A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma

Marvin J. Stone, Edward A. Sausville, Joseph W. Fay, Donna Headlee, Robert H. Collins, William D. Figg, Maryalice Stetler-Stevenson, Vinay Jain, Elaine S. Jaffe, Diane Solomon, Richard M. Lush, Adrian Senderowicz, Victor Ghetie, John Schindler, Jonathan W. Uhr, Ellen S. Vitetta

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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-α-methyl-α-(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 (C(max)) of 1,209 ± 430 ng/mL, with a median T(1/2)β 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 C(max) was 963 ± 473 ng/mL, with a median T(1/2)β 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.

Original languageEnglish (US)
Pages (from-to)1188-1197
Number of pages10
JournalBlood
Volume88
Issue number4
StatePublished - Aug 15 1996

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Stone, M. J., Sausville, E. A., Fay, J. W., Headlee, D., Collins, R. H., Figg, W. D., Stetler-Stevenson, M., Jain, V., Jaffe, E. S., Solomon, D., Lush, R. M., Senderowicz, A., Ghetie, V., Schindler, J., Uhr, J. W., & Vitetta, E. S. (1996). A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma. Blood, 88(4), 1188-1197.