PHASE IB TRIAL OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR COMBINED WITH MURINE MONOCLONAL-ANTIBODY R24 IN PATIENTS WITH METASTATICMELANOMA

R24, a murine monoclonal antibody, has been shown to mediate complemen t- and antibody-dependent cellular cytotoxicity (ADCC) of melanoma tum or targets. We conducted a Phase Ib clinical trial using granulocyte-m acrophage colony-stimulating factor (GM-CSF) and R24 in 20 patients wi th metastatic melanoma. The purpose of this study was to test the hypo thesis that treatment with GM-CSF could up-regulate monocyte and granu locyte ADCC and that the combination of GM-CSF plus R24, which mediate s ADCC, would lead to enhanced anti-tumor activity in patients with me lanoma. GM-CSF was administered by subcutaneous injection daily for 21 days at a dose of 150 mu g/m(2)/day. R24 was administered by continuo us intravenous infusion on days 8-15 at three dose levels: 0, 10, and 50 mg/m(2)/day. All 20 patients received one cycle of treatment only. Immune parameters measured were monocyte and granulocyte direct cytoto xicity and ADCC. All patients were evaluable for toxicity. Fifteen pat ients were evaluable for immune response. Treatment with GM-CSF alone was well tolerated. Toxicity from the combination of GM-CSF plus R24 i ncluded diffuse urticaria, nausea and vomiting, hypertension, and hypo tension. Hypotension was the dose-limiting toxicity. Two patients on t he 50-mg/m(2)/day dose level of R24 achieved a partial response lastin g 2+ and 5+ months. Treatment with GM-CSF led to a statistically signi ficant enhancement of monocyte and granulocyte direct cytotoxicity and ADCC. The maximally tolerated dose of R24 given at this schedule comb ined with GM-CSF is <50 mg/m(2)/day. We conclude that GM-CSF given by subcutaneous injection at 150 mu g/m(2) x 21 days can enhance effector cell ADCC and direct cytotoxicity and that the combination of GM-CSF and R24 can be therapeutic.