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A phase I study of bolus versus continuous infusion of the anti-CD19
immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma
MJ Stone, EA Sausville, JW Fay, D Headlee, RH Collins, WD Figg, M Stetler- Stevenson, V Jain, ES Jaffe, D Solomon, RM Lush, A Senderowicz, V Ghetie, J Schindler, JW Uhr and ES Vitetta
Baylor University Medical Center, Charles A. Sammons Cancer Center, Dallas,
TX 75235-8576, USA.
IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)-containing
immunotoxin (IT) prepared by conjugating the monoclonal murine (MoAb)
anti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered
disulfide linker, N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-
pyridyldithio) toluene (SMPT). In this report, we have used two regimens
for the administration of IgG-HD37-SMPT-dgA to patients with non-Hodgkin's
lymphoma (NHL) in two concomitant phase I trials. One trial examined four
intermittent bolus infusions administered at 48- hour intervals. The other
studied a continuous infusion (CI) administered over the same 8-day period.
In the intermittent bolus regimen, the maximum tolerated dose (MTD) was 16
mg/m2/8 d and the dose- limiting toxicity (DLT) consisted of vascular leak
syndrome (VLS), aphasia, and evidence of rhabdomyolysis encountered at 24
mg/m2/8 d. Using the CI regimen, the MTD was defined by VLS at 19.2 mg/m2/8
d. At the MTD of both regimens, a novel toxicity, consisting of
acrocyanosis with reversible superficial distal digital skin necrosis in
the absence of overt evidence of systemic vasculitis, occurred in 3
patients. Of 23 evaluable patients on the bolus schedule, there was 1
persisting complete response (CR; > 40 months) and 1 partial response
(PR). Of 9 evaluable patients on the continuous infusion regimen, there was
1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a
mean maximum serum concentration (Cmax) of 1,209 +/- 430 ng/mL, with a
median T1/2 beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours),
a volume of distribution (Vd) of 10.9 L (range, 3.1 to 34.5 L), and a
clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the CI regimen at
MTD, the mean Cmax was 963 +/- 473 ng/mL, with a median T1/2 beta for all
courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range,
4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five
percent of the patients on the bolus infusion regimen and 30% on the CI
regimen made antibody against mouse Ig (HAMA) and/or ricin A chain antibody
(HARA). We conclude that this IT can be administered safely and that both
regimens achieve comparable peak serum concentrations at the MTD; these
concentrations are similar to those achieved previously using other
regimens with IgG-dgA ITs at their respective MTDs. Thus, toxicity is
related to the serum level of the IT and does not differ with different
targeting MoAbs.
Volume 88,
Issue 4,
pp. 1188-1197,
08/15/1996
Copyright © 1996 by The American Society of Hematology
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