Phase I Trial of Intravenous and Intraperitoneal Administration of Granulocyte-Macrophage Colony-Stimulating Factor

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Abstract

Summary:

To assess the toxicity, pharmacokinetics, and local and systemic effects of the intraperitoneal (i.p.) administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) at various dosages, 13 patients with predominantly i.p. malignancies refractory to standard chemotherapy were studied. GM-CSF was administered intravenously (i.v.) for 5 consecutive days; 21 days later the same dosage of GM-CSF was administered i.p. for 5 consecutive days. Four dosage levels were studied: 1, 2, 4, and 8 fi,g/kg/ day. GM-CSF was well tolerated after i.v. and i.p. administration at doses up to 8 jjig/kg/day. A transient fall followed by an elevation of circulating white cells was observed over a 24-h period after both i.v. and i.p. GM-CSF administration (mean minimum ± SE as % baseline): 38 ± 8% at 30 min after i.v. administration, 21 ± 5% at 60 min after i.p. administration; mean maximum: 220 ± 41% at 6 h after i.v. administration, 202 ± 39% at 12 h after i.p. administration). The magnitude and time course of these changes were very similar for the two routes despite an up to 400-fold difference in serum GM-CSF levels at the same time points. Changes in leukocyte count and differential and neutrophil function were also similar over the 3-week period after both i.v. and i.p. administration. In the only patient who had i.p. GM-CSF levels assayed, i.p. administration achieved high levels of GM-CSF in peritoneal fluid (Cmax 343 ng/ml) with maintenance of high concentrations over 24 h (C24h 128 ng/ml). In a second patient who had i.p. fluid accessible, a dramatic increase (~ 100-fold) in the number of neutrophils in peritoneal fluid was observed after i.p. GM-CSF. Thus, GM-CSF can be administered safely into the peritoneal cavity. Intraperitoneal administration has similar systemic effects to i.v. administration but may have additional local effects, such as attraction into the peritoneal cavity and activation of neutrophils. Further exploration of i.p. GM-CSF in the management of intraperitoneal infection and malignancy is warranted.

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