Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration.
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 micrograms/kg/day) or 2-h i.v. infusion (3 to 20 micrograms/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 micrograms/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 micrograms/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 greater than or equal to 10 micrograms/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 micrograms/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 greater than or equal to 1 microgram/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 micrograms/kg/day. Phase II studies in which the derived effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 micrograms/kg/day.
Lieschke
G J
GJ
Clinical Research Program, Ludwig Institute for Cancer Research, Victoria, Australia.
Maher
D
D
O'Connor
M
M
Green
M
M
Sheridan
W
W
Rallings
M
M
Bonnem
E
E
Burgess
A W
AW
McGrath
K
K
Fox
R M
RM
D000328:Adult; D000368:Aged; D001491:Basophils; D003115:Colony-Stimulating Factors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004804:Eosinophils; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000008:administration & dosage*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007958:Leukocyte Count / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008214:Lymphocytes; D008875:Middle Aged; D009000:Monocytes; D009369:Neoplasms / Q000628:therapy*; D009504:Neutrophils; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D008055:Lipids; D011994:Recombinant Proteins; D012709:Serum Albumin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor