A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01)

Abstract

Aims: The pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed.

Methods: In this phase 1, double-blind trial (NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg(-1) intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration-time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab-EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria.

Results: Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax , AUC (0 , t last) and AUC(0,∞) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term 'pyrexia' was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA).

Conclusions: This study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.

Keywords: PF-05280014; biosimilar; immunogenicity; pharmacokinetics; safety; trastuzumab.

Figure 1

Study design. *Time/day on which samples were collected for ADA; samples for PK were collected at all times shown. ^†Subjects having an unresolved adverse event that was possibly related to ADA formation were asked to return for ADA and drug concentration blood sampling at up to 3 month intervals until the adverse event or its sequelae resolved or stabilized at a level acceptable to the investigator and the sponsor concurs with the investigator's assessment, up to 6 months from the visit on day 71 or the day of early withdrawal. ADA, anti-drug antibodies; PK, pharmacokinetics

Figure 2

Subject disposition. IRR, incomplete dosing due to infusion-related reaction

Figure 3

Individual (A–C) and mean ± SD (D) serum concentration–time profiles of PF-05280014, trastuzumab-EU and trastuzumab-US following a single dose of 6 mg kg⁻¹ in healthy subjects. SD, standard deviation. A, B and C: , median; , individual; D: •, PF-02580014; ▪, trastuzumab-EU; ▴, trastuzumab-US

Figure 4

Individual and mean estimates of (A) C_max, (B) and (C) AUC_(0,∞) of PF-05280014, trastuzumab-EU and trastuzumab-US. AUC_(0,∞), area under the concentration–time curve from time 0 extrapolated to infinite time; , area under the concentration-time curve from time 0 to last time point of measurable concentration; C_max, maximum drug concentration; EU, trastuzumab EU; PF, PF-05280014; US, trastuzumab-US