Vaccine Therapy With or Without Biological Therapy in Treating Patients With Metastatic Melanoma

OBJECTIVES:

* Determine immune response of vaccination with melanoma associated antigens (MART-1:27-35, gp100:209-217 (210M), and tyrosinase:368-376 (370D)) on the number of peptide specific CD8+ T-cell precursors in HLA-A2 positive patients with metastatic melanoma.
* Determine the influence of sargramostim (GM-CSF) and/or interferon alfa-2b (IFN-A) on the immune responses of these patients and toxicity of this melanoma peptide vaccine.
* Determine any antitumor and anti-pigmentary response that may result from immunization against MART-1, gp100 and tyrosinase peptides, and determine the relationship between such clinical observations and immune responses against lineage antigens with or without GM-CSF and/or IFN-A.
* Compare the relapse free survival and overall survival of patients treated with melanoma peptide vaccine alone or in combination with GM-CSF and/or IFN-A.

OUTLINE: This is a randomized, multicenter study.

Patients are randomized to 1 of 4 treatment arms.

* Arm I: Patients receive multiepitope peptide (MEP) vaccine comprising MART-1:27-35, gp100:209-217 (210M), and tyrosinase:368-376 (370D) peptides. Each peptide is separately emulsified in Montanide ISA-51 and administered subcutaneously (SC) (for a total of 2 injections per peptide) on days 1 and 15.
* Arm II: Patients receive MEP vaccine as in arm I and sargramostim (GM-CSF) subcutaneously (SC) daily on days 1-14.
* Arm III: Patients receive MEP vaccine as in arm I and interferon alfa-2b SC three times a week.
* Arm IV: Patients receive MEP vaccine as in arm I, GM-CSF as in arm II, and interferon alfa-2b as in arm III.

Treatment continues every 4 weeks for a maximum of 13 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 92 patients (23 per arm) will be accrued for this study within 13-16 months.

• MART-1 antigen (Biological)
• gp100 antigen (Biological)
• incomplete Freund's adjuvant (Biological)
• recombinant interferon alfa (Biological)
• sargramostim (Biological)
• tyrosinase peptide (Biological)

Sex: All, ages: 18 Years to any

DISEASE CHARACTERISTICS:

* Histologically proven stage IV melanoma
* Measurable disease

  * At least 1 lesion must be a minimum of 1.0 cm in diameter
  * Bone metastases are not considered to be measurable disease
  * No prior radiotherapy to area of measurable disease unless there is clearly progressive disease in this site or measurable disease exists outside the area of prior radiotherapy
* HLA-A2 positive
* No brain disease by MRI or CT scan within 4 weeks prior to randomization

  * Prior brain disease allowed if no evidence of active disease by 2 successive MRI evaluations completed at least 3 months apart

PATIENT CHARACTERISTICS:

Age:

* 18 and over

Performance status:

* ECOG 0-1

Life expectancy:

* Not specified

Hematopoietic:

* WBC at least 4,000/mm\^3
* Platelet count at least 100,000/mm\^3
* Lymphocyte count greater than 700/mm \^3

Hepatic:

* SGOT no greater than 2 times upper limit of normal (ULN)
* Bilirubin no greater than 2 times ULN
* Alkaline phosphatase and lactic dehydrogenase no greater than 2 times ULN

Renal:

* Creatinine no greater than 1.8 mg/dL

Other:

* No significant detectable infection
* HIV negative
* No other malignancy within the past 5 years except:

  * Any carcinoma in situ
  * Lobular carcinoma in situ of the breast
  * Carcinoma in situ of the cervix
  * Atypical melanocytic hyperplasia
  * Melanoma in situ
  * Basal cell or squamous cell skin cancer
* No autoimmune disorders or conditions of immunosuppression
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* No prior MART-1:27-35, gp100:209-217 (210M), or tyrosinase:368-376 (370D) peptide
* Greater than 4 weeks since prior adjuvant immunotherapy, including sargramostim (GM-CSF) or interferon alfa-2b

Chemotherapy:

* At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

Endocrine therapy:

* At least 2 weeks since prior and no concurrent systemic corticosteroids, including oral steroids (i.e., prednisone, dexamethasone); continuous use of topical steroid creams or ointments; or any inhalers containing steroids

Radiotherapy:

* See Disease Characteristics
* At least 4 weeks since prior radiotherapy for local control or palliation and recovered

Surgery:

* Recovered from any prior major surgery

• Results publication: Schaefer C, Butterfield LH, Lee S, Kim GG, Visus C, Albers A, Kirkwood JM, Whiteside TL. Function but not phenotype of melanoma peptide-specific CD8(+) T cells correlate with survival in a multiepitope peptide vaccine trial (ECOG 1696). Int J Cancer. 2012 Aug 15;131(4):874-84. doi: 10.1002/ijc.26481. Epub 2012 Jan 11. PMID 22021080
• Results publication: Kirkwood JM, Lee S, Moschos SJ, Albertini MR, Michalak JC, Sander C, Whiteside T, Butterfield LH, Weiner L. Immunogenicity and antitumor effects of vaccination with peptide vaccine+/-granulocyte-monocyte colony-stimulating factor and/or IFN-alpha2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. Clin Cancer Res. 2009 Feb 15;15(4):1443-51. doi: 10.1158/1078-0432.CCR-08-1231. PMID 19228745
• Results publication: Kirkwood JM, Lee S, Land S, et al.: E1696: final analysis of the clinical and immunological results of a multicenter ECOG phase II trial of multi-epitope peptide vaccination for stage IV melanoma with MART-1 (27-35), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) (MGT) +/- IFNα2b and GM-CSF. [Abstract] J Clin Oncol 22 (Suppl 14): A-7502, 710s, 2004.
• Results publication: Kirkwood JM, Lee S, Land S, et al.: E1696: phase II trial of multi-epitope peptide vaccination for melanoma with MGT (MART-1 (27-35), gp100 (209-217, 210M) and tyrosinase (368-376, 370D))+/- IFN alfa-2b and GM-CSF--immunological and clinical results. [Abstract] 22: A-2850, 709, 2003.

• John M. Kirkwood, MD, Study chair, University of Pittsburgh