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

Hoffmann-La Roche66 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Breast Cancer

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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).

Time frame: 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 Outcomes

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).

Time frame: 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.

Time frame: 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.

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.