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

• ClinicalTrials.gov Identifier: NCT00071981
• Recruitment Status: Completed
• First Posted: November 6, 2003
• Results First Posted: January 3, 2013
• Last Update Posted: October 28, 2015
• Sponsor: Eastern Cooperative Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Eastern Cooperative Oncology Group

Tracking Information

• First Submitted Date: November 4, 2003
• First Posted Date: November 6, 2003
• Results First Submitted Date: November 24, 2012
• Results First Posted Date: January 3, 2013
• Last Update Posted Date: October 28, 2015
• Study Start Date: March 2005
• Actual Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 30, 2012)

Cytotoxic T-cell Lymphocytes (CTL) Response Rate [ Time Frame: Immune response was assessed at pre-registrtion, in weeks 1, 3, 5, 7, 8 ]

Assessment of CTL response was based on a fold-increase in T cell response measure by interferon-gamma ELIspot assay.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: November 30, 2012)

• Helper T-cells Response to 6MHP [ Time Frame: Immune response was assessed at pre-registration, in weeks 1,3,5,7,8 ]
  Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.
• Helper T Cell Response to Tetanus [ Time Frame: Immune response was assessed at pre-registration, in weeks 1,3,5,7,8 ]
  Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.
• Objective Response Rate [ Time Frame: Tumor response was assessed in weeks 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 6 months after last vaccination ]
  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.
• Median Overall Survival (OS) [ Time Frame: assessed every 3 month within 2 years and every 6 months betwen 2 and 5 years ]
  OS was defined as the time from registration to death from any cause.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Vaccine Therapy Using Melanoma Peptides for Cytotoxic T Cells and Helper T Cells in Treating Patients With Metastatic Melanoma
• Official Title: 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

Brief Summary

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.

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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma (Skin)

Intervention

• Biological: incomplete Freund's adjuvant
  Given by injection
  Other Name: Montanide ISA-51
• 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
• 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

Study Arms

• 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.
  Interventions:

  • Biological: incomplete Freund's adjuvant
  • Biological: multi-epitope melanoma peptide vaccine
  • Biological: sargramostim
• 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.
  Interventions:

  • Biological: incomplete Freund's adjuvant
  • Biological: multi-epitope melanoma peptide vaccine
  • Biological: sargramostim
  • Biological: tetanus peptide melanoma vaccine
• 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.
  Interventions:

  • Biological: incomplete Freund's adjuvant
  • Biological: melanoma helper peptide vaccine
  • Biological: multi-epitope melanoma peptide vaccine
  • Biological: sargramostim
• 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.
  Interventions:

  • Biological: incomplete Freund's adjuvant
  • Biological: melanoma helper peptide vaccine
  • Biological: sargramostim

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 30, 2012): 175
• Original Enrollment: Not Provided
• Actual Study Completion Date: January 2014
• Actual Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00071981
• Other Study ID Numbers: CDR0000335055; U10CA021115 ( U.S. NIH Grant/Contract ); E1602 ( Other Identifier: Eastern Cooperative Oncology Group (ECOG) )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eastern Cooperative Oncology Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: Eastern Cooperative Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Craig L. Slingluff, MD; University of Virginia

• PRS Account: Eastern Cooperative Oncology Group
• Verification Date: October 2015