Showing papers by "Horst Lindhofer published in 2010"

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.

Structural and functional characterization of the trifunctional antibody catumaxomab.

Abstract: The Triomab family of trifunctional, bispecific antibodies that maintain an IgG-like shape are novel tumor targeting agents. These chimeras consist of two half antibodies, each with one light and one heavy chain, that originate from parental mouse IgG2a and rat IgG2b isotypes. This combination allows cost-effective biopharmaceutical manufacturing at an industrial scale since this specific mouse/rat isotype combination favors matching of corresponding antibody halves during production by means of quadroma technology. Whereas every Triomab family member is composed of an anti-CD3 rat IgG2b half antibody for T cell recognition, the antigen binding site presented by the mouse IgG2a isotype is exchangeable. Several Triomab antibodies have been generated that bind to tumor-associated antigens, e.g., EpCAM (catumaxomab), HER2/neu (ertumaxomab), CD20 (FBTA05), gangliosides GD2/GD3 (Ektomun), on appropriate tumor target cells associated with carcinomas, lymphomas or melanomas. Catumaxomab (Removab) was launched in Europe for treatment of malignant ascites in April 2009. Here, we report the structural and functional characterization of this product. Mass spectrometry revealed an intact mass of 150511 Dalton (Da) and 23717 Da, 24716 Da, 51957 Da and 52019 Da of the reduced and alkylated rat light chain, mouse light chain, rat heavy chain, mouse heavy chain chains, respectively. The observed masses were in agreement with the expected masses based on the amino acid sequence obtained from cDNA sequencing. The glycosylation profile was similar to other human IgG consisting of biantennary oligosaccharides with different numbers of terminal galactose. CD spectroscopy showed mainly beta-sheets secondary structure that is typical for IgG antibodies. Binding measurement revealed the unique trifunctional features of catumaxomab. Other analytical tools were used to evaluate characteristics of catumaxomab preparations, including the presence of isoforms and aggregates.

Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients.

Abstract: AIMS Catumaxomab is the first EMEA approved trifunctional anti-EpCAM×anti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development.

Intraoperative immunotherapy with the trifunctional antibody catumaxomab in patients with ovarian cancer: Results from a phase II study.

Abstract: 5039 Background: Despite recent improvements in cytoreductive surgery followed by chemotherapy in patients (pts) with advanced ovarian cancer the relapse and mortality rates are still too high. In ...

Abstract P3-14-21: Phase II Study of Single Agent Trifunctional Antibody Ertumaxomab (Anti-HER-2 & Anti-CD3) in HER-2 Low Expressing Hormone-Refractory Advanced Breast Cancer Patients (ABC)

Abstract: Background: Ertumaxomab is an intact bispecific trifunctional antibody targeting HER-2 and CD3 as well as activating Fcγ receptors on accessory cells. Trifunctional Abs mediate the elimination of cancer cells by simultaneous binding and activation of T-cells and accessory cells at the tumor site. A phase I study with ertumaxomab showed encouraging efficacy results in MBC patients (Kiewe et al. , 2006). Another trifunctional Ab of the same class, catumaxomab, was recently approved in Europe for the treatment of Malignant Ascites. Materials & Methods: This was an open-label, non-randomized, single agent phase II study. Enrolled pts had ER and/or PgR positive ABC with low HER-2 expression (defined as IHC 1+ or 2+ and FISH negative). Pts had to have PD after hormonal therapy including at least one aromatase inhibitor but no prior chemotherapy for advanced disease. Ertumaxomab was given i.v. once a week on days 0, 7, and 14 over three hours according to the schedule: 10 μg (day 0), 100 μg (day 7) and 100 μg (day 14). Primary endpoint was objective response rate (ORR) according to RECIST. Tumor response evaluation was performed at 4 and 8 weeks after the last dose of ertumaxomab, then every 2-3 months until PD. Secondary efficacy endpoints were time to progression (TTP), time to and duration of response, clinical benefit, and tumor marker levels. Safety and tolerability were also secondary endpoints. Results: Of the planned 40 pts, 28 were enrolled. Recruitment was prematurely terminated due to a strategic change in the sponsor9s clinical development program. No CR was observed. One patient had PR at follow up (FUP) 3, but this finding was not confirmed due to lack of further FUP data. 14 of 26 evaluable pts (53.8%) had SD at FUP 2 (day 42) and 8 of 26 patients (30.8%) had SD at FUP 3 (day 70). In one patient SD was sustained beyond 10 months. The median TTP in the evaluable population was 65.5 days (95%, CI: 43-98). Fourteen pts (51.9%) had at least one treatment-related adverse event (AE) after the 1 st infusion (10μg), and 25 pts (92.6%) had at least one AE after administration of 100μg. The most frequently observed AEs were pyrexia (74.1%), headache (40.7%), chill (33.3%), and vomiting (29.6%). AEs were mostly of mild or moderate intensity and the majority (73.8%) resolved within one day. Mean plasma concentrations of IL-10, IL-2, IL-6, TNF-α and IFN-α markedly increased after infusion 2 and 3 and returned to baseline levels 24 hours later. Discussion: The safety and tolerability profile of ertumaxomab in Her2 low expressing pts was similar to the profile of other immunotherapeutic Abs and to the results of the previous phase I study. The observed symptoms are most likely due to the release of cytokines and in line with the mode of action of ertumaxomab. They indicate a strong immunologic response. The clinical benefit obtained and safe toxicity profile support further clinical development of ertumaxomab. Further dose optimization studies as a single-agent and in combination as well as studies in HER-2 + pts are warranted. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-21.

Phase II clinical trial to evaluate the safety of repeated cycles of intraperitoneal catumaxomab for the treatment of malignant ascites (SECIMAS).

Abstract: TPS155 Background: The trifunctional anti-EpCAM/anti-CD3 antibody catumaxomab has been recently approved in the EU for i.p. treatment of malignant ascites as one cycle of 4 i.p. applications within 11 days. As a growing number of clinicians are gathering experience with this antibody, the question arised, if a second treatment cycle could be feasible and effective for patients who did profit from the first cycle but eventually presented back with recurrent malignant ascites. Up to this point it remained unclear if human-anti-mouse-antibody (HAMA) would interfere with the efficiency of a second cycle, due to interception of the antibody. In a case of a patient with heavily pretreated breast cancer the patient was retreated with 4 i.p. applications of catumaxomab (10–20–50–150 μ g), which was well tolerated. HAMA-values were measured in the patients blood and ascites at different time intervals before, during and after this second cycle of catumaxomab. During this second treatment cycle a clear reduction of...

The trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) in patients with malignant ascites: Immunomonitoring results of a pivotal phase II/III study (pooled population).

Abstract: 2521 Background: Malignant ascites (MA) is a symptom of late-stage tumor disease and associated with a poor prognosis. The trifunctional antibody catumaxomab is approved for treatment of MA. Method...

The trifunctional antibody catumaxomab: Correlation between immunological response and clinical outcome--New analysis of a pivotal phase II/III study.

Abstract: 2551 Background: Catumaxomab, a trifunctional anti-EpCAM/anti-CD3 antibody is approved in the EU for intraperitoneal treatment of malignant ascites. In the pivotal study (Parsons et al. J Clin Onco...

Catumaxomab observational study to investigate efficacy and safety profile in clinical practice.

Abstract: TPS156 Background: The trifunctional anti-EpCAM/anti-CD3 antibody catumaxomab was recently approved in the EU for intraperitoneal (i.p.) treatment of malignant ascites, based on data from an international, randomized clinical trial (Parsons et al. J Clin Oncol 2008; 26:abst 3000). In the PK analysis, the i.p. application of 10-20-50-150μ g catumaxomab resulted in high and effective local i.p. concentrations. As reported (Ruf et al. J Clin Oncol 2008; 26: abst 14006) the systemic catumaxomab exposure was low (< 5%) with a maximum median plasma concentration (C max) of 403 pg/ml and a mean plasma elimination half-life of 2.13 days. Nevertheless, catumaxomab remained immunologically active even after several days in the circulation. In the pivotal trial patients showed clinical benefit regardless of absence or presence of distant metastases (Heiss et al WCGIC 2009). Futhermore, an overall survival benefit in the gastric cancer subgroup was reported (Heiss et al ECCO/ESMO 2009). First anecdotal reports from p...