A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors

James A. Posey; Mohammad B. Khazaeli; Michael A. Bookman; Anahit Nowrouzi; William E. Grizzle; Jennifer Thornton; Delicia E. Carey; Jennifer M. Lorenz; Amy P. Sing; Clay B. Siegall; Albert F. LoBuglio; Mansoor N. Saleh

A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors

James A. Posey, Mohammad B. Khazaeli, Michael A. Bookman, Anahit Nowrouzi, William E. Grizzle, Jennifer Thornton, Delicia E. Carey, Jennifer M. Lorenz, Amy P. Sing, Clay B. Siegall, Albert F. LoBuglio, Mansoor N. Saleh

Research output: Contribution to journal › Article › peer-review

109 Citations (Scopus)

Abstract

Purpose: Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (V_H) and variable light (V_L) regions of BR96 monoclonal antibody. This antibody is specific for a Lewis^Y (Le^Y)-related carbohydrate antigen expressed on multiple carcinomas. Experimental Design: A total of 46 patients with Le^Y-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m², administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined. Results: The maximum tolerated dose of SGN-10 was 0.641 mg/m² with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m² dose revealed a t_[1/2] of 2.5 ± 0.3 h and a C_max of 389 ± 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of ≥0.384 mg/m². No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease. Conclusions: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m² with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.

Original language	English
Pages (from-to)	3092-3099
Number of pages	8
Journal	Clinical Cancer Research
Volume	8
Issue number	10
Publication status	Published - 1 Oct 2002
Externally published	Yes

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@article{8cb1eef8702c4164a5991b211664132c,

title = "A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors",

abstract = "Purpose: Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (VH) and variable light (VL) regions of BR96 monoclonal antibody. This antibody is specific for a LewisY (LeY)-related carbohydrate antigen expressed on multiple carcinomas. Experimental Design: A total of 46 patients with LeY-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m2, administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined. Results: The maximum tolerated dose of SGN-10 was 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m2 dose revealed a t[1/2] of 2.5 ± 0.3 h and a Cmax of 389 ± 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of ≥0.384 mg/m2. No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease. Conclusions: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.",

author = "Posey, {James A.} and Khazaeli, {Mohammad B.} and Bookman, {Michael A.} and Anahit Nowrouzi and Grizzle, {William E.} and Jennifer Thornton and Carey, {Delicia E.} and Lorenz, {Jennifer M.} and Sing, {Amy P.} and Siegall, {Clay B.} and LoBuglio, {Albert F.} and Saleh, {Mansoor N.}",

year = "2002",

month = oct,

day = "1",

language = "English",

volume = "8",

pages = "3092--3099",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "10",

}

TY - JOUR

T1 - A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors

AU - Posey, James A.

AU - Khazaeli, Mohammad B.

AU - Bookman, Michael A.

AU - Nowrouzi, Anahit

AU - Grizzle, William E.

AU - Thornton, Jennifer

AU - Carey, Delicia E.

AU - Lorenz, Jennifer M.

AU - Sing, Amy P.

AU - Siegall, Clay B.

AU - LoBuglio, Albert F.

AU - Saleh, Mansoor N.

PY - 2002/10/1

Y1 - 2002/10/1

N2 - Purpose: Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (VH) and variable light (VL) regions of BR96 monoclonal antibody. This antibody is specific for a LewisY (LeY)-related carbohydrate antigen expressed on multiple carcinomas. Experimental Design: A total of 46 patients with LeY-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m2, administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined. Results: The maximum tolerated dose of SGN-10 was 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m2 dose revealed a t[1/2] of 2.5 ± 0.3 h and a Cmax of 389 ± 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of ≥0.384 mg/m2. No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease. Conclusions: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.

AB - Purpose: Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (VH) and variable light (VL) regions of BR96 monoclonal antibody. This antibody is specific for a LewisY (LeY)-related carbohydrate antigen expressed on multiple carcinomas. Experimental Design: A total of 46 patients with LeY-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m2, administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined. Results: The maximum tolerated dose of SGN-10 was 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m2 dose revealed a t[1/2] of 2.5 ± 0.3 h and a Cmax of 389 ± 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of ≥0.384 mg/m2. No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease. Conclusions: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.

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M3 - Article

C2 - 12374676

AN - SCOPUS:0036793823

SN - 1078-0432

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 10

ER -

A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors

Abstract

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