Inhaled Sargramostim in Treating Patients With Melanoma Metastatic to the Lung

OBJECTIVES:

- Determine immunomodulatory effects of aerosolized sargramostim (GM-CSF) in patients
with metastatic melanoma to the lung (part A).

- Determine toxicity profile of this therapy, in terms of pulmonary and hematologic
toxicity, in these patients.

- Determine, preliminarily, the therapeutic effects of this therapy, in terms of
progression-free survival, overall survival, and objective response rate, in these
patients.

- Determine the maximum tolerated dose of GM-CSF in these patients (part B).

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive aerosolized sargramostim (GM-CSF) twice a day on days 1-7 and 15-21.
Treatment repeats every 28 days for 2 courses. Patients with no disease progression after
completion of course 2 may continue on treatment until disease progression. Patients are
grouped to 1 of 2 dose-escalation regimens (part A vs B).

- Part A: Cohorts of 5-10 patients receive escalating doses of GM-CSF until the optimal
immunostimulatory dose (ISD) is determined. The optimal ISD is defined as the dose at
which at least 7 of 10 patients experience immunostimulation. Once the optimal ISD is
determined, 10 patients receive aerosolized GM-CSF at a dose halfway between the
optimal ISD and the preceding dose. Dose escalation is discontinued if at least 2 of 5
or at least 4 of 10 patients on a particular dose level experience dose-limiting
toxicity.

- Part B: Cohorts of 3-6 patients receive escalating doses of GM-CSF until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at
which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients
are treated at the MTD.

After completion of study therapy, patients are followed at 3 months, every 2 months for 1
year, and then every 3-4 months for 5 years.

PROJECTED ACCRUAL: A total of 85 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically confirmed metastatic melanoma to the lung for which no known standard
therapy exists

- At least 1 unidimensionally measurable lesion

- HLA-A2 positive (part A patients only)

- Previously treated CNS metastases allowed provided there is no evidence of disease
progression within the past 3 months

PATIENT CHARACTERISTICS:

Age:

- 18 and over

Performance status:

- ECOG 0-2

Life expectancy:

- At least 12 weeks

Hematopoietic:

- Absolute neutrophil count at least 1,000/mm^3

- Platelet count at least 75,000/mm^3

- Hemoglobin at least 8.0 g/dL

Hepatic:

- Bilirubin no greater than 2 times upper limit of normal (ULN)

- AST no greater than 3 times ULN

Renal:

- Creatinine no greater than 2.5 times ULN

Cardiovascular:

- No New York Heart Association class III or IV heart disease

Pulmonary:

- No pulmonary disease requiring concurrent active therapy (e.g., supplemental oxygen
or bronchodilator)

- FEV_1 at least 65% of predicted and at least 1.5 L

Immunologic:

- No known immunodeficiency state

- No known autoimmune disease

- No uncontrolled infection

Other:

- No active psychotic disorder requiring pharmacotherapy

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- More than 2 weeks since prior biologic therapy

- More than 2 weeks since prior immunotherapy

- More than 4 weeks since prior filgrastim (G-CSF) or sargramostim (GM-CSF)

- No other concurrent biologic therapy or immunotherapy

- No concurrent G-CSF

- No concurrent GM-CSF other than study drug

Chemotherapy:

- More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

- No concurrent chemotherapy

Endocrine therapy:

- More than 2 weeks since prior corticosteroids

- No concurrent glucocorticosteroids

Radiotherapy:

- More than 2 weeks since prior radiotherapy

- No concurrent radiotherapy

Surgery:

- Not specified

Other:

- More than 7 days since prior parenteral antibiotics

- No concurrent parenteral antibiotics

- No concurrent immunosuppressive agents