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 mug, 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.

Figure 1

(a) Study design. (b) CONSORT flow diagram (only results for the intent-to-treat and safety populations are included in this article). *The main cancer types in the nonovarian stratum were gastric (n = 66, 51%), breast (n = 13, 10%), pancreas (n = 9, 7%), colon (n = 8, 6%) and endometrial (n = 6, 5%).

Figure 2

Kaplan-Meier estimates of puncture-free survival, time to next paracentesis and overall survival (intent-to-treat population). (a) Puncture-free survival in the pooled population; (b) time to next paracentesis in the pooled population; (c) overall survival in the pooled population; (d) overall survival in patients with ovarian cancer and (e) overall survival in patients with gastric cancer.

Figure 3

Patients without ascites signs and symptoms as assessed by interview 8 days after last infusion (catumaxomab) or 8 days after paracentesis (control group).

Figure 4

(a) Tumor-cell load in the ascites fluid before, during and after catumaxomab treatment. Number of EpCAM+ tumor cells per 10⁶ total cells evaluated by immunocytochemistry. The median tumor-cell count at the repuncture visit was statistically significantly lower (p = 0.0012) in the catumaxomab group. (b) Fluorescent double staining of ascites fluid cells: evaluation of CD45+ leukocyte:EpCAM+ tumor cell ratio during catumaxomab therapy. (i) Malignant ascites harvested at screening puncture (before catumaxomab treatment). (ii) At Day 3 after 10 μg catumaxomab i.p. (iii) At Day 11 after a total of 230 μg catumaxomab i.p. Dotplot analysis: every plot resembles a fluorescence-labeled cell that was detected and counted by the computerized image analysis system.