Pharmacokinetics and in vivo stability of intraperitoneally administered therapeutic antibody catumaxomab

Abstract

14006 Background: The EpCAM-specific trifunctional rat/mouse hybrid antibody catumaxomab simultaneously activates T cells and Fcγ-receptor positive immune cells redirecting them against the tumor. In a phase II/III randomized study catumaxomab significantly prolonged puncture free survival and time to progression in cancer patients (pts) with symptomatic ascites. Here, the results of the corresponding pharmacokinetic trial are presented. Methods: The pharmacokinetics of catumaxomab were evaluated in a phase II, open- label, multi-centre study in 13 pts with malignant ascites requiring paracentesis. Four intraperitoneal (i.p.) infusions of 10, 20, 50 and 150 μg catumaxomab were administered within 11 days. Antibody concentrations were quantified by a high-sensitivity ELISA in ascites and plasma to determine local and systemic exposure. Immunological activity of catumaxomab was measured using a potency assay. Anti-drug antibody (ADA) development was monitored applying a bridging ELISA. Results: 10 pts receiving all four infusions were evaluable. Increasing concentrations (C) of free catumaxomab were detected in ascites fluid during the course of the treatment. Median Cascites before the last infusion was 6121 pg/ml. Systemic exposure was observed in 9 pts with median Cmax of 403 pg/ml. High inter-individual variability was demonstrated by Area Under the Curve AUC0-tlast values ranging between 0 and 10,020 day*pg/ml (median = 2,045). There was no correlation between safety parameters and systemic C. Elimination half life t1/2 was 2.13 days in mean. The therapeutic antibody exhibited remarkable in vivo stability remaining almost fully immunologically active (80–100%) even after three days of circulation in ascites. Also systemic catumaxomab in plasma still revealed 50–60% bioactivity. None of the pts developed significant ADA responses (> 100 ng/ml) until the time of last infusion. Conclusions: The relatively long t1/2 of 2.13 days and the high in vivo stability of immunologically active catumaxomab support its observed clinical efficacy. High local C, minor systemic exposure with an acceptable safety profile and ADA onset not until the last i.p. infusion confirm the appropriateness of the chosen dosing scheme. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Fresenius Biotech, Trion Pharma, Trion Research Trion Pharma, Trion Research