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

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

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.

Study Overview

• Status: Completed
• Conditions: Stage IV Cutaneous Melanoma AJCC v6 and v7; Recurrent Melanoma; Stage IIIC Cutaneous Melanoma AJCC v7; Mucosal Melanoma; Iris Melanoma; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IV Uveal Melanoma AJCC v7; Medium/Large Size Posterior Uveal Melanoma; Recurrent Uveal Melanoma; Stage IIIA Uveal Melanoma AJCC v7; Stage IIIB Uveal Melanoma AJCC v7; Stage IIIC Uveal Melanoma AJCC v7; Stage IIB Cutaneous Melanoma AJCC v6 and v7; Stage IIC Cutaneous Melanoma AJCC v6 and v7; Ocular Melanoma With Extraocular Extension; Small Size Posterior Uveal Melanoma; Stage IIA Cutaneous Melanoma AJCC v6 and v7; Stage IIA Uveal Melanoma AJCC v7; Stage IIB Uveal Melanoma AJCC v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Sargramostim; Biological: Tyrosinase Peptide; Other: Placebo; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 815
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
    • Mobile, Alabama, United States, 36607
      • Mobile Infirmary Medical Center
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center - Tucson
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Berkeley, California, United States, 94704
      • Alta Bates Summit Medical Center-Herrick Campus
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Orange, California, United States, 92868
      • Saint Joseph Hospital - Orange
    • Palo Alto, California, United States, 94304
      • VA Palo Alto Health Care System
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Institute Palo Alto
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • San Diego, California, United States, 92134
      • Naval Medical Center -San Diego
    • San Diego, California, United States, 92108
      • Kaiser Permanente-San Diego Mission
    • San Diego, California, United States, 92161
      • Veterans Administration-San Diego Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80012
      • The Medical Center of Aurora
    • Boulder, Colorado, United States, 80301
      • Boulder Community Hospital
    • Denver, Colorado, United States, 80218
      • SCL Health Saint Joseph Hospital
    • Englewood, Colorado, United States, 80113
      • Swedish Medical Center
    • Grand Junction, Colorado, United States, 81501
      • Saint Mary's Hospital and Regional Medical Center
  • Connecticut
    • Manchester, Connecticut, United States, 06040
      • Manchester Memorial Hospital
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Southwest Florida Regional Medical Center
    • Jacksonville, Florida, United States, 32207
      • Baptist MD Anderson Cancer Center
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
    • Jupiter, Florida, United States, 33458
      • Jupiter Medical Center
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Health Hollis Cancer Center
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists-West Palm Beach
    • Weston, Florida, United States, 33331
      • Cleveland Clinic-Weston
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center
    • Decatur, Georgia, United States, 30033
      • Atlanta VA Medical Center
    • Fort Gordon, Georgia, United States, 30905-5650
      • Eisenhower Army Medical Center
    • Macon, Georgia, United States, 31201
      • Medical Center of Central Georgia
    • Valdosta, Georgia, United States, 31602
      • South Georgia Medical Center/Pearlman Cancer Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • Saint Luke's Mountain States Tumor Institute
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Rush - Copley Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Springfield, Illinois, United States, 62781
      • Memorial Medical Center
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University/Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • IU Health Methodist Hospital
    • Muncie, Indiana, United States, 47303
      • IU Health Ball Memorial Hospital
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic PC - Ames
    • Davenport, Iowa, United States, 52803
      • Genesis Medical Center - East Campus
    • Des Moines, Iowa, United States, 50309
      • Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50309
      • Medical Oncology and Hematology Associates-Des Moines
    • Des Moines, Iowa, United States, 50309
      • Iowa-Wide Oncology Research Coalition NCORP
    • Sioux City, Iowa, United States, 51101
      • Siouxland Regional Cancer Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center
    • Wichita, Kansas, United States, 67214
      • Wichita NCI Community Oncology Research Program
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • The James Graham Brown Cancer Center at University of Louisville
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Ochsner Health Center-Summa
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center Jefferson
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Anne Arundel Medical Center
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Baltimore, Maryland, United States, 21204
      • Greater Baltimore Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
    • Greenfield, Massachusetts, United States, 01301
      • Franklin Medical Center
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Grand Rapids, Michigan, United States, 49503
      • Cancer Research Consortium of West Michigan NCORP
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
  • Minnesota
    • Robbinsdale, Minnesota, United States, 55422
      • North Memorial Medical Health Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Hattiesburg Clinic - Hematology/Oncology Clinic
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri - Ellis Fischel
    • Saint Louis, Missouri, United States, 63141
      • Saint Louis-Cape Girardeau CCOP
    • Springfield, Missouri, United States, 65804
      • Cancer Research for the Ozarks NCORP
  • Montana
    • Billings, Montana, United States, 59101
      • Saint Vincent Healthcare
    • Billings, Montana, United States, 59102
      • Montana Cancer Consortium NCORP
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • CHI Health Saint Francis
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68124
      • Alegent Health Bergan Mercy Medical Center
    • Omaha, Nebraska, United States, 68122
      • Alegent Health Immanuel Medical Center
    • Omaha, Nebraska, United States, 68131
      • Creighton University Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • University Medical Center of Southern Nevada
    • Las Vegas, Nevada, United States, 89106
      • Nevada Cancer Research Foundation CCOP
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • East Orange, New Jersey, United States, 07018-1095
      • Veterans Adminstration New Jersey Health Care System
    • Hamilton, New Jersey, United States, 08690
      • The Cancer Institute of New Jersey Hamilton
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico Cancer Center
  • New York
    • Bronx, New York, United States, 10466
      • Montefiore Medical Center-Wakefield Campus
    • Glens Falls, New York, United States, 12801
      • Glens Falls Hospital
    • Middletown, New York, United States, 10940
      • Orange Regional Medical Center
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Rochester, New York, United States, 14623
      • Interlakes Foundation Inc-Rochester
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center/Levine Cancer Institute
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Winston-Salem, North Carolina, United States, 27104
      • Southeast Clinical Oncology Research (SCOR) Consortium NCORP
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Sanford Bismarck Medical Center
    • Bismarck, North Dakota, United States, 58501
      • Mid Dakota Clinic
  • Ohio
    • Canton, Ohio, United States, 44710
      • Aultman Health Foundation
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati/Barrett Cancer Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • Dayton, Ohio, United States, 45420
      • Dayton NCI Community Oncology Research Program
  • Oklahoma
    • Lawton, Oklahoma, United States, 73505
      • Cancer Centers of Southwest Oklahoma Research
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at Saint Francis
    • Tulsa, Oklahoma, United States, 74104
      • Saint John Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital-Cedar Crest
    • Bethlehem, Pennsylvania, United States, 18015
      • Saint Luke's University Hospital-Bethlehem Campus
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Drexel Hill, Pennsylvania, United States, 19026
      • Delaware County Memorial Hospital
    • Langhorne, Pennsylvania, United States, 19047
      • Saint Mary Medical and Regional Cancer Center
    • Paoli, Pennsylvania, United States, 19301
      • Paoli Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania/Abramson Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
    • Pottstown, Pennsylvania, United States, 19464
      • Pottstown Hospital
    • Sayre, Pennsylvania, United States, 18840
      • Guthrie Medical Group PC-Robert Packer Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Cancer Center Oncology Clinic
  • Tennessee
    • Johnson City, Tennessee, United States, 37614-0054
      • East Tennessee State University
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont and State Agricultural College
  • Washington
    • Mount Vernon, Washington, United States, 98274
      • Skagit Valley Hospital
    • Seattle, Washington, United States, 98112
      • Kaiser Permanente Washington
    • Seattle, Washington, United States, 98122-4307
      • Swedish Medical Center-First Hill
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • West Virginia University Charleston Division
  • Wisconsin
    • Glendale, Wisconsin, United States, 53212
      • Aurora Cancer Care-Glendale
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital Cancer Center Green Bay
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Manitowoc, Wisconsin, United States, 54221
      • Holy Family Memorial Hospital
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Medical Center-Marshfield
    • Oconomowoc, Wisconsin, United States, 53066
      • ProHealth Oconomowoc Memorial Hospital
    • Waukesha, Wisconsin, United States, 53188
      • ProHealth Waukesha Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (sargramostim, peptide vaccine); 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; Correlative studies; Biological: Sargramostim; Given SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin; Biological: Tyrosinase Peptide; Given SC; Other Names: Tyrosinase Peptides
Experimental: Arm II (sargramostim placebo, peptide vaccine); 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; Correlative studies; Biological: Tyrosinase Peptide; Given SC; Other Names: Tyrosinase Peptides; Other: Placebo; Given GM-CSF placebo SC; Other Names: placebo therapy; PLCB; sham therapy; Other: Placebo; Given peptide placebo SC; Other Names: placebo therapy; PLCB; sham therapy
Experimental: Arm III (sargramostim, peptide placebo); 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; Correlative studies; Biological: Sargramostim; Given SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin; Other: Placebo; Given GM-CSF placebo SC; Other Names: placebo therapy; PLCB; sham therapy; Other: Placebo; Given peptide placebo SC; Other Names: placebo therapy; PLCB; sham therapy
Placebo Comparator: Arm IV (placebo, peptide placebo); 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; Correlative studies; Other: Placebo; Given GM-CSF placebo SC; Other Names: placebo therapy; PLCB; sham therapy; Other: Placebo; Given peptide placebo SC; Other Names: placebo therapy; PLCB; sham therapy
Experimental: Arm V (sargramostim); Patients receive sargramostim SC on days 1-14.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Sargramostim; Given SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin
Placebo Comparator: Arm VI (sargramostim placebo); Patients receive sargramostim placebo SC on days 1-14.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Placebo; Given GM-CSF placebo SC; Other Names: placebo therapy; PLCB; sham therapy; Other: Placebo; Given peptide placebo SC; Other Names: placebo therapy; PLCB; sham therapy

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: David H Lawson, Eastern Cooperative Oncology Group

Publications and helpful links

General Publications

• Lawson DH, Lee S, Zhao F, Tarhini AA, Margolin KA, Ernstoff MS, Atkins MB, Cohen GI, Whiteside TL, Butterfield LH, Kirkwood JM. Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (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: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). J Clin Oncol. 2015 Dec 1;33(34):4066-76. doi: 10.1200/JCO.2015.62.0500. Epub 2015 Sep 8.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2000
• Primary Completion (Actual): October 8, 2012
• Study Completion (Actual): January 31, 2013

Study Registration Dates

• First Submitted: November 18, 2013
• First Submitted That Met QC Criteria: November 18, 2013
• First Posted (Estimate): November 21, 2013

Study Record Updates

• Last Update Posted (Actual): July 7, 2020
• Last Update Submitted That Met QC Criteria: June 24, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Eye Diseases; Disease Attributes; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Uveal Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Recurrence; Melanoma; Skin Neoplasms; Uveal Neoplasms; Physiological Effects of Drugs; Immunologic Factors; Sargramostim
• Other Study ID Numbers: NCI-2013-02101 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA021115 (U.S. NIH Grant/Contract); CALGB 500101; ECOG-4697; CDR0000067568; SWOG-E4697; 9546; E4697 (Other Identifier: CTEP)