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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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