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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Immunotoxins
Maximum Tolerated Dose
Toluene
B-Cell Lymphoma
Toxicity
Ricin
Immunoglobulin G
Cells
Antibodies
Pharmacokinetics
Disulfides
Blood Vessels
Skin
Serum
Systemic Vasculitis
Rhabdomyolysis
Aphasia
Non-Hodgkin's Lymphoma
Anti-Idiotypic Antibodies
Appointments and Schedules

ASJC Scopus subject areas

  • Hematology

Cite this

A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma. / Stone, Marvin J.; Sausville, Edward A.; Fay, Joseph W.; Headlee, Donna; Collins, Robert H.; Figg, William D.; Stetler-Stevenson, Maryalice; Jain, Vinay; Jaffe, Elaine S.; Solomon, Diane; Lush, Richard M.; Senderowicz, Adrian; Ghetie, Victor; Schindler, John; Uhr, Jonathan W.; Vitetta, Ellen S.

In: Blood, Vol. 88, No. 4, 15.08.1996, p. 1188-1197.

Research output: Contribution to journalArticle

Stone, MJ, Sausville, EA, Fay, JW, Headlee, D, Collins, RH, Figg, WD, Stetler-Stevenson, M, Jain, V, Jaffe, ES, Solomon, D, Lush, RM, Senderowicz, A, Ghetie, V, Schindler, J, Uhr, JW & Vitetta, ES 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, vol. 88, no. 4, pp. 1188-1197.
Stone, Marvin J. ; Sausville, Edward A. ; Fay, Joseph W. ; Headlee, Donna ; Collins, Robert H. ; Figg, William D. ; Stetler-Stevenson, Maryalice ; Jain, Vinay ; Jaffe, Elaine S. ; Solomon, Diane ; Lush, Richard M. ; Senderowicz, Adrian ; Ghetie, Victor ; Schindler, John ; Uhr, Jonathan W. ; Vitetta, Ellen S. / A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma. In: Blood. 1996 ; Vol. 88, No. 4. pp. 1188-1197.
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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.",
author = "Stone, {Marvin J.} and Sausville, {Edward A.} and Fay, {Joseph W.} and Donna Headlee and Collins, {Robert H.} and Figg, {William D.} and Maryalice Stetler-Stevenson and Vinay Jain and Jaffe, {Elaine S.} and Diane Solomon and Lush, {Richard M.} and Adrian Senderowicz and Victor Ghetie and John Schindler and Uhr, {Jonathan W.} and Vitetta, {Ellen S.}",
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TY - JOUR

T1 - A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma

AU - Stone, Marvin J.

AU - Sausville, Edward A.

AU - Fay, Joseph W.

AU - Headlee, Donna

AU - Collins, Robert H.

AU - Figg, William D.

AU - Stetler-Stevenson, Maryalice

AU - Jain, Vinay

AU - Jaffe, Elaine S.

AU - Solomon, Diane

AU - Lush, Richard M.

AU - Senderowicz, Adrian

AU - Ghetie, Victor

AU - Schindler, John

AU - Uhr, Jonathan W.

AU - Vitetta, Ellen S.

PY - 1996/8/15

Y1 - 1996/8/15

N2 - 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.

AB - 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.

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