Vaccine Therapy Using Melanoma Peptides for Cytotoxic T Cells and Helper T Cells in Treating Patients With Metastatic Melanoma

A Randomized Phase II Trial of Multi-Epitope Vaccination With Melanoma Peptides For Cytotoxic T Cells And Helper T Cells For Patients With Metastatic Melanoma

RATIONALE: Vaccines made from peptides may make the body build an immune response to kill tumor cells.

PURPOSE: This randomized phase II trial is studying four different vaccines using melanoma peptides from cytotoxic T cells and helper T cells to see how well they work in treating patients with metastatic melanoma.

Study Overview

• Status: Completed
• Conditions: Melanoma (Skin)
• Intervention / Treatment: Biological: incomplete Freund's adjuvant; Biological: multi-epitope melanoma peptide vaccine; Biological: sargramostim; Biological: tetanus peptide melanoma vaccine; Biological: melanoma helper peptide vaccine

Detailed Description

OBJECTIVES:

• Compare the cytotoxic T-cell response to each of 12 melanoma peptides restricted by Human Leukocyte Antigen (HLA)-A1, -A2, or -A3 in patients with metastatic melanoma vaccinated with or without these 12 melanoma peptides and with or without helper peptides.
• Compare the helper T-cell response to each of 6 melanoma helper peptides restricted by HLA-DR molecules in patients treated with these vaccinations.
• Determine whether the addition of 6 melanoma helper peptides to a vaccine containing multiple class I Major histocompatibility complex (MHC)-restricted peptides augments T-cell responses to the class I restricted peptides in these patients.
• Determine, preliminarily, whether booster vaccination maintains immune response in patients treated with these vaccinations.
• Compare the rates of clinical response and survival in patients treated with these vaccinations.
• Determine, preliminarily, whether cellular immune response correlates with clinical response and survival rates in patients treated with these vaccinations.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to HLA type (HLA-A1 vs HLA-A2 vs HLA-A1 and -A2 vs HLA-A3) and planned sentinel immunized node biopsy (yes vs no). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (Granulocyte-macrophage colony-stimulating factor, GM-CSF) and Montanide ISA-51 or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Arm II: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 1 tetanus helper peptide emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Arm III (closed to accrual as of 5/19/08): Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Arm IV: Patients receive 2 injections of multi-epitope peptide vaccine comprising 6HP emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

In all arms, patients continue therapy in the absence of unacceptable toxicity or disease progression necessitating other urgent therapy.

Patients are evaluated at 8 and 12 weeks. Beginning 2-3 weeks after the week-12 evaluation, patients with no evidence of disease progression may receive booster vaccinations according to their randomized treatment arm. Patients receive booster vaccination ID and SC once weekly for 3 weeks. Treatment repeats every 9 weeks for 1 course, every 12 weeks for 2 courses, and then every 24 weeks for 2 courses OR for up to 2 years (whichever comes first) provided the patient does not require an urgent change in therapy.

After completion of study treatment, patients are followed every 6 months for 2 years and then for survival for 5 years from study randomization.

ACTUAL ACCRUAL: A total of 175 patients were accrued for this study during March 2005 and January 2009.

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Veterans Affairs Medical Center - Palo Alto
    • Stanford, California, United States, 94305-5824
      • Stanford Cancer Center
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Tunnell Cancer Center at Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Rush-Copley Cancer Care Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60611
      • Hematology and Oncology Associates
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology-Hematology Associates, Limited - West
    • Joliet, Illinois, United States, 60432
      • Midwest Center for Hematology/Oncology
    • Libertyville, Illinois, United States, 60048
      • North Shore Oncology and Hematology Associates, Limited - Libertyville
    • Niles, Illinois, United States, 60714
      • Cancer Care and Hematology Specialists of Chicagoland - Niles
    • Skokie, Illinois, United States, 60076
      • Hematology Oncology Associates - Skokie
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center at Carle Foundation Hospital
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • William N. Wishard Memorial Hospital
    • Michigan City, Indiana, United States, 46360
      • Saint Anthony Memorial Health Centers
  • Iowa
    • Ottumwa, Iowa, United States, 52501
      • McCreery Cancer Center at Ottumwa Regional
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Baltimore, Maryland, United States, 21204
      • Greater Baltimore Medical Center Cancer Center
    • Elkton, Maryland, United States, 21921
      • Union Hospital Cancer Program at Union Hospital
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology Hematology, PA - Maplewood
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
    • Robbinsdale, Minnesota, United States, 55422-2900
      • Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Cancer Center
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Shakopee, Minnesota, United States, 55379
      • St. Francis Cancer Center at St. Francis Medical Center
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology Hematology, PA - Woodbury
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • CCOP - Northern New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Christ Hospital Cancer Center
    • Cleveland, Ohio, United States, 44106-5065
      • Case Comprehensive Cancer Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest
    • Langhorne, Pennsylvania, United States, 19047
      • St. Mary Regional Cancer Center
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
    • Sioux Falls, South Dakota, United States, 57105
      • Medical X-Ray Center, PC
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sanford Cancer Center at Sanford USD Medical Center
  • Wisconsin
    • Eau Claire, Wisconsin, United States, 54701
      • Center for Cancer Treatment & Prevention at Sacred Heart Hospital
    • Eau Claire, Wisconsin, United States, 54701
      • Marshfield Clinic Cancer Care at Regional Cancer Center
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Center for Cancer and Blood
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Saint Joseph's Hospital
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Minocqua, Wisconsin, United States, 54548
      • Marshfield Clinic - Lakeland Center
    • Rhinelander, Wisconsin, United States, 54501
      • Ministry Medical Group at Saint Mary's Hospital
    • Rice Lake, Wisconsin, United States, 54868
      • Marshfield Clinic - Indianhead Center
    • Stevens Point, Wisconsin, United States, 54481
      • Saint Michael's Hospital Cancer Center
    • Wausau, Wisconsin, United States, 54401
      • Marshfield Clinic - Wausau Center
    • Weston, Wisconsin, United States, 54476
      • Marshfield Clinic - Weston Center
    • Wisconsin Rapids, Wisconsin, United States, 54494
      • Marshfield Clinic - Wisconsin Rapids Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed stage IV melanoma

  • Multiple primary melanomas allowed
  • Metastasis may be from a cutaneous, mucosal, ocular, or unknown primary site
• Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST criteria)
• Must have 2 extremities uninvolved with tumor

• Must have at least 2 intact (undissected) axillary and/or inguinal lymph node basins

  • Prior sentinel node biopsy may not have violated the integrity of a nodal basin

    • This extremity may still be considered for vaccination
• Human Lymphocyte Antigen (HLA)-A1, -A2, or -A3 positive

• Prior brain metastases allowed provided all of the following are true:

  • Surgically resected or treated with gamma-knife or stereotactic radiosurgery
  • No disease progression in the brain for the past 3 months
  • More than 30 days since prior steroids for the management of brain metastases
• Age: 18 and over
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Adequate organ function measured within 4 weeks before randomization:

  • White blood cell (WBC) at least 4,000/mm^3
  • Platelet count at least 100,000/mm^3
  • Lymphocyte count at least 700/mm^3
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) no greater than 2 times upper limit of normal (ULN)
  • Bilirubin no greater than 2 times ULN
  • Alkaline phosphatase no greater than 2 times ULN
  • Lactic dehydrogenase no greater than 2 times ULN
  • Creatinine no greater than 1.8 mg/dL
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except nonmetastatic squamous cell or basal cell skin cancer, ductal or lobular carcinoma in situ of the breast, or carcinoma in situ of the cervix
• At least 4 weeks since prior sargramostim (GM-CSF), interferon alfa-2b, or interleukin-2
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

• More than 30 days since prior systemic corticosteroids, including any of the following:

  • Therapeutic doses of oral steroids (e.g., prednisone or dexamethasone)

  • Steroid inhalers (e.g., Advair)

    • Topical steroids and nasal steroids with low systemic absorption (e.g., fluticasone) or steroids with low systemic absorption (e.g., triamcinolone hexacetonide) injected into a joint space allowed
• At least 4 weeks since prior local control or palliative radiotherapy and recovered
• Recovered from prior major surgery

Exclusion criteria:

• More than 3 brain metastases
• Metastatic lesions greater than 2 cm
• Concurrent radiotherapy
• Prior radiotherapy to measurable disease
• Concurrent surgery
• Concurrent corticosteroids
• Concurrent topical or systemic steroids
• Concurrent chemotherapy
• Prior vaccination with any of the study peptides
• Recent (within the past year) or concurrent addiction to alcohol or illicit drugs
• Pregnant or nursing
• Known or suspected major allergy to any components of the study vaccine
• Significant detectable infection
• Immunosuppression conditions

• Prior or active autoimmune disorder requiring cytotoxic or mmunosuppressive therapy, except for any of the following:

  • Presence of laboratory evidence of autoimmune disease (e.g., positive antinuclear antibody (ANA) titer) without symptoms
  • Clinical evidence of vitiligo or other forms of depigmenting illness
  • Mild arthritis requiring nonsteroidal anti-inflammatory medication
• Autoimmune disorder with visceral involvement

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (12MP); Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51; Biological: multi-epitope melanoma peptide vaccine; Given by injection; Other Names: 12 Melanoma peptides from melanocyte differentiation protein (MDP) and cancer testis antigen (CTA),; 12 melanoma peptides restricted by class I MHC molecules,restricted by HLA-A1, A2, or A3 molecules; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF,; Leukine,; Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
Experimental: Arm II (12MP/Tet); Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51; Biological: multi-epitope melanoma peptide vaccine; Given by injection; Other Names: 12 Melanoma peptides from melanocyte differentiation protein (MDP) and cancer testis antigen (CTA),; 12 melanoma peptides restricted by class I MHC molecules,restricted by HLA-A1, A2, or A3 molecules; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF,; Leukine,; Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF); Biological: tetanus peptide melanoma vaccine; Given by injection; Other Names: Modified Tetanus p2 peptide restricted by class II MHC molecules,; Peptide-Tet
Experimental: Arm III (12MP/6MHP); Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51; Biological: multi-epitope melanoma peptide vaccine; Given by injection; Other Names: 12 Melanoma peptides from melanocyte differentiation protein (MDP) and cancer testis antigen (CTA),; 12 melanoma peptides restricted by class I MHC molecules,restricted by HLA-A1, A2, or A3 molecules; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF,; Leukine,; Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF); Biological: melanoma helper peptide vaccine; Given by injection; Other Names: 6 melanoma helper peptides restricted by class II MHC molecules, restricted by; HLADR molecules,; 6 class II MHC-Restricted Melanoma-Associated Peptides
Experimental: Arm IV (6MHP); Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF,; Leukine,; Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF); Biological: melanoma helper peptide vaccine; Given by injection; Other Names: 6 melanoma helper peptides restricted by class II MHC molecules, restricted by; HLADR molecules,; 6 class II MHC-Restricted Melanoma-Associated Peptides

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytotoxic T-cell Lymphocytes (CTL) Response Rate	Assessment of CTL response was based on a fold-increase in T cell response measure by interferon-gamma ELIspot assay.	Immune response was assessed at pre-registrtion, in weeks 1, 3, 5, 7, 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Helper T-cells Response to 6MHP	Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.	Immune response was assessed at pre-registration, in weeks 1,3,5,7,8
Helper T Cell Response to Tetanus	Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.	Immune response was assessed at pre-registration, in weeks 1,3,5,7,8
Objective Response Rate	Tumor response was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Objective response rate is calculated as the number of patients with complete response (disappearance of all lesions) or partial response () divided by total number of evaluable patients.	Tumor response was assessed in weeks 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 6 months after last vaccination
Median Overall Survival (OS)	OS was defined as the time from registration to death from any cause.	assessed every 3 month within 2 years and every 6 months betwen 2 and 5 years

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Craig L. Slingluff, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2005
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: November 4, 2003
• First Submitted That Met QC Criteria: November 5, 2003
• First Posted (Estimated): November 6, 2003

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: recurrent melanoma; stage IV melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Vaccines; Sargramostim; Freund's Adjuvant; Molgramostim
• Other Study ID Numbers: CDR0000335055; U10CA021115 (U.S. NIH Grant/Contract); E1602 (Other Identifier: Eastern Cooperative Oncology Group (ECOG))