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Background: Macrophage colony-stimulating factor is a bone marrow-derived glycoprotein that can stimulate monocytes and macrophages, resulting in production of factors involved in immune response. In vitro and in vivo preclinical studies in animals have demonstrated that recombinant human macrophage colony-stimulating factor (rHuM-CSF) can have antitumor activity. Purpose: A phase I clinical trial was undertaken to evaluate the toxicity, pharmacokinetics, and immunologic effects of rHuM-CSF given by continuous intravenous infusion in patients with cancer. Methods: Eighteen patients with metastatic solid tumors refractory to conventional therapy were treated with rHuM-CSF. Twelve patients received two 14-day cycles of rHuM-CSF by continuous infusion, with a 2-week interval. Dose escalation levels were 50, 100, and 150 [mu]g/kg over 24 hours. Consecutive cohorts of three to six patients were planned at each dose level. Six patients received a modified regimen of four 7-day periods of infusion at 100 [mu]g/kg over 24 hours, with 1-week intervals. Results: Dose-limiting toxicity was grade 4 thrombocytopenia at a dose of 150 [mu]g/kg over 24 hours in two patients receiving the 2-week regimen. Platelet count nadirs and concomitant monocytosis were seen on days 7-9, but recovery occurred during the treatment period. Macrophage colony-stimulating factor serum levels were maximal on day I and returned to near baseline on day 7 of infusion. Patients treated with four 7-day infusions had no treatment-limiting thrombocytopenia. There were no cumulative effects on platelet or monocyte counts or significant constitutional symptoms. Subclinical conjunctival injection was noted in rive of 10 patients receiving screening ophthalmologic evaluation. Grade 2 episcleritis was diagnosed in one patient, and asymptomatic perilimbal and retinal hemorrhages were seen in two. Two patients developed sepsis caused by the intravenous line, which required cessation of therapy. No objective responses were documented. Conclusion: The maximum tolerated dose of rHuM-CSF given by continuous intravenous infusion for 14 days was 100 [mu]g/kg over 24 hours, with rapidly reversible, dose-limiting thrombocytopenia at 150 [mu]g/kg over 24 hours. A regimen alternating weekly cycles of infusion avoids dose-limiting toxicity and allows long-term treatment. Implications: The regimen of repeated 7-day infusions may be useful for future studies evaluating rHuM-CSF-activated monocytes in therapy for long-term infectious diseases or in investigation of new modes of cancer therapy using rHuM-CSF in conjunction with a tumor-specific antibody. [J Natl Cancer Inst 86:39-45, 1994]