Phase 1 Study of Trastuzumab Administered as a Single Intravenous Infusion

Phase 1

Completed

• Conditions: Healthy
• Interventions: Biological: Herceptin EU; Biological: Herceptin US; Biological: Hercules

• Registration Number: NCT02594761
• Lead Sponsor: Mylan Pharmaceuticals Inc

Brief Summary

The primary objective of this study was to demonstrate pharmacokinetic similarity of Mylan trastuzumab (Hercules) versus EU-approved Herceptin® and US-licensed Herceptin® and pharmacokinetic similarity of EU-approved Herceptin® versus US-licensed Herceptin® after 8 mg/kg as single dose administered as intravenous infusion over 90 minutes in healthy male subjects based on the equivalence criterion that AUC0-∞, AUC0-last, and Cmax least square mean ratios are bounded within the 90% confidence intervals, 80.00% - 125.00%. Three similarity assessments were performed, 1) Hercules vs. EU-approved Herceptin®, 2) Hercules vs. US-licensed Herceptin® and 3) EU-approved Herceptin® vs. US-licensed Herceptin®. Secondary objectives included further pharmacokinetic assessment of similarity of Hercules, EU-approved Herceptin® and US-licensed Herceptin® λz, tmax and t1/2 along with assessment of safety (including immunogenicity) and local tolerance.

Detailed Description

All subjects checked into the clinical facility on the day prior to dosing. On study day 1, each subject received either a single i.v. infusion of 8 mg/kg BW in 250 mL normal saline over a 90 minute period of Mylan trastuzumab (Hercules), EU-approved Herceptin®, or US-licensed Herceptin®. Dosing occurred following an overnight fast of at least 8 hours. On the day of dosing, subjects fasted for the first 3 hours after the start of the infusion then received standard meals approximately 3, 6 and 9 hours post-dose. In each study period, blood samples were collected just immediately prior to dose administration (0 hour) and at 45 and 90 minutes (just prior to end of infusion). Blood samples were collected post-dose at 3, 6, 9, 24 and 48 hours, relative to the start of infusion. The subjects were allowed to leave the clinical facility after the 48-hour blood sample collection. Subjects returned to the clinical facility for the scheduled blood sample collections post-dose on Day 5, 8, 11, 15, 22, 29, 43, 57, and 71. Serum samples were stored at -80°C ± 15°C until shipment for analysis. Blood samples for anti-drug antibodies (ADA) were collected prior to dosing on Day 1 and on Day 71. Blood samples for C-reactive protein (CRP) were obtained at Screening, prior to dosing and at 3, 24 and 48 hours post-dose and on Day 8 and 71. Blood samples for analysis of immunoglobulins were collected prior to dosing on Day 1 and on Day 8 and 71.

Study Timeline

• Study Start: 2013-08
• Primary Completion: 2014-02
• Study Completion: 2014-02
• Status Verified: 2015-10
• Study First Submitted: 2015-10-29
• Study First Submitted QC: 2015-10-30
• Last Update Submitted: 2015-10-30
• Study First Posted: 2015-11-03
• Last Update Posted: 2015-11-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 132

Inclusion Criteria

• healthy adult subjects, age 18 to 55 years old
• able to understand procedures, agree to participate and willing to give informed consent

Exclusion Criteria

• history of any significant disease
• use of any medication 7 days prior to start of study
• participation in a clinical trial within 30 days of start of study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment B	Herceptin EU	Herceptin EU: 8 mg/kg i.v. infusion over 90 minutes
Treatment C	Herceptin US	Herceptin US: 8 mg/kg i.v. infusion over 90 minutes
Treatment A	Hercules	Hercules: 8 mg/kg i.v. infusion over 90 minutes

Primary Outcome Measures

Name	Time	Method
Peak Plasma Concentration (Cmax)	71 days	The primary pharmacokinetic variables for assessment of bioequivalence are dose-normalized Cmax based on the equivalence criterion that Cmax least square mean ratios are bounded within the 90% confidence intervals, 80.00% - 125.00%.
Area Under the Plasma Concentration Versus Time Curve (AUC) - Time 0 to Last Blood Draw (AUC0-last)	71 days	The primary pharmacokinetic variables for assessment of bioequivalence are dose-normalized AUC0-last based on the equivalence criterion that AUC0-last least square mean ratios are bounded within the 90% confidence intervals, 80.00% - 125.00%.
Area Under the Plasma Concentration Versus Time Curve (AUC) - Time 0 to Infinity AUC0-∞)	71 days	The primary pharmacokinetic variables for assessment of bioequivalence are dose-normalized AUC0-∞, based on the equivalence criterion that AUC0-∞ least square mean ratios are bounded within the 90% confidence intervals, 80.00% - 125.00%.

Secondary Outcome Measures

Name	Time	Method
Measurement of C-reactive Protein	71 days
Monitoring of Heart Function (ECG and Echocardiography)	71 days
Incidence of Treatment-Emergent Adverse Events (AEs)	71 days
Local Infusion Tolerance	71 days
Immunogenicity	71 days