Monoclonal Antibody Therapy and Vaccine Therapy in Treating Patients With Resected Stage III or Stage IV Melanoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Vaccines may make the body build an immune response to kill tumor cells. Combining the vaccines with Montanide ISA-51 may cause a stronger immune response and kill more tumor cells. Giving monoclonal antibody therapy together with vaccine therapy may be an effective treatment for stage III or stage IV melanoma. PURPOSE: This phase II trial is studying how well giving monoclonal antibody therapy together with vaccine therapy works in treating patients with resected stage III or stage IV melanoma.

Detailed Description
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OBJECTIVES: Primary Achieve at least a 40% autoimmune breakthrough event rate, as defined by the induction of grade 1, grade 2, or acceptable grade 3 drug-related autoimmune adverse events, in patients with resected stage III or IV melanoma treated with anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen emulsified in Montanide ISA-51. Secondary Determine the incidence of drug-related autoimmune adverse events of any grade in patients treated with this regimen. Determine the time to disease relapse in patients treated with this regimen. Determine the immunologic response in patients treated with this regimen. OUTLINE: This is an open-label study. Patients receive anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) IV over 90 minutes on day 1 of weeks 1, 9, 17, 25, 33, 41, and 53 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen emulsified in Montanide ISA-51 subcutaneously on day 1 of weeks 1, 3, 5, 7, 9, 11, 17, 21, 25, 33, 41, and 53. Patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

Official Title
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An Extended Dosing, Two-phase Study of MDX-010 as Monotherapy or in Combination With Tyrosinase/gp100/MART-1 Peptides Emulsified With Montanide ISA 51 VG in the Treatment of Subjects With Resected Stage III or Stage IV Melanoma

Conditions
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Intraocular Melanoma, Melanoma (Skin)

Intervention / Treatment
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* Biological: ipilimumab
* Biological: Tyrosinase/gp100/MART-1 Peptides


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed melanoma Stage III (≥ 3 positive lymph nodes) or stage IV disease Mucosal or ocular melanoma allowed Completely resected within the past 6 months Patients with stage III resected melanoma rendered free of disease may have failed, been ineligible for, or refused prior treatment with interferon alfa Positive staining of tumor tissue for at least one of the following: Antibody HMB-45 for gp100 Antibody HMB-45 for tyrosinase Antibody HMB-45 for MART-1 HLA-A*0201 positive by DNA allele-specific polymerase chain reaction assay PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-1 Life expectancy At least 6 months Hematopoietic WBC ≥ 2,500/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hematocrit ≥ 30% Hemoglobin ≥ 10 g/dL Hepatic AST ≤ 3 times upper limit of normal (ULN)* Bilirubin ≤ ULN* (< 3.0 mg/dL for patients with Gilbert's syndrome) No significant hepatic disease that would preclude study participation Hepatitis B surface antigen negative Hepatitis C antibody negative NOTE: * Unless attributable to disease Renal Creatinine ≤ 2.0 mg/dL No significant renal disease that would preclude study participation Cardiovascular No significant cardiac disease that would preclude study participation Pulmonary No significant pulmonary disease that would preclude study participation Immunologic No history of any of the following: Inflammatory bowel disease or any other autoimmune bowel disease Systemic lupus erythematosus Rheumatoid arthritis Autoimmune ocular disease No systemic hypersensitivity to Montanide ISA-51 or any vaccine component No active infection requiring therapy HIV negative Other No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix No significant gastrointestinal disease that would preclude study participation No significant psychiatric disease that would preclude study participation No other medical condition that would preclude study participation Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 4 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics No prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) No prior gp100 antigen, MART-1 antigen, or tyrosinase peptide At least 4 weeks since prior immunotherapy for melanoma and recovered No other concurrent immunotherapy Chemotherapy At least 4 weeks since prior chemotherapy for melanoma (6 weeks for nitrosoureas) and recovered No concurrent chemotherapy Endocrine therapy At least 4 weeks since prior hormonal therapy for melanoma and recovered At least 4 weeks since prior systemic, inhaled, or topical corticosteroids No concurrent systemic, inhaled, or topical corticosteroids Radiotherapy At least 4 weeks since prior radiotherapy for melanoma and recovered Surgery See Disease Characteristics At least 4 weeks since prior surgery for melanoma and recovered Other No concurrent immunosuppressive agents (e.g., cyclosporine and its analog) Concurrent analgesic therapy allowed provided the dose is stable for the past 14 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Arm 1<br> | Biological: ipilimumab<br>* IV over 90 mins on day 1, wks 1,9,17,25,33,41,53 Dose: 3 mg/kg (Part I), 10 mg/kg (Part II)<br>Biological: Tyrosinase/gp100/MART-1 Peptides<br>* (All subjects in Part I and HLA-A*0201 positive subjects only in Part II): SC, day 1 of wks 1,3,5,7,9,11,17, 21,25,33,41,53 Dose: 1 mg peptide emulsified in 1 mL Montanide ISA 51 VG.)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Immune-related Adverse Events (irAEs) | Percentage of participants who experienced an irAE during the course of the study defined by the induction of Grade 1, Grade 2, or acceptable Grade 3 drug-related irAEs. For the purposes of this trial, acceptable drug-related irAEs are skin-related immune-mediated adverse events < or = Grade 3 (potentially reversible inflammation < Grade 4 that can be attributable to a local antitumor reaction that could potentially be a therapeutic response will also be considered an acceptable irAE). Note: The confidence interval was calculated using the Clopper Pearson method | Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase) | 
| Time to Disease Relapse | To determine the time (months) from first dose to disease relapse. Time to disease relapse is defined from the start of treatment to the first occurrence of any new lesion (reported by the investigator on physical exam or diagnostic imaging assessments that are attributed to metastatic melanoma) or death. Participants who neither relapse nor died will be censored on the date of their last tumor evaluation. Median estimated using Kaplan-Meier method; A two-sided 95% CI for median in each treatment group was computed via the log-log transformation method. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Drug-related irAEs of Any Grade | The number of participants who experienced a drug-related irAE of any grade over the course of the study. Note: The confidence interval was calculated using the Clopper Pearson method | Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase) | 
| Immunologic Response to the Dose Regimen | The secondary objective was to determine the immunologic response to the dosing regimen, via Human Anti-Human Antibody (HAHA) Assessment, displayed by number of participants observed as HAHA positive or negative. Note: If participant had at least one post-baseline HAHA result with increase in titer over pre-study, the participant is counted as HAHA Positive. A participant with all negative post-baseline results is counted as HAHA negative. | up to 3 years | 
| Number of Participants Experiencing Hematology-related Lab Abnormalities | The number of participants who experienced a Hematology-related laboratory abnormality (grade 1-4 and grade 3-4 categories, grade 4 being the worst) during the course of the study. Laboratory tests were graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. | Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase) | 
| Number of Participants Experiencing Serum Chemistry-related Lab Abnormalities | The number of participants who experienced a Serum Chemistry-related laboratory abnormality (grade 1-4 and grade 3-4 categories, grade 4 being the worst) during the course of the study. Laboratory tests were graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. | Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase) | 
| Time to Disease Relapse | To determine the time (months) from first dose to disease relapse. Time to disease relapse is defined from the start of treatment to the first occurrence of any new lesion (reported by the investigator on physical exam or diagnostic imaging assessments that are attributed to metastatic melanoma) or death. Participants who neither relapse nor died will be censored on the date of their last tumor evaluation. Median estimated using Kaplan-Meier method; A two-sided 95% CI for median in each treatment group was computed via the log-log transformation method. | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III melanoma, stage IV melanoma, ciliary body and choroid melanoma, medium/large size, extraocular extension melanoma, iris melanoma, recurrent melanoma, recurrent intraocular melanoma, metastatic intraocular melanoma