Sargramostim, Vaccine Therapy, or Sargramostim and Vaccine Therapy in Preventing Disease Recurrence in Patients With Melanoma That Has Been Removed By Surgery

Study Overview
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Brief Summary
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This randomized phase III trial studies sargramostim or vaccine therapy alone to see how well they work compared to sargramostim and vaccine therapy together in preventing disease recurrence in patients with melanoma that has been removed by surgery. Sargramostim may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. It is not yet known whether yeast derived sargramostim and vaccine therapy are more effective alone or together in preventing recurrence of melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare overall survival and disease-free survival of patients with completely resected stage IV melanoma or stage III melanoma with gross extranodal extension, satellites, and/or intransit lesions, treated with granulocyte macrophage colony-stimulating factor (GM-CSF) (sargramostim) vs. no GM-CSF, or other high risk patients listed in the eligibility section. SECONDARY OBJECTIVES: I. To compare, using a 2 x 2 factorial design, overall survival and disease-free survival of human leukocyte antigen (HLA)-A2 positive patients treated with peptide vaccination vs. no peptide vaccination. II. The following descriptive evaluations of survival and disease-free survival are planned for the HLA-A2 positive patients: (1) GM-CSF plus peptide vaccination vs. peptide vaccination alone; (2) GM-CSF plus peptide vaccination vs. GM-CSF alone; (3) GM-CSF plus peptide vaccination vs. placebo. III. Survival and disease-free survival of HLA-A2 positive patients not receiving peptide vaccination will be compared to that of HLA-A2 negative patients not receiving peptide vaccination. IV. To determine the influence of GM-CSF on circulating dendritic cell numbers and subpopulations in peripheral blood of patients receiving and not receiving GM-CSF. V. To determine, in HLA-A2 positive patients, whether immunization with peptides with or without GM-CSF elicits a measurable T-cell response as assessed by enzyme-linked immunosorbent spot (ELISPOT) and the major histocompatibility complex (MHC) tetramer assay, and to determine the functionality of these cells by intracellular cytokine staining. OUTLINE: HLA-A2 positive patients are randomized to 1 of 4 treatment regimens (Arms I-IV). HLA-A2 negative patients are randomized to 1 of 2 treatment arms (Arms V-VI). ARM I: Patients receive sargramostim subcutaneously (SC) on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). ARM II: Patients receive sargramostim placebo SC on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). ARM III: Patients receive sargramostim SC on days 1-14 and peptide placebo mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). ARM IV: Patients receive sargramostim placebo SC on days 1-14 and peptide placebo mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). ARM V: Patients receive sargramostim SC on days 1-14. ARM VI: Patients receive sargramostim placebo SC on days 1-14. In all arms, treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. In the event of recurrence, patients who undergo complete resection of the recurrence may continue treatment for 6 courses or until completion of 1 year of therapy (whichever is longer). For patients with recurrence that is not surgically resectable or experiencing second recurrence, treatment will be discontinued. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 10 years.

Official Title
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A Randomized, Placebo-Controlled Phase III Trial of Yeast Derived GM-CSF Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma

Conditions
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Iris Melanoma, Medium/Large Size Posterior Uveal Melanoma, Mucosal Melanoma, Ocular Melanoma With Extraocular Extension, Recurrent Melanoma, Recurrent Uveal Melanoma, Small Size Posterior Uveal Melanoma, Stage IIA Cutaneous Melanoma AJCC v6 and v7, Stage IIA Uveal Melanoma AJCC v7, Stage IIB Cutaneous Melanoma AJCC v6 and v7, Stage IIB Uveal Melanoma AJCC v7, Stage IIC Cutaneous Melanoma AJCC v6 and v7, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIA Uveal Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIB Uveal Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IIIC Uveal Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Stage IV Uveal Melanoma AJCC v7

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Placebo
* Other: Placebo
* Biological: Sargramostim
* Biological: Tyrosinase Peptide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have HLA-A2 status known prior to randomization; typing may be obtained through a local laboratory facility or through a reference lab utilized by the initiating institution; if typing is not available through these means, it may be obtained from the University of Pittsburgh All patients must have disease completely resected with one of the following in order to be eligible: Completely resected disease Any locoregional recurrence after prior adjuvant interferon or failure on S008 Any local recurrence of disease after adequate surgical excision of the original primary Mucosal melanoma Stage IV melanoma (cutaneous, ocular, mucosal, or unknown primary) The following groups of patients may be entered onto this trial only if they are ineligible for S0008 or are, in the opinion of the managing physician, medically unfit to receive standard high-dose interferon: Any clinically evident satellite or in-transit disease Stage II disease with gross extracapsular extension Recurrence in a previously resected nodal basin Four or more involved lymph nodes or matted lymph nodes Ulcerated primary melanoma and any involved lymph nodes NOTE: Patients who are eligible for S0008 will be strongly encouraged to participate in that study in preference to this one Patients must have been surgically rendered free of disease with negative margins on resected specimens; patients rendered free of disease by non-surgical means are not eligible Patients must be randomized within 112 days (16 weeks) of surgical resection; if more than one surgical procedure is required to render the patient disease-free, all required surgeries must be accomplished within this 16 week time period Patients must not have received any adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after the resection(s) that make(s) them eligible for this trial; one systemic treatment after a prior surgery is allowed, and must have been completed >= 8 weeks prior to randomization; (when chemotherapy and biotherapy are given together as one planned treatment [biochemotherapy], this counts as one regimen); NOTE: Previous radiation therapy, including after the resection, is allowed as long as 30 days elapse between the radiation and initiation of therapy Prior treatment with GM-CSF or any peptides used in this protocol, is not allowed Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Patients must not have an active infection requiring treatment with parenteral antibiotics Patients must not have other significant medical, surgical, or psychiatric conditions or require any medication or treatment that may interfere with compliance on any of the E4697 treatment regimens Patients must not have a diagnosis or evidence of organic brain syndrome or significant impairment of basal cognitive function or any psychiatric disorder that might preclude participation in the full protocol Patients must be able to self-administer or arrange for administration of subcutaneous injections Patients who have other current malignancies are not eligible Patients with prior history at any time of any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or Clark I melanoma in situ are eligible; patients who meet this criteria must be disease-free at time of randomization Patients with prior history of basal or squamous skin cancer are eligible; patients who meet this criteria must be disease-free at time of randomization Patients who have had multiple primary melanomas are eligible Patients with other malignancies are eligible if they have been continuously disease free for > 5 years prior to the time of randomization Patients must not have autoimmune disorders, conditions of immunosuppression or treatment with systemic corticosteroids, including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or any steroid containing inhalers; replacement doses of steroids for patients with adrenal insufficiency are allowed; patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization are eligible if, in the judgment of the treating physician, the patient is not likely to require these classes of drugs during the study Women of childbearing potential must not be pregnant (negative beta human chorionic gonadotropin [bHCG] within 2 weeks prior to randomization) or breast-feeding Women of childbearing potential and sexually active males must be counseled to use an accepted and effective method of contraception (including abstinence) while on treatment and for a period of 18 months after completing or discontinuing treatment All patients must have brain computed tomography (CT) or magnetic resonance imaging (MRI), chest CT or chest x-ray (CXR), and abdominal (liver) CT or MRI within 4 weeks prior to randomization; positron emission tomography (PET) scans are also acceptable in place of CT, CXR and/or abdominal MRI if obtained within 4 weeks prior to randomization; patients with lesions on the lower extremity must also have pelvic imaging within this time period; this is also strongly recommended for patients with lesions on the lower trunk; PET scans are acceptable Patients with resection of visceral disease must have imaging of the affected area/organ documenting disease-free status within 2 weeks prior to randomization White blood cells (WBC) >= 3,000/mm? Platelet count >= 100,000/mm? Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2 x institutional upper limit (IUL) of normal Bilirubin =< 2 x IUL of normal Serum creatinine =< 1.8 mg/dl Alkaline phosphatase and lactate dehydrogenase (LDH) must be performed within 4 weeks prior to randomization; LDH must be normal; patients with abnormal alkaline phosphatase which is =< 1.25 times the institutional upper limit of normal who have a negative CT or MRI of the liver and negative bone scan or a negative PET scan are eligible Patients with bone pain must have a bone scan within 4 weeks prior to randomization to document the absence of tumor

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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (sargramostim, peptide vaccine)<br>Patients receive sargramostim SC on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Biological: Tyrosinase Peptide<br>* Given SC<br>* Other names: Tyrosinase Peptides;|
| Experimental: Arm II (sargramostim placebo, peptide vaccine)<br>Patients receive sargramostim placebo SC on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given GM-CSF placebo SC<br>* Other names: sham therapy;Biological: Tyrosinase Peptide<br>* Given SC<br>* Other names: Tyrosinase Peptides;|
| Experimental: Arm III (sargramostim, peptide placebo)<br>Patients receive sargramostim SC on days 1-14 and peptide placebo mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given peptide placebo SC<br>* Other names: sham therapy;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;|
| Placebo Comparator: Arm IV (placebo, peptide placebo)<br>Patients receive placebo SC on days 1-14 and peptide placebo on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses). | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given GM-CSF placebo SC<br>* Other names: sham therapy;Other: Placebo<br>* Given peptide placebo SC<br>* Other names: sham therapy;|
| Experimental: Arm V (sargramostim)<br>Patients receive sargramostim SC on days 1-14. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;|
| Placebo Comparator: Arm VI (sargramostim placebo)<br>Patients receive sargramostim placebo SC on days 1-14. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given GM-CSF placebo SC<br>* Other names: sham therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as time from randomization to death from any cause. | assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years, up to year 15 | 
| Recurrence Free Survival | Recurrence free survival is defined as time from randomization to first disease recurrence or death from any cause (whichever occur first), censoring cases without recurrence or death at the last date of known free of recurrence free survival events. Disease recurrence was determined based on positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease, or a positive brain CT or MRI scan or CSF cytology. | assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years, up to year 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival in Human Leukocyte Antigens-A2 (HLA-A2) Positive Patients | Overall survival is defined as time from randomization to death from any cause. | assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years,up to year 15 | 
| Recurrence Free Survival in HLA-A2 Positive Patients | Recurrence free survival is defined as time from randomization to first disease recurrence or death from any cause (whichever occur first), censoring cases without recurrence or death at the last date of known free of recurrence free survival events. Disease recurrence was determined based on positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease, or a positive brain CT or MRI scan or CSF cytology. | assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years, up to year 15 | 
| 5-year Overall Survival Rate | Overall survival is defined as time from randomization to death from any cause, and 5-year overall survival rate is estimated via Kaplan-Meier method. | assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years, up to year 15 | 
| 5-year Recurrence Free Survival Rate | Recurrence free survival is defined as time from randomization to first disease recurrence or death from any cause (whichever occur first), censoring cases without recurrence or death at the last date of known free of recurrence free survival events, and 5-year overall survival rate is estimated via Kaplan-Meier method. Disease recurrence was determined based on positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease, or a positive brain CT or MRI scan or CSF cytology. | assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years, up to year 15 |