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01.05.2015 | Original Article

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

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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2015

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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.

Went P, Lugli A, Meier S et al (2004) Frequent EpCAM protein expression in human carcinomas. Hum Pathol 35:122–128CrossRefPubMed

Went P, Vasei M, Bubendorf L et al (2006) Frequent high-level expression of the immunotherapeutic target EpCAM in colon, stomach, prostate and lung cancers. Br J Cancer 94:128–135CrossRefPubMedCentralPubMed

Spizzo G, Went P, Dirnhofer S et al (2004) High EpCAM expression is associated with poor prognosis in node-positive breast cancer. Breast Cancer Res Treat 86:207–213CrossRefPubMed

Spizzo G, Went P, Dirnhofer S et al (2006) Overexpression of epithelial cell adhesion molecule (EpCAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol 103:483–488CrossRefPubMed

Balzar M, Winter MJ, de Boer CJ et al (1999) The biology of the 17-1A antigen (EpCAM). J Mol Mod 77:699–712CrossRef

Pauli C, Muenz M, Kieu C et al (2003) Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer Lett 193:25–32CrossRefPubMed

Lindhofer H, Mocikat R, Steipe B et al (1995) Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies. J Immunol 155:219–225PubMed

Zeidler R, Reisbach G, Wollenberg B et al (1999) Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. J Immunol 163:1246–1252PubMed

Zhang S, Zhang HS, Cordon-Cardo C et al (1998) Selection of tumor antigens as targets for immune attack using immunohistochemistry: protein antigens. Clin Cancer Res 4:2669–2676PubMed

10.

Riesenberg R, Buchner A, Pohla H et al (2001) Lysis of prostate carcinoma cells by trifunctional bispecific antibodies (alpha EpCAM x alpha CD3). J Histochem Cytochem 49:911–917CrossRefPubMed

11.

Zeidler R, Mysliwietz J, Csanady M et al (2000) The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer 83:261–266CrossRefPubMedCentralPubMed

12.

Schmitt M, Schmitt A, Reinhardt P et al (2004) Opsonization with a trifunctional bispecific (alphaCD3 x alphaEpCAM) antibody results in efficient lysis in vitro and in vivo of EpCAM positive tumor cells by cytotoxic T lymphocytes. Int J Oncol 25:841–848PubMed

13.

Seimetz D, Lindhofer H, Bokemeyer C (2010) Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev 36:458–467CrossRefPubMed

14.

Heiss MM, Murawa P, Koralewski P et al (2010) The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int J Cancer 127:2209–2221CrossRefPubMedCentralPubMed

15.

Petrelli F, Borgonovo K, Lonati V et al (2013) Regression of liver metastases after treatment with intraperitoneal catumaxomab for malignant ascites due to breast cancer. Target Oncol 8:291–294CrossRefPubMed

16.

Bezan A, Hohla F, Meissnitzer T et al (2013) Systemic effect of catumaxomab in a patient with metastasized colorectal cancer: a case report. BMC Cancer 13:618CrossRefPubMedCentralPubMed

17.

Sebastian M, Passlick B, Friccius-Quecke H et al (2007) Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM x anti-CD3): a phase I study. Cancer Immunol Immunother 56:1637–1644CrossRefPubMed

18.

Le Tourneau C, Lee JJ, Siu LL (2009) Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 101:708–720CrossRefPubMedCentralPubMed

19.

Ruf P, Kluge M, Jäger M et al (2010) Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients. Br J Clin Pharmacol 69:617–625CrossRefPubMedCentralPubMed

20.

Amacher DE (1998) Serum transaminase elevations as indicators of hepatic injury following the administration of drugs. Regul Toxicol Pharmacol 27:119–130CrossRefPubMed

21.

Suntharalingam G, Perry MR, Ward S et al (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028CrossRefPubMed

22.

Riechelmann H, Wiesneth M, Schauwecker P et al (2007) Adoptive therapy of head and neck squamous cell carcinoma with antibody coated immune cells: a pilot clinical trial. Cancer Immunol Immunother 56:1397–1406CrossRefPubMed

23.

Bugelski PJ, Achuthanandam R, Capocasale RJ et al (2009) Monoclonal antibody-induced cytokine-release syndrome. Expert Rev Clin Immunol 5:499–521CrossRefPubMed

24.

Burges A, Wimberger P, Kümper C et al (2007) Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study. Clin Cancer Res 13:3899–3905CrossRefPubMed

25.

Pietzner K, Vergote I, Santoro A et al (2014) Re-challenge with catumaxomab in patients with malignant ascites: results from the SECIMAS study. Med Oncol 31:308CrossRefPubMed

26.

Thomaidis T, Wörns MA, Galle PR et al (2014) Treatment of malignant ascites with a second cycle of catumaxomab in gastric signet cell carcinoma—a report of 2 cases. Oncol Res Treat 37:674–677CrossRefPubMed

Titel: A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3
verfasst von: Morten Mau-Sørensen
Christian Dittrich
Rodrigo Dienstmann
Ulrik Lassen
Wilfried Büchler
Holger Martinius
Josep Tabernero
Publikationsdatum: 01.05.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2015
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2728-5

Springer Medizin

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