* 720,000 IU/kg as an intravenous bolus over a 15 minute period every 8 hours and continuing for up to 4 days (a maximum of 12 doses).<br>* Other names: Interleukin-2;Drug: Montanide ISA 51<br> <br> Drug: 27-35 (27L): melanoma antigen recognized by T-cells (MART)-1<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunologic Response Rate | Immunologic monitoring will be conducted using in vitro sensitization assays. The immunologic response in these assays will be considered positive if at least a two-fold increase in vaccine specific interferon gamma (y-IFN) secretion is seen between post vaccination specimens compared to the pre vaccination specimens. | 11 months | 
| Response Rate | Response is measured from the time measurement criteria are first met for complete response (CR) or partial response (PR) (whichever is first) until the first date that recurrent disease is objectively documented. Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here are the number of participants with adverse events. For details about the adverse events see the adverse event module. | 11 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adjuvant Therapy, MART-1 Peptides, GP100 Peptide, Immunologic Response, Melanoma