The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial

Abstract

Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti-epithelial cell-adhesion molecule x anti-CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004-000723-15; NCT00836654), cancer patients (n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 μg, respectively. The primary efficacy endpoint was puncture-free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture-free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer (n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile.

Surgical treatment for peritoneal carcinomatosis from gastric cancer

“…Surgical bypasses or venting gastrostomy tubes even in the setting of gastric cancer are acceptable for palliation. The application of intraperitoneal therapy such as anti-EPCAM (epithelial cell adhesion) antibodies has shown significant benefits in puncture-free survival (survival without repeated paracentesis) for patients with malignant ascites in a phase II/III randomized trial [16]. In addition, for EPCAM+ tumors, the use of intraperitoneal catumaxomab has also shown an improved progression-free interval in phase II studies [17].…”

A phase II study of catumaxomab administered intra- and postoperatively as part of a multimodal approach in primarily resectable gastric cancer

“…The targeted immunotherapy catumaxomab [Removab Ò , Neovii (formerly Fresenius) Biotech GmbH, Munich, Germany] has been approved in the European Union since April 2009 for the intraperitoneal treatment of malignant ascites in patients with epithelial cell-adhesion molecule (EpCAM)-positive carcinomas for whom no further standard therapy is available or feasible [17,18]. Catumaxomab, a trifunctional antibody, has two different antigen-binding sites for EpCAM on tumour cells and CD3 receptors on T cells, respectively, plus a functional Fc domain that binds to type I, IIa and III Fcc receptors on accessory cells, e.g., natural killer cells, macrophages and dendritic cells [19].…”

“…Catumaxomab has demonstrated efficacy and acceptable tolerability in the treatment of malignant ascites and has shown promising results in the treatment of advanced intraabdominal carcinoma, peritoneal carcinomatosis, gastric cancer and ovarian cancer [17,21,22].…”

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

“…Trifunctional antibodies combine the characteristics of classical monospecifi c antibodies and bispecifi c molecules: In addition to the two specifi c antigen binding sites, trifunctional antibodies retain their intact Fc region, which mediates recruitment and activation of accessory cells (macrophages, dendritic cells, NK cells) [11]. Thus, the mode of action of these trifunctional antibodies is based on the simultaneous recruitment of T cells and accessory cells to the tumour site leading to improved tumour cell elimination by various immunologic killing mechanisms [8][9][10][11][12][13]. The trifunctional antibody catumaxomab (anti-EpCAManti-CD3, Removab ® ) has been approved recently in the European Union for the intraperitoneal treatment of malignant ascites due to EpCAM-positive carcinoma where standard therapy is not available or no longer feasible [8,9].…”

“…Thus, the mode of action of these trifunctional antibodies is based on the simultaneous recruitment of T cells and accessory cells to the tumour site leading to improved tumour cell elimination by various immunologic killing mechanisms [8][9][10][11][12][13]. The trifunctional antibody catumaxomab (anti-EpCAManti-CD3, Removab ® ) has been approved recently in the European Union for the intraperitoneal treatment of malignant ascites due to EpCAM-positive carcinoma where standard therapy is not available or no longer feasible [8,9]. The related trifunctional antibody ertumaxomab (anti-HER-2/neuanti-CD3) is in clinical development.…”