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Phase I Study of Intravenously Administered Bacterially Synthesized Granulocyte-Macrophage Colony-stimulating Factor and Comparison with Subcutaneous Administration

Clinical Research Program, Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research [G. J. L., M. O., A. W. B., G. M.] and Departments of Diagnostic Hematology [D. M., K. M.] and of Hematology and Medical Oncology [M. G., W. S., R. M. F.], The Royal Melbourne Hospital, Victoria 3050, Australia; and Clinical Research Division, Schering-Plough Corporation, Kenilworth, New Jersey [M. R., E. B.]

A Phase I study of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was undertaken in 21 patients with advanced malignancy or neutropenia. rhGM-CSF was administered once daily by i.v. bolus injection (0.3 to 3 µg/kg/day) or 2-h i.v. infusion (3 to 20 µg/kg day) for 10 days. rhGM-CSF at all i.v. doses caused an immediate transient decrease in circulating neutrophils, eosinophils, and monocytes. By 6 h after rhGM-CSF, circulating leukocyte levels were restored. Daily i.v. bolus dosing (0.3 to 3 µg/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 µg/kg/day) caused a dose-dependent leukocytosis with increased levels of neutrophils (up to 4.3-fold), eosinophils (up to 18-fold), and monocytes (up to 3.5-fold). Marrow aspirates showed increased proportions of promyelocytes and myelocytes during rhGM-CSF administration. Retreatment after 10 days without rhGM-CSF resulted in a more marked leukocytosis at doses 10 µg/kg/day. Platelet levels decreased for the first 3 days and then increased during the first course of rhGM-CSF administration. Two patients with chronic lymphocytic leukemia had a transient reduction in lymphocytosis. Serum cholesterol and albumin levels decreased, and vitamin B₁₂ levels increased during rhGM-CSF treatment. At doses of up to 15 µg/kg/day, rhGM-CSF was relatively well tolerated by the patients, but adverse effects included bone pain, lethargy, fever, rash, and weight gain. A first dose reaction characterized by hypoxia and hypotension was identified at dose levels 1 µg/kg. Dosing i.v. was less potent at inducing a leukocytosis than previously observed for equivalent s.c. doses and was associated with a higher incidence of generalized rash and first dose reactions. The maximal tolerated dose of i.v. rhGM-CSF was 15 µg/kg/day. Phase II studies in which the desired effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 µg/kg/day.

¹ To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, Post Office Royal Melbourne Hospital, Victoria 3050, Australia.

Received 7/ 5/89. Revised 10/23/89. Accepted 10/30/89.

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