Advertisement

A Randomized Phase I Pharmacokinetic Study Comparing Biosimilar Candidate SB3 and Trastuzumab in Healthy Male Subjects

      Abstract

      Purpose

      This first-in-human study with SB3 was designed to evaluate the pharmacokinetic (PK) equivalence between SB3 and trastuzumab sourced in the European Union (EU trastuzumab), between SB3 and trastuzumab sourced in the United States (US trastuzumab), and between EU and US trastuzumab (NCT02075073).

      Methods

      In this randomized, double-blind, parallel group, single-dose comparative PK study, 109 healthy male subjects were randomized to receive a single 6-mg/kg IV dose of SB3, EU -trastuzumab, or US trastuzumab. The PK parameters were calculated using noncompartmental methods. The PK equivalence in terms of AUC0-–∞), AUC0–last, and Cmax for the pairwise comparisons (SB3 vs EU trastuzumab, SB3 vs US trastuzumab, and EU trastuzumab vs US trastuzumab) were determined using the predefined equivalence margin of 0.8 to 1.25.

      Findings

      Baseline demographic characteristics for the randomized subjects were similar across the 3 groups. The 90% CIs for the geometric least square means of the AUC0–∞, AUC0–last, and Cmax were completely contained within the margin of 0.8 to 1.25. The proportions of subjects who experienced adverse events related to the study drug were 36.1%, 44.4%, and 61.1% in the SB3, EU trastuzumab, and US trastuzumab groups, respectively. The most frequently reported adverse events related to the study drug was infusion-related reactions. No subjects had positive results for antidrug antibodies after a single dose of SB3, EU trastuzumab, or US trastuzumab.

      Implications

      This study revealed PK equivalence between SB3 and EU trastuzumab, between SB3 and US trastuzumab, and between EU trastuzumab and US trastuzumab. SB3 is well tolerated without tolerability concerns after single-dose administration in healthy male subjects.

      Key words

      To read this article in full you will need to make a payment
      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hudis C.A.
        Trastuzumab--mechanism of action and use in clinical practice.
        N Engl J Med. 2007; 357: 39-51
        • Baselga J.
        • Norton L.
        • Albanell J.
        • et al.
        Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts.
        Cancer Res. 1998; 58: 2825-2831
        • Pegram M.
        • Hsu S.
        • Lewis G.
        • et al.
        Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers.
        Oncogene. 1999; 18: 2241-2251
        • Pegram M.D.
        • Konecny G.
        • Siamon D.
        The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer.
        Cancer Treat Res. 2000; 103: 57-75
        • Romond E.H.
        • Perez E.A.
        • Bryant J.
        • et al.
        Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
        N Engl J Med. 2005; 353: 1673-1684
        • Piccart Gebhart M.J.
        • Procter M.
        • Leyland Jones B.
        • et al.
        Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
        N Engl J Med. 2005; 353: 1659-1672
        • Slamon D.
        • Eiermann W.
        • Robert N.
        • et al.
        Adjuvant trastuzumab in HER2-positive breast cancer.
        N Engl J Med. 2011; 365: 1273-1283
        • Slamon D.J.
        • Leyland Jones B.
        • Shak S.
        • et al.
        Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
        N Engl J Med. 2001; 344: 783-792
        • Marty M.
        • Cognetti F.
        • Maraninchi D.
        • et al.
        Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.
        J Clin Oncol. 2005; 23: 4265-4274
        • Pivot X.
        • Manikhas A.
        • Zurawski B.
        • et al.
        CEREBEL (EGF111438): a phase III, randomized, open label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.
        J. Clin. Oncol. 2015; 33: 1564-1573
        • HERCEPTIN [Trastuzumab]: European Public AU: Please provide publisher locations for refs 11-15, 18, 19.Assessment Report (EPAR)
        European Medicines Agency, 2015
        • Committee for Medicinal Products for Human Use (CHMP)
        Guideline on similar biological medicinal products containing monoclonal antibodies-non clinical and clinical issues.
        European Medicines Agency, 2012
        • Committee for Medicinal Products for Human Use (CHMP)
        Guideline on similar biological medicinal product.
        European Medicines Agency, 2005
        • Food and Drug Administration Center for Drug Evaluation and Research
        Guidance for Industry: scientific considerations in demonstrating biosimilarity to a reference product.
        U.S. Department of Health and Human Services, 2015
        • Committee for Medicinal Products for Human Use (CHMP)
        Guideline on similar biologic medicinal products containing biotechnology-derived protein as active substance: quality issue (revision 1).
        European Medicines Agency, 2012
        • Wynne C.
        • Harvey V.
        • Schwabe C.
        • et al.
        Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer.
        J Clin Pharmacol. 2013; 53: 192-201
        • Leyland-Jones B.
        • Gelmon K.
        • Ayoub J.P.
        • et al.
        Ghahramani P. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel.
        J Clin Oncol. 2003; 21: 3965-3971
        • Committee for Medicinal Products for Human Use (CHMP)
        Guideline on the investigation of bioequivalence.
        European Medicines Agency, 2010
        • Food and Drug Administration Center for Drug Evaluation and Research
        Guidance for Industry: statistical approaches to establishing bioequivalence.
        U.S. Department of Health and Human Services, 2001
        • Jones L.B.
        • Gelmon K.
        • Ayoub J.
        • et al.
        Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel.
        J Clin Oncol. 2003; 21: 3965-3971
        • Ismael G.
        • Hegg R.
        • Muehlbauer S.
        • et al.
        Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial.
        Lancet Oncol. 2012; 13: 869-878
        • Yin D.
        • Barker K.B.
        • Li R.
        • et al.
        A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01).
        Br J Cin Pharmacol. 2014; 78: 1281-1290
        • Jackisch C.
        • Kim S.B.
        • Semiglazov V.
        • et al.
        Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study.
        Ann Oncol. 2015; 26: 320-325