Elsevier

Clinical Therapeutics

Volume 40, Issue 3, March 2018, Pages 396-405.e4
Clinical Therapeutics

Original Research
A Randomized Phase I Study Comparing the Pharmacokinetics of HD201, a Trastuzumab Biosimilar, With European Union–sourced Herceptin

https://doi.org/10.1016/j.clinthera.2018.01.009Get rights and content

Abstract

Purpose

This first-in-human study of HD201 was designed to evaluate the pharmacokinetic (PK) equivalence between this biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab)*.

Methods

In this randomized, blinded, single-dose comparative PK study, healthy male subjects were randomized to receive a single 6 mg/kg IV dose of HD201 or EU-trastuzumab. The primary PK end point was AUC0–∞. Equivalence was determined by using the predefined margins of 0.8 to 1.25. Other PK parameters were included as secondary end points.

Findings

Baseline demographic characteristics for the 73 randomized subjects were similar across the 2 groups: median age 29 and 30 years old (ranges 19 - 45), median weight 78.6 and 81.7 kg (ranges 60.2 – 101). The 90% CIs for the geometric least squares mean of the AUC0–∞ were included within the margins of 0.8 to 1.25. All other PK parameters were comparable for both HD201 and EU-trastuzumab. The proportions of subjects who experienced adverse events related to the study drug were 61.8% and 82.9% in the HD201 and EU-trastuzumab groups, respectively. The most frequently reported adverse events related to the study drug were infusion-related reactions. No subjects had positive results for antidrug antibodies after a single dose.

Implications

This study reported the PK equivalence between HD201 and EU-trastuzumab. HD201 was well tolerated with no safety concerns after single-dose administration in healthy male subjects. EudraCT No.: 2012-000805-56.

Introduction

Trastuzumab-containing regimens are the backbone of treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, providing significant clinical benefit for metastatic breast cancer and increasing the proportion of cure patients in the adjuvant setting for early breast cancer.1 Trastuzumab* is a humanized immunoglobulin G1 monoclonal antibody selectively targeting to HER2.2 Prestige BioPharma Pte Ltd has developed HD201, a biosimilar candidate of the reference trastuzumab product, produced by recombinant DNA technology by using CHO-K1 Chinese hamster ovary cells transformed with the expression plasmid pCA201LHIG. Extensive comparability exercises were performed to demonstrate similar physicochemical and functional biological characteristics between HD201 and trastuzumab.3, 4, 5 Identical amino acid sequence and superimposable primary structure through Lys-C and Glu-C peptide mapping have been established (see Supplemental Figure 1A in the online version at https://doi.org/10.1016/j.clinthera.2018.01.009). Physicochemical characterization in terms of purity, impurity, charge variations, total proteins, and conformational presentation were identical (see Supplemental Figures 1B and 1C in the online version at https://doi.org/10.1016/j.clinthera.2018.01.009). N-Glycan and carbohydrate structures were the same (see Supplemental Figure 1D in the online version at https://doi.org/10.1016/j.clinthera.2018.01.009), and in vitro functional activities, including HER2 binding and FcγR-related binding, were equivalent (see Supplemental Figure 1E in the online version at https://doi.org/10.1016/j.clinthera.2018.01.009). Antibody-dependent cell-mediated cytotoxicity, the complement-dependent cytotoxicity effect, and tumor cell proliferation inhibition demonstrated their similarity between HD201 and trastuzumab (see Supplemental Figures 1F–1H in the online version at https://doi.org/10.1016/j.clinthera.2018.01.009). A pharmacodynamics study in mice, in addition to pharmacokinetic (PK)/pharmacodynamics studies in cynomolgus monkeys, established that there were no significant difference between HD201 and trastuzumab (see Supplemental Figure 2 and Supplemental Table I in the online version at https://doi.org/10.1016/j.clinthera.2018.01.009).

The present article provides the results of the first-in-human study designed to evaluate the PK equivalence between HD201, a biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab).

Section snippets

Study Design

This study was a single-dose, blinded, randomized study in healthy male subjects. The primary objective of the study was to demonstrate PK equivalence between HD201 and EU-trastuzumab. Secondary objectives included assessment of other PK parameters, tolerability, and immunogenicity between the 2 arms.

For inclusion into the study, subjects had to be between the ages of 18 and 45 years. All subjects had to have normal screening results for vital signs, physical examination, and hematologic,

Subject Characteristics and Disposition

A total of 73 healthy male subjects were enrolled in this study from November 21, 2012, to February 1, 2014. Baseline demographic characteristics were similar between the 2 groups (Table I). Nevertheless, 4 subjects were excluded from the study (poor venous access), and 5 additional subjects were excluded from the PK population (1, pump using wrong calibration; 1, infusion stopped due to AE; 1, <90% of the dose was administered; and 2, PK sample taken at a wrong time). The safety and PK

Discussion

In this randomized, blinded, single-dose study in healthy male subjects, PK equivalence between HD201 and the reference trastuzumab was shown. This study was the first step of a clinical evaluation in the stepwise development for a biosimilar candidate.3, 4, 5

The study design is considered appropriate and standard for this type of research. Addressing the long t1/2 with trastuzumab, a parallel study design was preferred to save time, even if a crossover design might have reduced the variability.

Conclusions

The results of this study showed the PK equivalence between HD201 and reference trastuzumab. As the next step in the biosimilar development, the efficacy, safety, and immunogenicity of HD201 will be evaluated in the TROIKA (A Phase III Trial to Compare the Efficacy, Safety and Pharmacokinetics of HD201 to Herceptin® in HER2+ Early Breast Cancer Patients) study. This study is an ongoing Phase III trial assessing HD201 versus referent trastuzumab concomitantly administered with standard docetaxel

Conflicts of Interest

Drs. Deslypere, Soyeon Park, Jinwoo Kim, W. Lee, and J. Lee are employees of Prestige BioPharma Pte Ltd. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

The funding source validated the study as designed by the trial’s steering committee as well as subsequent amendments. The sponsor organized the collection of data. Data were interpreted by the trial’s steering committee, independently from the sponsor. The corresponding author had

Acknowledgments

This study was funded by Prestige BioPharma Pte Ltd.

The authors acknowledgment the assistance of Dr. Pui Man Leung, Dr. John Bolodeoku, and Dr. Cyril Clarke, from ICON Development Solutions Ltd; Dr. Ronnie Beboso, from BioKinetic Europe Ltd; and Leon Conradie, from ICON Clinical Research (UK) Ltd.

X Pivot has written the manuscript and has performed the interpretation of the data. JP Deslypere, Soyeon Park W. Lee, J. Lee and Jinwoo Kim have collected the data, have valided the interpretation and

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