Vaccine Therapy With or Without Interleukin-12 Followed by Daclizumab in Treating Patients With Metastatic Melanoma

PRIMARY OBJECTIVES:

I. To determine whether admixture of recombinant interleukin-12 (IL-12) with vaccine
emulsion will increase the frequency of vaccine-induced CD8+ T cells in the blood.

II. To determine whether administration of daclizumab will deplete CD4+CD25+ regulatory T
cells from the peripheral and potentiate specific immune responses induced by vaccination.

III. To determine whether vaccination with or without daclizumab will be safe in this
patient population.

SECONDARY OBJECTIVES:

I. To determine whether vaccination with or without daclizumab will have clinical activity
in patients with advanced melanoma.

II. To determine whether clinical response may be associated with particular gene expression
profiles in the tumor microenvironment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive multipeptide vaccination comprising recombinant MAGE-3.1 antigen,
MART-1 antigen, gp100 antigen, and NA17-A2 peptide emulsified with Montanide ISA-51
intradermically (ID) or subcutaneously (SC) on days 1, 22, and 50.

ARM II: Patients receive vaccination as in arm I with an admixture of recombinant
interleukin-12 (IL-12) on days 1, 22, and 50.

In both arms, patients are evaluated for immune response. Patients with partial response or
stable disease may be immunized for up to a maximum of 1 year. Patients with complete
response may be treated with 1 additional course of 3 vaccinations.

EXPANDED COHORT: Additional patients are accrued to the arm with higher immune response and
receive daclizumab IV over 15 minutes on day -7. Patients then receive vaccination as in arm
I or arm II on days 1, 22, and 50 in the absence of disease progression or unacceptable
toxicity.

Peripheral blood mononuclear cells are collected at baseline and periodically during study
for correlative studies.

After completion of study therapy, patients are followed up every 3 months.

Inclusion Criteria:

- Patients must have histologically confirmed melanoma with evidence of metastatic
disease by radiologic or physical examination

- In-transit metastases are allowed

- Biopsy should be performed to reconfirm the diagnosis in cases of doubt

- Patients must have measurable disease

- For CT imaging, this is defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm
by conventional techniques or as ≥ 10 mm by spiral CT scan

- For cutaneous lesions, these must be measurable with a ruler and documented
photographically with a ruler in place

- HLA-A2 positive by flow cytometry or standard HLA typing

- Must agree to undergo biopsy of accessible tumor before and after therapy, when
feasible

- If a biopsy cannot be done, then a prior pathologic specimen from the patient
must show tumor cells that are positive for HMB45 and MelanA

- The tumor must express at least 2 antigens in the vaccine for the patient to be
eligible

- No untreated brain metastases

- Patients with no brain metastases or with brain lesions successfully treated by
stereotactic radiation or surgical removal without progression at 28-day
follow-up and off corticosteroids for 4 weeks are eligible

- Life expectancy ≥ 12 weeks

- ECOG performance status (PS) 0-1 (Karnofsky PS 80-100%)

- WBC ≥ 3,000/mm³

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Total bilirubin ≤ 1.5 times ULN

- AST and ALT ≤ 2 times ULN

- LDH < 1.25 times ULN

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal, barrier method of birth control, or abstinence) prior to study entry, for
the duration of treatment, and for 2 months after completion of treatment

- Negative pregnancy test

- Not pregnant or nursing

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition of recombinant interleukin-12 (IL-12) or other agents used in
the study

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
significant cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- No patients with intrinsic immunosuppression, including seropositivity for HIV
antibody

- Patients should be tested for HIV infection

- No psychiatric illness that may make compliance to the clinical protocol unmanageable
or may compromise the ability of the patient to give informed consent

- Patients with clinical evidence of dementia should have a competent designee
participate in decision making

- No serious concurrent infection, including active tuberculosis, hepatitis B, or
hepatitis C

- Patients should be tested for hepatitis B surface antigen and hepatitis C
antibody

- Patients who are hepatitis C antibody positive can be eligible provided they are
PCR-negative

- No active or history of autoimmune disease including, but not limited to, rheumatoid
arthritis (RF-positive with current or recent flare), inflammatory bowel disease,
systemic lupus erythematosus (clinical evidence with ANA 1:80 or greater), ankylosing
spondylitis, scleroderma, multiple sclerosis, autoimmune hemolytic anemia, or immune
thrombocytopenic purpura

- Seropositivity alone will not be considered active autoimmunity

- Patients with immune-mediated hypothyroidism and/or vitiligo are allowed

- No active gastrointestinal bleeding or uncontrolled peptic ulcer disease

- Any number of prior therapies allowed

- At least 4 weeks since prior chemotherapy or radiotherapy (6 weeks for carmustine or
mitomycin C) and recovered

- No prior vaccine containing any of the melanoma antigen peptides or prior daclizumab

- No other concurrent investigational agents

- No concurrent systemic corticosteroids (except physiologic replacement doses), or
other immunosuppressive drugs (e.g., cyclosporin A)