274P - A Phase I Dose Escalation and Bioequivalence Study of a Trastuzumab Biosimilar (FTMB) in Healthy Male Volunteers

Abstract

ABSTRACT Disclosure All authors have declared no conflicts of interest. FTMB is a biosimilar of trastuzumab (Herceptin®), a humanized monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2). Herceptin® is registered for treatment of HER2-positive breast cancer and metastatic gastric cancer. Pharmacokinetic profiles of FTMB were compared to Herceptin® in this combined dose escalation and bioequivalence study. In the dose escalation part healthy male volunteers received single doses of 0.5, 1.5, 3.0 or 6.0 mg/kg FTMB in consecutive cohorts to assess the safety profile. At each dose level, subjects were randomized to FTMB (n = 6) or placebo (n = 2), with the exception of the 6 mg/kg cohort, where subjects were randomized to FTMB (n = 9), Herceptin® (n = 9) or placebo (n = 2). Safety data were evaluated by an independent data safety monitoring board. To establish bioequivalence a total of 92 healthy male subjects, including those of the 6 mg/kg dose escalation cohort, were randomized equally to FTMB or Herceptin®. Blood samples were taken prior and at regular, predefined time points up to 9 weeks after dosing. Trastuzumab levels were determined in serum with a validated bridging ELISA method. The mean area under the concentration-time curve from time zero to infinity (AUC0-inf), normalized to 1 mg/kg and corrected for content differences between FTMB (Test) and Herceptin® (Reference) was 221.4 µg.d/mL for Test and 245.6 µg.d/mL for Reference. The ln-transformed Test/Reference (T/R) ratio for AUC0-inf was 89.6% (90% confidence interval (CI): 85.1-94.4%), demonstrating bioequivalence based on the acceptance interval of 80.0-125.0%. For the secondary endpoint, maximum concentration observed (Cmax), the T/R ratio was 89.4% (90% CI: 83.4-95.9%). Interestingly, the elimination of both FTMB and Herceptin® was shown to be non-linear. Adverse events other than the documented side effects of trastuzumab (fever, influenza-like illness, and fatigue) did not occur, and signs of cardiotoxicity were not observed. In conclusion, in this first bioequivalence study with a trastuzumab biosimilar in healthy male volunteers, single administration of FTMB was considered well tolerated in doses up to 6 mg/kg, and FTMB was demonstrated to be bioequivalent to Herceptin®.