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

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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.

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Acknowledgments

We are grateful to the participating patients and their families. Professor Meinolf Karthaus (Chair) and Professor Lena Specht served as voting members of the Dose Steering Board. Statistician Ib Jarle Christensen is acknowledged for excellent statistical advice. The trial was sponsored by Neovii Biotech GmbH, formerly Fresenius Biotech GmbH. Medical writing assistance was provided by Neovii Biotech GmbH.

Conflict of interest

M.M.S served on an advisory board for Fresenius Biotech GmbH. C.D declares no potential conflict of interest concerning catumaxomab and its development. R.D declares no potential conflicts of interest. U.L declares no potential conflict of interest W.B declares no potential conflict of interest concerning catumaxomab and its development. H.M is an employee of Neovii Biotech GmbH. J.T declares no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark

    Morten Mau-Sørensen & Ulrik Lassen

  2. Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna) – LB Cluster Translational Oncology, Centre for Oncology and Haematology, Kaiser Franz Josef-Spital, Vienna, Austria

    Christian Dittrich & Wilfried Büchler

  3. Vall d’Hebron Institute of Oncology, Vall d’Hebron Hospital, Barcelona, Spain

    Rodrigo Dienstmann & Josep Tabernero

  4. Neovii Biotech GmbH, Munich, Germany

    Holger Martinius

Authors
  1. Morten Mau-Sørensen
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  2. Christian Dittrich
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  3. Rodrigo Dienstmann
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  4. Ulrik Lassen
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  5. Wilfried Büchler
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  6. Holger Martinius
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  7. Josep Tabernero
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Correspondence to Morten Mau-Sørensen.

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Mau-Sørensen, M., Dittrich, C., Dienstmann, R. et al. A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3. Cancer Chemother Pharmacol 75, 1065–1073 (2015). https://doi.org/10.1007/s00280-015-2728-5

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  • DOI: https://doi.org/10.1007/s00280-015-2728-5

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