A Dose-Finding Study of Subcutaneous Herceptin (Trastuzumab) in Healthy Male Volunteers and Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Females

Study Overview
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Brief Summary
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This two-part study is designed to select the subcutaneous (SC) dose of Herceptin that results in comparable exposure to intravenous (IV) Herceptin in healthy male participants and in HER2-positive female participants. The study will also assess the safety and tolerability of the SC and IV formulations. In Part 1 of the study, four cohorts will be treated with a single dose of Herceptin as follows: Cohort 1 (6 milligrams per kilogram [mg/kg] IV in healthy male participants); Cohort 2 (6 mg/kg IV in HER2-positive female participants); Cohort 3 (6 mg/kg SC in healthy male participants); Cohort 4 (10 mg/kg SC in healthy male participants). An additional cohort of healthy volunteers (Cohort 5) will be opened if both SC dose levels from Cohorts 3 and 4 result in Herceptin exposures different from the target concentration produced by a single IV dose, or if the variability in pharmacokinetic (PK) parameter values cannot be used to define the target SC dose level. In Part 2 of the study, HER2-positive female participants will receive a single dose of SC Herceptin at the dose level defined in Part 1. Participants from Part 1 are eligible to enter Part 2 provided they receive the second (Part 2) study dose of Herceptin a minimum of 22 days after their first (Part 1) dose.

Official Title
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An Open-Label, Two-Part, Multi-Centre, Trastuzumab Dose-Finding Study in Healthy Male Volunteers and HER2 Positive Female Patients

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Herceptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Participants (Part 1 only) Males 18 to 45 to years of age Baseline left ventricular ejection fraction (LVEF) greater than (>) 60 percent (%) HER2-Positive Females (Parts 1 and 2) Females greater than or equal to (≥) 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status of 0 Previous non-metastatic operable primary invasive HER2-positive breast cancer Baseline LVEF >55% Exclusion Criteria: Healthy Participants (Part 1 only) Clinically significant abnormalities in laboratory test results or electrocardiogram History of significant allergies, gastrointestinal, renal, hepatic, cardiovascular, or pulmonary disease History of hypersensitivity or allergic reaction, spontaneous or following drug administration History of cardiac conditions HER2-Positive Females (Parts 1 and 2) Metastatic disease Concurrent other malignancy requiring therapy of any modality which may interfere with PK investigations or result in unexpected toxicity Use of Herceptin in previous 5 months Serious cardiac illness

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Cohort 1<br>Healthy male participants will receive Herceptin 6 mg/kg IV on Day 1. | Drug: Herceptin<br>* Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.<br>* Other names: Trastuzumab;|
| Experimental: Part 1: Cohort 2<br>Female participants with HER2-positive breast cancer will receive Herceptin 6 mg/kg IV on Day 1. | Drug: Herceptin<br>* Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.<br>* Other names: Trastuzumab;|
| Experimental: Part 1: Cohort 3<br>Healthy male participants will receive Herceptin 6 mg/kg SC on Day 1. | Drug: Herceptin<br>* Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.<br>* Other names: Trastuzumab;|
| Experimental: Part 1: Cohort 4<br>Healthy male participants will receive Herceptin 10 mg/kg SC on Day 1. | Drug: Herceptin<br>* Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.<br>* Other names: Trastuzumab;|
| Experimental: Part 1: Cohort 5<br>Healthy male participants will receive Herceptin SC at an adjusted dose level based on preliminary PK analysis of Cohorts 1, 2, 3, and 4. | Drug: Herceptin<br>* Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.<br>* Other names: Trastuzumab;|
| Experimental: Part 2: Cohort A<br>Female participants with HER2-positive breast cancer will receive Herceptin SC at the dose level determined in Part 1. | Drug: Herceptin<br>* Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.<br>* Other names: Trastuzumab;|
| Experimental: Part 2: Cohort B<br>Female participants with HER2-positive breast cancer will receive Herceptin SC at an adjusted dose level based on preliminary PK analysis of Cohort A. | Drug: Herceptin<br>* Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.<br>* Other names: Trastuzumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | AUCinf represents the area under the concentration-time curve of trastuzumab in serum over the time interval from 0 extrapolated to infinity. Values for AUCinf of trastuzumab were derived by non-compartmental analysis across all pharmacokinetic (PK) collections and expressed in days by micrograms per milliliter (days•μg/mL). | Predose (0 hours) and postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | CDay22 of trastuzumab was derived from the single PK collection on Day 22 and expressed in micrograms per milliliter (μg/mL). | Day 22 | 
| Maximum Observed Serum Concentration of Trastuzumab (Cmax) | Cmax of trastuzumab was derived across all post-dose PK collections and expressed in μg/mL. | Postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall) | 
| Time to Maximum Serum Concentration (Tmax) of Trastuzumab | Tmax of trastuzumab was based on the Cmax derived across all post-dose PK collections and expressed in hours. | Postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall) | 
| Terminal Elimination Half-Life (T1/2) of Trastuzumab | T1/2 of trastuzumab was measured as the time required for trastuzumab concentration to decrease by one-half. T1/2 was derived across all PK collections and expressed in hours. | Postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall) |