scholarly journals A phase I study of an anti-CD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2624-2633 ◽  
Author(s):  
PL Amlot ◽  
MJ Stone ◽  
D Cunningham ◽  
J Fay ◽  
J Newman ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Dose Escalation Study ◽  
Ricin A Chain ◽  
A Chain ◽  
Reduced Toxicity ◽  
Mild Toxicity ◽  
Ricin A

Abstract Twenty-six patients, whose B-cell lymphoma had relapsed after conventional therapies, were treated in a phase I dose escalation study with an immunotoxin consisting of a mouse CD22 monoclonal antibody (RFB4:IgG1K) coupled to chemically deglycosylated ricin A chain (dgA). Two to 12 doses of the immunotoxin were infused intravenously at 48- hour intervals. The peak serum concentration and half-life (T1/2) did not correlate directly with the dose and averaged 3.8 micrograms/mL and 7.8 hours, respectively. The main dose-limiting toxicity was caused by the vascular leak syndrome (VLS) consisting of weight gain, edema, serum albumin decrease, and critically by pulmonary edema. Myalgia occurred frequently and was only dose limiting in one patient who developed rhabdomyolysis. The presence of lymphoma cells in the blood (> or = 10(10)/L) and clinically detectable splenomegaly were associated with reduced toxicity and a shorter T1/2. Nine of 24 evaluable patients (37.5%) made antibody to either mouse Ig or dgA. There were five partial responses (PR) and one complete response (CR) lasting 30 to 78 days. High peak concentrations of immunotoxin in the serum, a long T1/2, and large areas under the curve (AUC) correlated with both clinical response and toxicity. None of three patients with CD5+ lymphomas (including two CLL patients) had more than mild toxicity or responded to the immunotoxin.

scholarly journals A phase I study of an anti-CD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2624-2633 ◽  
Author(s):  
PL Amlot ◽  
MJ Stone ◽  
D Cunningham ◽  
J Fay ◽  
J Newman ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Dose Escalation Study ◽  
Ricin A Chain ◽  
A Chain ◽  
Reduced Toxicity ◽  
Mild Toxicity ◽  
Ricin A

Twenty-six patients, whose B-cell lymphoma had relapsed after conventional therapies, were treated in a phase I dose escalation study with an immunotoxin consisting of a mouse CD22 monoclonal antibody (RFB4:IgG1K) coupled to chemically deglycosylated ricin A chain (dgA). Two to 12 doses of the immunotoxin were infused intravenously at 48- hour intervals. The peak serum concentration and half-life (T1/2) did not correlate directly with the dose and averaged 3.8 micrograms/mL and 7.8 hours, respectively. The main dose-limiting toxicity was caused by the vascular leak syndrome (VLS) consisting of weight gain, edema, serum albumin decrease, and critically by pulmonary edema. Myalgia occurred frequently and was only dose limiting in one patient who developed rhabdomyolysis. The presence of lymphoma cells in the blood (> or = 10(10)/L) and clinically detectable splenomegaly were associated with reduced toxicity and a shorter T1/2. Nine of 24 evaluable patients (37.5%) made antibody to either mouse Ig or dgA. There were five partial responses (PR) and one complete response (CR) lasting 30 to 78 days. High peak concentrations of immunotoxin in the serum, a long T1/2, and large areas under the curve (AUC) correlated with both clinical response and toxicity. None of three patients with CD5+ lymphomas (including two CLL patients) had more than mild toxicity or responded to the immunotoxin.

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

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1188-1197 ◽  
Author(s):  
MJ Stone ◽  
EA Sausville ◽  
JW Fay ◽  
D Headlee ◽  
RH Collins ◽  
...  
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
B Cell Lymphoma ◽  
Pharmacokinetic Parameters ◽  
Maximum Serum ◽  
Ricin A Chain ◽  
Intermittent Bolus ◽  
A Chain ◽  
Infusion Regimen ◽  
Ricin A

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.

PHASE I TRIAL OF ANTI-CD22 RICIN-A-CHAIN IMMUNOTOXIN (IgG-RFB4-dgA) FOR TREATMENT OF AIDS-LYMPHOMA

1997 ◽  
Vol 14 (4) ◽  
pp. A38 ◽  
Author(s):  
Lawrence D. Kaplan ◽  
Robert Robles ◽  
James O. Kahn ◽  
John Schindler ◽  
Victor Ghetie ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Ricin A Chain ◽  
A Chain ◽  
Ricin A

Evaluation of four CD22 antibodies as ricin a chain-containing immunotoxins for thein vivo therapy of human B-cell leukemias and lymphomas

1988 ◽  
Vol 42 (5) ◽  
pp. 792-797 ◽  
Author(s):  
Guo-Liang Shen ◽  
Jia-Ling Li ◽  
Maria-Ana Ghetie ◽  
Victor Ghetie ◽  
Richard D. May ◽  
...  
Keyword(s):  
B Cell ◽  
Ricin A Chain ◽  
A Chain ◽  
Ricin A ◽  
Leukemias And Lymphomas ◽  
Human B Cell

Phase I Study of Monoclonal Antibody-Ricin A Chain Immunoconjugate Xomazyme-791 in Patients with Metastatic Colon Cancer

1995 ◽  
Vol 18 (4) ◽  
pp. 307-312 ◽  
Author(s):  
P. M. LoRusso ◽  
P. L. Lomen ◽  
B. G. Redman ◽  
E. Poplin ◽  
J. J. Bander ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Colon Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Metastatic Colon Cancer ◽  
Ricin A Chain ◽  
A Chain ◽  
Ricin A

scholarly journals Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

2020 ◽  
Vol 38 (5) ◽  
pp. 1472-1482 ◽  
Author(s):  
Frank Kroschinsky ◽  
Jan Moritz Middeke ◽  
Martin Janz ◽  
Georg Lenz ◽  
Mathias Witzens-Harig ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Transmembrane Protein ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma

Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

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