Analyses of Immunologic Responses in Patients Receiving Recombinant Human Granulocyte-Macrophage Stimulating Factor (GM-CSF, Sargramostim) As Adjuvant Therapy of Stage II (T4), III and IV Melanoma and its Association with Clinical Response, a Phase 2 Study

THIS PROTOCOL HAS COMPLETED ACCRUAL AND THERE ARE NO OPENINGS FOR ADDITIONAL PATIENTS.

Our previous studies suggested that GM-CSF may have clinical benefit as adjuvant therapy in patients with malignant melanoma who are at high risk for recurrence. Although the results are encouraging, the immunological responses of patients receiving GM-CSF have not been well studied. In particular, it is not known what happens to the immunological responses during the 2 weeks the patient is not receiving injections of GM-CSF. Similarly, it is not known whether the enhanced immunological function stimulated by GM-CSF persists on long-term (1 year) therapy. Clinical and immunologic endpoints will be followed. Fifty patients will be treated under this protocol.

To be eligible to participate in this study, patients must be seen at the Northern California Melanoma Center, have all required tests, and begin the protocol medication within 90 days of the last positive surgery – that is the last surgery at which melanoma cells were present. All patients receive the active drug in the full dosage; no patients in this study receive placebo. Participation in the trial requires 7 trips to San Francisco in a period of 1 year. There is no funding to cover the cost of these trips. The first 3 trips occur in the first month of the study.

Inclusion Criteria (conditions the patient must meet) are:

1. Eligible patients will be males or females with histologically proven melanoma. Patients must have Stage II(T4), III, and IV malignant melanoma surgically resected with no clinical evidence of disease by clinical, laboratory criteria or radiologic examination as defined below.
2. Individuals must be at least 14 years of age.
3. Pregnant women are not eligible. Men and women will be required to use an effective form of contraception.
4. Patients requiring corticosteroid therapy or are receiving other forms of immunotherapy are not eligible.
5. Patients may have received immunotherapy for prior disease. They must have completed therapy at least one month prior to study entry. Patients may not have received prior chemotherapy or therapy with GM-CSF. Patients are permitted to receive adjuvant radiation therapy but these patients will not be selected as part of the sub-set undergoing studies of cellular immunologic responses.
6. Patients must undergo examination for evidence of residual disease, including physical examination, CBC, chemistry panel, CT scan of the chest and abdomen (and pelvis for lower extremity or lower trunk lesions), and single sequence with gadolinium MRI or CT of the brain. A PET scan may be substituted for the CT of the chest and abdomen (and pelvis). These tests must be negative for residual disease before entry into the study.
7. Administration of the protocol medication must be initiated within 90 days of the definitive surgical excision rendering the patient NED.

Treatment Regimen
Patients will be treated with GM-CSF according to the standard dosing regimen: 125 µg/m² once daily (maximum dose 250 µg) for 14 days followed by 14 days of rest (28 day cycle). Treatment will continue until disease recurrence requiring systemic therapy of for 1 year, whichever comes first.

During the treatment period, we will evaluate immunologic response in all patients based on plasma neopterin levels, a marker of macrophage activation and serum S100B, a measure of disease activity. In addition, in a selected sub-set of patients, additional studies of cellular responses will be done including monocyte cytotoxicity to melanoma cells, and phenotypic markers of monocytes, mature dendritic cells and T cell activation, including zeta-chain determination in peripheral blood mononuclear cells. End points of the study include safety, immunologic response, time to disseminated disease, and survival.

Patients will continue to be monitored until death or until the patient has been tumor free for five years, whichever event occurs first.