Sargramostim and/or Vaccine Therapy in Preventing Disease Recurrence in Patients With Advanced Melanoma

PRIMARY OBJECTIVES:

I. To compare overall survival and recurrence-free survival of patients with completely
resected stage IV melanoma or stage III melanoma with gross extranodal extension, satellites,
and/or intransit lesions, treated with granulocyte macrophage colony-stimulating factor
(GM-CSF) (sargramostim) vs. no GM-CSF, or other high risk patients listed in the eligibility
section.

SECONDARY OBJECTIVES:

I. To compare, using a 2 x 2 factorial design, overall survival and recurrence-free survival
of human leukocyte antigen (HLA)-A2 positive patients treated with peptide vaccination vs. no
peptide vaccination.

II. The following descriptive evaluations of survival and recurrence-free survival are
planned for the HLA-A2 positive patients: (1) GM-CSF plus peptide vaccination vs. peptide
vaccination alone; (2) GM-CSF plus peptide vaccination vs. GM-CSF alone; (3) GM-CSF plus
peptide vaccination vs. placebo.

III. Survival and recurrence-free survival of HLA-A2 positive patients not receiving peptide
vaccination will be compared to that of HLA-A2 negative patients not receiving peptide
vaccination.

IV. To determine the influence of GM-CSF on circulating dendritic cell numbers and
subpopulations in peripheral blood of patients receiving and not receiving GM-CSF.

V. To determine, in HLA-A2 positive patients, whether immunization with peptides with or
without GM-CSF elicits a measurable T-cell response as assessed by enzyme-linked
immunosorbent spot (ELISPOT) and the major histocompatibility complex (MHC) tetramer assay,
and to determine the functionality of these cells by intracellular cytokine staining.

OUTLINE: After patients are screened for HLA-A2 positivity, patients would be categorized
into two groups: HLA-A2 positive patients and HLA-A2 negative patients. HLA-A2 positive
patients are randomized to 1 of 4 treatment regimens (Arms I-IV). HLA-A2 negative patients
are randomized to 1 of 2 treatment arms (Arms V-VI).

ARM I: Patients receive sargramostim subcutaneously (SC) on days 1-14 and peptide vaccine
comprising tyrosinase, gp100 antigen, and melanoma antigen recognized by T-cells 1 (MART-1)
mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG subcutaneously on days
1 and 15 (course 1) and day 1 (course 2 and subsequent courses).

ARM II: Patients receive sargramostim placebo SC on days 1-14 and peptide vaccine comprising
tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant
or Montanide ISA-51 VG subcutaneously on days 1 and 15 (course 1) and day 1 (course 2 and
subsequent courses).

ARM III: Patients receive sargramostim SC on days 1-14 and peptide placebo mixed with either
incomplete Freund's adjuvant or Montanide ISA-51 VG subcutaneously on days 1 and 15 (course
1) and day 1 (course 2 and subsequent courses).

ARM IV: Patients receive sargramostim placebo SC on days 1-14 and peptide placebo mixed with
either incomplete Freund's adjuvant or Montanide ISA-51 VG subcutaneously on days 1 and 15
(course 1) and day 1 (course 2 and subsequent courses).

ARM V: Patients receive sargramostim SC on days 1-14.

ARM VI: Patients receive sargramostim placebo SC on days 1-14.

In all arms, treatment repeats every 28 days for up to 13 courses in the absence of disease
progression or unacceptable toxicity.

In the event of recurrence, patients who undergo complete resection of the recurrence may
continue treatment for 6 courses or until completion of 1 year of therapy (whichever is
longer). For patients with recurrence that is not surgically resectable or experiencing
second recurrence, treatment will be discontinued.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then every 12 months for 15 years.

PROJECTED ACCRUAL: 800 patients

Inclusion Criteria:

- Patients must have HLA-A2 status known prior to randomization; typing may be obtained
through a local laboratory facility or through a reference lab utilized by the
initiating institution; if typing is not available through these means, it may be
obtained from the University of Pittsburgh

- All patients must have disease completely resected with one of the following in order
to be eligible:

- Completely resected disease

- Any locoregional recurrence after prior adjuvant interferon or failure on S008

- Any local recurrence of disease after adequate surgical excision of the original
primary

- Mucosal melanoma

- Stage IV melanoma (cutaneous, ocular, mucosal, or unknown primary)

- The following groups of patients may be entered onto this trial only if they are
ineligible for S0008 or are, in the opinion of the managing physician, medically unfit
to receive standard high-dose interferon:

- Any clinically evident satellite or in-transit disease

- Stage II disease with gross extracapsular extension

- Recurrence in a previously resected nodal basin

- Four or more involved lymph nodes or matted lymph nodes

- Ulcerated primary melanoma and any involved lymph nodes

- NOTE: Patients who are eligible for S0008 will be strongly encouraged to
participate in that study in preference to this one

- Patients must have been surgically rendered free of disease with negative margins on
resected specimens; patients rendered free of disease by non-surgical means are not
eligible

- Patients must be randomized within 112 days (16 weeks) of surgical resection; if more
than one surgical procedure is required to render the patient disease-free, all
required surgeries must be accomplished within this 16 week time period

- Patients must not have received any adjuvant treatment (chemotherapy, biotherapy, or
limb perfusion) after the resection(s) that make(s) them eligible for this trial; one
systemic treatment after a prior surgery is allowed, and must have been completed >= 8
weeks prior to randomization; (when chemotherapy and biotherapy are given together as
one planned treatment [biochemotherapy], this counts as one regimen); NOTE: Previous
radiation therapy, including after the resection, is allowed as long as 30 days elapse
between the radiation and initiation of therapy

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Patients must be able to self-administer or arrange for administration of subcutaneous
injections

- Patients with prior history at any time of any in situ cancer, lobular carcinoma of
the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or Clark
I melanoma in situ are eligible; patients who meet this criteria must be disease-free
at time of randomization

- Patients with prior history of basal or squamous skin cancer are eligible; patients
who meet this criteria must be disease-free at time of randomization

- Patients who have had multiple primary melanomas are eligible

- Patients with other malignancies are eligible if they have been continuously disease
free for > 5 years prior to the time of randomization

- Patients must not have autoimmune disorders, conditions of immunosuppression or
treatment with systemic corticosteroids, including oral steroids (i.e., prednisone,
dexamethasone), continuous use of topical steroid creams or ointments, or any steroid
containing inhalers; replacement doses of steroids for patients with adrenal
insufficiency are allowed; patients who discontinue use of these classes of medication
for at least 2 weeks prior to randomization are eligible if, in the judgment of the
treating physician, the patient is not likely to require these classes of drugs during
the study

- Women of childbearing potential must not be pregnant (negative beta human chorionic
gonadotropin [bHCG] within 2 weeks prior to randomization) or breast-feeding

- Women of childbearing potential and sexually active males must be counseled to use an
accepted and effective method of contraception (including abstinence) while on
treatment and for a period of 18 months after completing or discontinuing treatment

- All patients must have brain computed tomography (CT) or magnetic resonance imaging
(MRI), chest CT or chest x-ray (CXR), and abdominal (liver) CT or MRI within 4 weeks
prior to randomization; positron emission tomography (PET) scans are also acceptable
in place of CT, CXR and/or abdominal MRI if obtained within 4 weeks prior to
randomization; patients with lesions on the lower extremity must also have pelvic
imaging within this time period; this is also strongly recommended for patients with
lesions on the lower trunk; PET scans are acceptable

- Patients with resection of visceral disease must have imaging of the affected
area/organ documenting disease-free status within 2 weeks prior to randomization

- White blood cells (WBC) >= 3,000/mm³

- Platelet count >= 100,000/mm³

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2
x institutional upper limit (IUL) of normal

- Bilirubin =< 2 x IUL of normal

- Serum creatinine =< 1.8 mg/dl

- Alkaline phosphatase and lactate dehydrogenase (LDH) must be performed within 4 weeks
prior to randomization; LDH must be normal; patients with abnormal alkaline
phosphatase which is =< 1.25 times the institutional upper limit of normal who have a
negative CT or MRI of the liver and negative bone scan or a negative PET scan are
eligible

- Patients with bone pain must have a bone scan within 4 weeks prior to randomization to
document the absence of tumor

Exclusion criteria:

- Prior treatment with GM-CSF or any peptides used in this protocol

- Patients who have other current malignancies are not eligible

- Patients have an active infection requiring treatment with parenteral antibiotics

- Patients have other significant medical, surgical, or psychiatric conditions or
require any medication or treatment that may interfere with compliance on any of the
E4697 treatment regimens

- Patients have a diagnosis or evidence of organic brain syndrome or significant
impairment of basal cognitive function or any psychiatric disorder that might preclude
participation in the full protocol