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

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.

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