A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3

Morten Mau-Sørensen; Christian Dittrich; Rodrigo Dienstmann; Ulrik Lassen; Wilfried Büchler; Holger Martinius; Josep Tabernero

doi:10.1007/s00280-015-2728-5

A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD₃

Morten Mau-Sørensen, Christian Dittrich, Rodrigo Dienstmann, Ulrik Lassen, Wilfried Büchler, Holger Martinius, Josep Tabernero

32 Citations (Scopus)

Abstract

PURPOSE: The aim of the study was to evaluate the safety and determine the maximum tolerated dose (MTD) of intravenous catumaxomab, a trifunctional bispecific antibody that binds to EpCAM on epithelial cancer cells and CD3 on T cells.

METHODS: The trial was a dose-escalation study with a 3 + 3 design in epithelial cancers with known EpCAM expression. The dose-limiting toxicity (DLT) period consisted of 4 weeks, with weekly intravenous administration of catumaxomab. Key DLTs were ≥grade 3 optimally treated non-hematological toxicity; ≥grade 3 infusion-related reactions refractory to supportive care; ≥grade 3 increase in liver enzymes and/or bilirubin not resolving to grade 2.

RESULTS: Sixteen patients were enrolled receiving doses of 2 (n = 5), 4 (n = 3), 7 (n = 7) and 10 µg catumaxomab (n = 1). The most common treatment-emergent adverse events (TEAEs) were chills (93.8 %) and pyrexia (87.5 %). The most common TEAE of grade ≥3 was transient dose-dependent increases in aspartate aminotransferase (56.3 %). The intensity of toxicities decreased with the number of infusions. Also, serum IL-6 increased in a dose-dependent manner and reverted to low or undetectable levels after four infusions. A reversible decrease in liver function test (prothrombin time) at the 7-µg dose level was considered a DLT. The first patient at 10 µg experienced a fatal hepatic failure related to catumaxomab that led to the termination of the study.

CONCLUSIONS: The MTD of weekly intravenous catumaxomab was 7 µg. Major toxicities were cytokine release-related symptoms and hepatotoxicity.

Original language	English
Journal	Cancer Chemotherapy and Pharmacology
Volume	75
Issue number	5
Pages (from-to)	1065-73
Number of pages	9
ISSN	0344-5704
DOIs	https://doi.org/10.1007/s00280-015-2728-5
Publication status	Published - 1 May 2015
Externally published	Yes

Keywords

Adult
Aged
Antibodies, Bispecific
Antigens, CD3
Antigens, Neoplasm
Cell Adhesion Molecules
Dose-Response Relationship, Drug
Female
Humans
Male
Middle Aged
Neoplasms
T-Lymphocytes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00280-015-2728-5

Cite this

@article{5da91e1be2c34a9c8c1cec9888c0499a,

title = "A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3",

abstract = "PURPOSE: The aim of the study was to evaluate the safety and determine the maximum tolerated dose (MTD) of intravenous catumaxomab, a trifunctional bispecific antibody that binds to EpCAM on epithelial cancer cells and CD3 on T cells.METHODS: The trial was a dose-escalation study with a 3 + 3 design in epithelial cancers with known EpCAM expression. The dose-limiting toxicity (DLT) period consisted of 4 weeks, with weekly intravenous administration of catumaxomab. Key DLTs were ≥grade 3 optimally treated non-hematological toxicity; ≥grade 3 infusion-related reactions refractory to supportive care; ≥grade 3 increase in liver enzymes and/or bilirubin not resolving to grade 2.RESULTS: Sixteen patients were enrolled receiving doses of 2 (n = 5), 4 (n = 3), 7 (n = 7) and 10 µg catumaxomab (n = 1). The most common treatment-emergent adverse events (TEAEs) were chills (93.8 %) and pyrexia (87.5 %). The most common TEAE of grade ≥3 was transient dose-dependent increases in aspartate aminotransferase (56.3 %). The intensity of toxicities decreased with the number of infusions. Also, serum IL-6 increased in a dose-dependent manner and reverted to low or undetectable levels after four infusions. A reversible decrease in liver function test (prothrombin time) at the 7-µg dose level was considered a DLT. The first patient at 10 µg experienced a fatal hepatic failure related to catumaxomab that led to the termination of the study.CONCLUSIONS: The MTD of weekly intravenous catumaxomab was 7 µg. Major toxicities were cytokine release-related symptoms and hepatotoxicity.",

keywords = "Adult, Aged, Antibodies, Bispecific, Antigens, CD3, Antigens, Neoplasm, Cell Adhesion Molecules, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Neoplasms, T-Lymphocytes",

author = "Morten Mau-S{\o}rensen and Christian Dittrich and Rodrigo Dienstmann and Ulrik Lassen and Wilfried B{\"u}chler and Holger Martinius and Josep Tabernero",

year = "2015",

month = may,

day = "1",

doi = "10.1007/s00280-015-2728-5",

language = "English",

volume = "75",

pages = "1065--73",

journal = "Cancer Chemotherapy and Pharmacology",

issn = "0344-5704",

publisher = "Springer",

number = "5",

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TY - JOUR

T1 - A phase I trial of intravenous catumaxomab

T2 - a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3

AU - Mau-Sørensen, Morten

AU - Dittrich, Christian

AU - Dienstmann, Rodrigo

AU - Lassen, Ulrik

AU - Büchler, Wilfried

AU - Martinius, Holger

AU - Tabernero, Josep

PY - 2015/5/1

Y1 - 2015/5/1

N2 - PURPOSE: The aim of the study was to evaluate the safety and determine the maximum tolerated dose (MTD) of intravenous catumaxomab, a trifunctional bispecific antibody that binds to EpCAM on epithelial cancer cells and CD3 on T cells.METHODS: The trial was a dose-escalation study with a 3 + 3 design in epithelial cancers with known EpCAM expression. The dose-limiting toxicity (DLT) period consisted of 4 weeks, with weekly intravenous administration of catumaxomab. Key DLTs were ≥grade 3 optimally treated non-hematological toxicity; ≥grade 3 infusion-related reactions refractory to supportive care; ≥grade 3 increase in liver enzymes and/or bilirubin not resolving to grade 2.RESULTS: Sixteen patients were enrolled receiving doses of 2 (n = 5), 4 (n = 3), 7 (n = 7) and 10 µg catumaxomab (n = 1). The most common treatment-emergent adverse events (TEAEs) were chills (93.8 %) and pyrexia (87.5 %). The most common TEAE of grade ≥3 was transient dose-dependent increases in aspartate aminotransferase (56.3 %). The intensity of toxicities decreased with the number of infusions. Also, serum IL-6 increased in a dose-dependent manner and reverted to low or undetectable levels after four infusions. A reversible decrease in liver function test (prothrombin time) at the 7-µg dose level was considered a DLT. The first patient at 10 µg experienced a fatal hepatic failure related to catumaxomab that led to the termination of the study.CONCLUSIONS: The MTD of weekly intravenous catumaxomab was 7 µg. Major toxicities were cytokine release-related symptoms and hepatotoxicity.

AB - PURPOSE: The aim of the study was to evaluate the safety and determine the maximum tolerated dose (MTD) of intravenous catumaxomab, a trifunctional bispecific antibody that binds to EpCAM on epithelial cancer cells and CD3 on T cells.METHODS: The trial was a dose-escalation study with a 3 + 3 design in epithelial cancers with known EpCAM expression. The dose-limiting toxicity (DLT) period consisted of 4 weeks, with weekly intravenous administration of catumaxomab. Key DLTs were ≥grade 3 optimally treated non-hematological toxicity; ≥grade 3 infusion-related reactions refractory to supportive care; ≥grade 3 increase in liver enzymes and/or bilirubin not resolving to grade 2.RESULTS: Sixteen patients were enrolled receiving doses of 2 (n = 5), 4 (n = 3), 7 (n = 7) and 10 µg catumaxomab (n = 1). The most common treatment-emergent adverse events (TEAEs) were chills (93.8 %) and pyrexia (87.5 %). The most common TEAE of grade ≥3 was transient dose-dependent increases in aspartate aminotransferase (56.3 %). The intensity of toxicities decreased with the number of infusions. Also, serum IL-6 increased in a dose-dependent manner and reverted to low or undetectable levels after four infusions. A reversible decrease in liver function test (prothrombin time) at the 7-µg dose level was considered a DLT. The first patient at 10 µg experienced a fatal hepatic failure related to catumaxomab that led to the termination of the study.CONCLUSIONS: The MTD of weekly intravenous catumaxomab was 7 µg. Major toxicities were cytokine release-related symptoms and hepatotoxicity.

KW - Adult

KW - Aged

KW - Antibodies, Bispecific

KW - Antigens, CD3

KW - Antigens, Neoplasm

KW - Cell Adhesion Molecules

KW - Dose-Response Relationship, Drug

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasms

KW - T-Lymphocytes

U2 - 10.1007/s00280-015-2728-5

DO - 10.1007/s00280-015-2728-5

M3 - Journal article

C2 - 25814216

SN - 0344-5704

VL - 75

SP - 1065

EP - 1073

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 5

ER -