Aldesleukin With or Without Vaccine Therapy in Treating Patients With Locally Advanced or Metastatic Melanoma

Study Overview
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Brief Summary
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This randomized phase III trial studies aldesleukin with vaccine therapy to see how well it works compared to aldesleukin alone in treating patients with melanoma that has spread from where it started to nearby tissue or lymph nodes or to other places in the body. Aldesleukin may stimulate a person's white blood cells to kill melanoma cells. Vaccines may make the body build an immune response to kill tumor cells. It is not yet known whether combining aldesleukin with vaccine therapy is more effective than aldesleukin alone in treating melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To identify whether the addition of the peptide vaccine to high dose interleukin (IL)-2 (aldesleukin) can result in a clinical response rate which may be superior to that found in similar patients treated with high dose IL-2 alone. SECONDARY OBJECTIVES: I. To evaluate the toxicity profile of patients treated on this trial, according to the regimen received. II. To compare the disease free/progression free survival of patients treated on both arms of the study. III. To determine the immunologic response experienced by patients who have received the peptide vaccination, as measured by changes in T-cell precursors from before to after treatment. IV. To evaluate the quality of life of patients before and after high-dose IL-2. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive aldesleukin intravenously (IV) over 15 minutes every 8 hours for 12 doses. ARM II: Patients receive gp100 antigen emulsified in Montanide ISA-51 subcutaneously (SC) on day 1. Patients also receive aldesleukin as in Arm I beginning on day 2. In both arms, treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease 3 weeks after completing 2 courses may receive a maximum of 12 additional courses. Patients with complete response may receive a maximum of 2 additional courses. After completion of treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Official Title
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A Phase III Multi-Institutional Randomized Study of Immunization With the gp100: 209-217 (210M) Peptide Followed by High Dose IL-2 vs. High Dose IL-2 Alone in Patients With Metastatic Melanoma

Conditions
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Recurrent Melanoma, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma

Intervention / Treatment
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* Biological: Aldesleukin
* Biological: gp100 Antigen
* Drug: Montanide ISA 51 VG
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient with measurable metastatic (stage IV or locally advanced stage III) cutaneous melanoma and an expected survival of greater than three months will be considered Serum creatinine of 1.6 mg/dl or less Total bilirubin 1.6 mg/dl or less 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 then 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 Pathologic confirmation of cutaneous melanoma; patients may enter the study with a pathologic diagnosis of cutaneous melanoma from any institution; all slides will be reviewed at National Institutes of Health (NIH) (department of Anatomic Pathology) and if the diagnosis is not confirmed, the patient will be excluded from the study Tissue type human leukocyte antigen (HLA) A0201 Exclusion Criteria: Patients who have types of melanoma other than cutaneous, i.e. ocular or mucosal Patients who are undergoing or have undergone in the past 4 weeks any other form of therapy except surgery for their cancer, including radiation therapy to any site Patients who have active systemic infections, coagulation disorders, autoimmune disease or history of other major medical illnesses such as insulin dependent diabetes mellitus, cardiac ischemia, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary diseases and inflammatory bowel disorders Patients who have significant psychiatric disease which in the opinion of the principal investigator would prevent adequate informed consent or render immunotherapy unsafe or contraindicated Patients who require steroid therapy or steroid-containing compounds, or have used systemic steroids in the past 4 weeks, or have used topical or inhalational steroids in the past 2 weeks Patients who are pregnant Patients who are known to be positive for viral hepatitis B or C (hepatitis B surface antigen [HBsAg] or anti hepatitis C virus [HCV]) or human immunodeficiency virus (HIV) (HIV antibody) Patients who have any form of primary or secondary immunodeficiency Patients who have received previous high dose IL-2 (> 600,000 IU/kg) Patients who have received previous gp100 vaccines Patients who have an abnormal stress cardiac test (stress thallium, stress multi gated acquisition scan [MUGA], dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) Patients who have abnormal pulmonary function tests (forced expiratory volume in one second [FEV1] < 65% or forced vital capacity [FVC] < 65% of predicted) Patients who have brain metastasis or history of brain metastasis No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease free for 5 years

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (aldesleukin)<br>Patients receive aldesleukin IV over 15 minutes every 8 hours for 12 doses. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease 3 weeks after completing 2 courses may receive a maximum of 12 additional courses. Patients with complete response may receive a maximum of 2 additional courses. | Biological: Aldesleukin<br>* Given IV<br>* Other names: Ro-236019;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II (gp100 antigen in Montanide IDA-51 and aldesleukin)<br>Patients receive gp100 antigen emulsified in Montanide ISA-51 SC on day 1. Patients also receive aldesleukin as in Arm I beginning on day 2. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease 3 weeks after completing 2 courses may receive a maximum of 12 additional courses. Patients with complete response may receive a maximum of 2 additional courses. | Biological: Aldesleukin<br>* Given IV<br>* Other names: Ro-236019;Biological: gp100 Antigen<br>* Given SC<br>* Other names: gp100;Drug: Montanide ISA 51 VG<br>* Given SC<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response Rate (Partial Response [PR] + Complete Response [CR]) | A complete response (CR) was defined as the disappearance of all clinical evidence of disease for at least 4 weeks. A partial response (PR) was defined as a 50% or greater decrease in the sum of the products of perpendicular diameters of all measurable lesions for at least one month. No new lesions could appear, and none could increase 25% or more. | Up to 12 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression free survival was compared between groups by means of Kaplan-Meier curves using the log-rank test to evaluate the significance of the difference between the arms. | From the date of randomization until documentation of progression or last follow up, assessed up to 12 years | 
| Change in T-cell Precursors | To measure change in T-cell precursors, PBMC were tested for reactivity by measuring gamma-interferon release after overnight coculture with peptide pulsed T2 cells. PBMC obtained after 4 cycles of study treatment were compared to pre treatment PBMC. A positive assay was defined as greater than 100pg/ml gamma-interferon release and at least twice the release (including all control peptides) by post treatment PBMC compared to pre treatment PBMC. | Baseline to up to 12 years | 
| Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | QOL was measured before and after 2 cycles of treatment using 4 measures: FACT-G is a 27 item measure of QOL. A total score is calculated by summing across responses on a 5 point scale and ranges from 0-135, with higher scores indicating better QOL. FACT-F is 13 item measure of fatigue. A total score is calculated by summing across responses on a 5 point scale. Total score ranges from 0-52, with higher scores indicating less fatigue. SF-36 is a 36 item measure of self-reported health status. SF-36 is comprised of 8 subscales: physical function, role physical, bodily pain vitality, role emotional function, mental health, social function and general health. Summated scores range from 0-100, with higher scores indicating a better health state. SDS is a 13 item measure of symptom distress. A total score is calculated by summing across responses on a 5 point scale. Total score ranges from 13 to 65, with higher scores indicating more symptom distress. | Baseline to up to 8 weeks |