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

111 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 (US)
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 (US)",

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.

UR - https://www.scopus.com/pages/publications/0036793823

M3 - Article

C2 - 12374676

AN - SCOPUS:0036793823

SN - 1078-0432

VL - 8

SP - 3092

EP - 3099

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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