274P - A phase I dose escalation and bioequivalence study of a trastuzumab biosimilar (FTMB) in healthy male volunteers

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Breast Cancer, Early Stage
Presenter Liselijn Wisman
Authors L. Wisman1, E. De Cock2, J. Reijers3, I. De Visser3, M. De Kam3, S. van Os2, G. Voortman2, L. Hooftman2, K. Burggraaf3
  • 1Clinical Pharmacology, Synthon BV, Nijmegen/NL
  • 2Clinical Operations, Synthon BV, Nijmegen/NL
  • 3Cardiovascular Research, Center for Human Drug Research, 2333 CL - Leiden/NL


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®.


All authors have declared no conflicts of interest.