Phase 1 Study of Trastuzumab Administered as a Single Intravenous Infusion

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pharmacokinetic Study Comparing Hercules, EU-approved Herceptin® and US-Licensed Herceptin® Administered as a Single Intravenous Infusion to Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Biological: Hercules
* Biological: Herceptin EU
* Biological: Herceptin US


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Hercules: 8 mg/kg i.v. infusion over 90 minutes | Biological: Hercules<br>* Powder Concentrate for Intravenous Infusion, 150 mg/vial<br>* Other names: Trastuzumab;|
| Active Comparator: Treatment B<br>Herceptin EU: 8 mg/kg i.v. infusion over 90 minutes | Biological: Herceptin EU<br>* Powder for Concentrate for Solution for Infusion, 150 mg/vial<br>* Other names: Trastuzumab;|
| Active Comparator: Treatment C<br>Herceptin US: 8 mg/kg i.v. infusion over 90 minutes | Biological: Herceptin US<br>* Intravenous Infusion, 440 mg/vial<br>* Other names: Trastuzumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) | 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%. | 71 days | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) - Time 0 to Last Blood Draw (AUC0-last) | 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%. | 71 days | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) - Time 0 to Infinity AUC0-∞) | 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%. | 71 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (AEs) |  | 71 days | 
| Local Infusion Tolerance |  | 71 days | 
| Immunogenicity |  | 71 days | 
| Measurement of C-reactive Protein |  | 71 days | 
| Monitoring of Heart Function (ECG and Echocardiography) |  | 71 days |