title: A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma.
abstract: 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.
authors.affiliation: Baylor University Medical Center, Charles A. Sammons Cancer Center, Dallas, TX 75235-8576, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Stone
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: J W
authors.initials: JW
authors.lastname: Fay
authors.forename: D
authors.initials: D
authors.lastname: Headlee
authors.forename: R H
authors.initials: RH
authors.lastname: Collins
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: M
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.forename: V
authors.initials: V
authors.lastname: Jain
authors.forename: E S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: D
authors.initials: D
authors.lastname: Solomon
authors.forename: R M
authors.initials: RM
authors.lastname: Lush
authors.forename: A
authors.initials: A
authors.lastname: Senderowicz
authors.forename: V
authors.initials: V
authors.lastname: Ghetie
authors.forename: J
authors.initials: J
authors.lastname: Schindler
authors.forename: J W
authors.initials: JW
authors.lastname: Uhr
authors.forename: E S
authors.initials: ES
authors.lastname: Vitetta
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D018941:Antigens, CD19 / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007167:Immunotherapy; D000922:Immunotoxins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D016393:Lymphoma, B-Cell / Q000628:therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D012276:Ricin / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000922:Immunotoxins; D012276:Ricin