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Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in
hematologic malignancies expressing the IL-2 receptor
CF LeMaistre, C Meneghetti, M Rosenblum, J Reuben, K Parker, J Shaw, A Deisseroth, T Woodworth and DR Parkinson
Dept. of Medicine, Univ. of Texas Health Science Center, San Antonio
78284-7880.
DAB486IL-2 is a recombinant fusion toxin in which the native receptor
binding domain of diphtheria toxin has been replaced with human
interleukin-2 (IL-2). It selectively binds and intoxicates only cells that
bear the high-affinity receptor for IL-2. In the first clinical trial of a
genetically engineered ligand fusion-toxin, we have treated 18 patients
with chemotherapy-resistant IL-2 receptor expressing hematologic
malignancies with escalating doses of DAB486IL-2. The maximal tolerated
dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for
10 doses, established by asymptomatic, reversible elevations of hepatic
transaminases without changes in other tests of liver function. Other mild
reversible side effects noted were rash, nausea, elevated creatinine, chest
tightness, and fever. Pharmacokinetic analysis showed a monophasic
clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL
at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody
response to diphtheria toxin or DAB486IL-2. The presence of such antibodies
did not preclude patients from experiencing an antitumor response as four
of the six patients with antitumor effect had detectable antibody titers.
Although this was a phase I trial designed to define the safety of
DAB486IL-2, remissions were observed in three patients lasting from 5 to
over 18 months. The ability to achieve significant tumor reductions in this
group of heavily treated patients is encouraging and suggests additional
trials are warranted in hematologic malignancies.
Volume 79,
Issue 10,
pp. 2547-2554,
05/15/1992
Copyright © 1992 by The American Society of Hematology
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