PHASE-I TRIAL OF INTRAVENOUS AND INTRAPERITONEAL ADMINISTRATION OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR

To assess the toxicity, pharmacokinetics, and local and systemic effec ts of the intraperitoneal (i.p.) administration of granulocyte-macroph age colony-stimulating factor (GM-CSF) at various dosages, 13 patients with predominantly i.p. malignancies refractory to standard chemother apy were studied. GM-CSF was administered intravenously (i.v.) for 5 c onsecutive days; 21 days later the same dosage of GM-CSF was administe red i.p. for 5 consecutive days. Four dosage levels were studied: 1, 2 , 4, and 8 mu g/kg/day. GM-CSF was well tolerated after i.v. and i.p. administration at doses up to 8 mu g/kg/day. A transient fall followed by an elevation of circulating white cells was observed over a 24-h p eriod 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. admin istration). The magnitude and time course of these changes were very s imilar for the two routes despite an up to 400-fold difference in seru m GM-CSF levels at the same time points. Changes in leukocyte count an d differential and neutrophil function were also similar over the 3-we ek 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 (C-max 343 ng/ml) with maintenan ce of high concentrations over 24 h (C-24h 128 ng/ml). In a second pat ient who had i.p. fluid accessible, a dramatic increase (similar to 10 0-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 pe ritoneal cavity. Intraperitoneal administration has similar systemic e ffects to i.v. administration but may have additional local effects, s uch as attraction into the peritoneal cavity and activation of neutrop hils. Further exploration of i.p. GM-CSF in the management of intraper itoneal infection and malignancy is warranted.