Breast Cancer
Conditions
Brief summary
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.
Interventions
DRUGHerceptin
Herceptin will be administered IV or SC at various dosages (depending upon the cohort to which the participant is assigned) on Day 1.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 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) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | Day 22 | CDay22 of trastuzumab was derived from the single PK collection on Day 22 and expressed in micrograms per milliliter (μg/mL). |
| Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 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) | Cmax of trastuzumab was derived across all post-dose PK collections and expressed in μg/mL. |
| Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 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) | 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 | 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) | 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. |
Countries
Australia, New Zealand
Participant flow
Pre-assignment details
Four participants were counted twice as they were treated in both Cohort 2 and Cohort A.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Cohort 1 Healthy male participants received Herceptin 6 mg/kg IV on Day 1. | 6 |
| Part 1: Cohort 2 Female participants with HER2-positive breast cancer received Herceptin 6 mg/kg IV on Day 1. | 6 |
| Part 1: Cohort 3 Healthy male participants received Herceptin 6 mg/kg SC on Day 1. | 6 |
| Part 1: Cohort 4 Healthy male participants received Herceptin 10 mg/kg SC on Day 1. | 6 |
| Part 1: Cohort 5 Healthy male participants received Herceptin 8 mg/kg SC on Day 1. | 6 |
| Part 2: Cohort A Female participants with HER2-positive breast cancer received Herceptin 8 mg/kg SC on Day 1. | 20 |
| Part 2: Cohort B Female participants with HER2-positive breast cancer received Herceptin 12 mg/kg SC on Day 1. | 20 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Part 1: Cohort 1 | Part 1: Cohort 2 | Part 1: Cohort 3 | Part 1: Cohort 4 | Part 1: Cohort 5 | Part 2: Cohort A | Part 2: Cohort B |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 41.2 years STANDARD_DEVIATION 14.85 | 22.7 years STANDARD_DEVIATION 2.58 | 46.2 years STANDARD_DEVIATION 5.19 | 25.7 years STANDARD_DEVIATION 9.29 | 23.0 years STANDARD_DEVIATION 6.16 | 22.0 years STANDARD_DEVIATION 4.34 | 50.7 years STANDARD_DEVIATION 7.21 | 51.6 years STANDARD_DEVIATION 9.04 |
| Gender Female | 46 Participants | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 20 Participants | 20 Participants |
| Gender Male | 24 Participants | 6 Participants | 0 Participants | 6 Participants | 6 Participants | 6 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 6 | 6 / 6 | 5 / 6 | 5 / 6 | 6 / 6 | 19 / 20 | 20 / 20 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 20 | 0 / 20 |
Outcome results
Primary
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)
Population: PK Population: All enrolled participants who adhered to the protocol (per protocol basis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 1610 days•μg/mL | Standard Deviation 303 |
| Part 1: Cohort 2 | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 1800 days•μg/mL | Standard Deviation 250 |
| Part 1: Cohort 3 | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 1350 days•μg/mL | Standard Deviation 320 |
| Part 1: Cohort 4 | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 2500 days•μg/mL | Standard Deviation 515 |
| Part 1: Cohort 5 | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 1960 days•μg/mL | Standard Deviation 244 |
| Part 2: Cohort A | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 2090 days•μg/mL | Standard Deviation 638 |
| Part 2: Cohort B | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab | 3550 days•μg/mL | Standard Deviation 982 |
Secondary
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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 | Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 150 μg/mL | Standard Deviation 14.4 |
| Part 1: Cohort 2 | Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 185 μg/mL | Standard Deviation 42.9 |
| Part 1: Cohort 3 | Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 66.8 μg/mL | Standard Deviation 11.4 |
| Part 1: Cohort 4 | Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 102 μg/mL | Standard Deviation 17.2 |
| Part 1: Cohort 5 | Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 82.0 μg/mL | Standard Deviation 11.3 |
| Part 2: Cohort A | Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 88.4 μg/mL | Standard Deviation 33.3 |
| Part 2: Cohort B | Maximum Observed Serum Concentration of Trastuzumab (Cmax) | 151 μg/mL | Standard Deviation 58.6 |
Secondary
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.
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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 | Terminal Elimination Half-Life (T1/2) of Trastuzumab | 254 hours | Standard Deviation 32.2 |
| Part 1: Cohort 2 | Terminal Elimination Half-Life (T1/2) of Trastuzumab | 244 hours | Standard Deviation 69.2 |
| Part 1: Cohort 3 | Terminal Elimination Half-Life (T1/2) of Trastuzumab | 227 hours | Standard Deviation 55.9 |
| Part 1: Cohort 4 | Terminal Elimination Half-Life (T1/2) of Trastuzumab | 240 hours | Standard Deviation 34.4 |
| Part 1: Cohort 5 | Terminal Elimination Half-Life (T1/2) of Trastuzumab | 236 hours | Standard Deviation 43.9 |
| Part 2: Cohort A | Terminal Elimination Half-Life (T1/2) of Trastuzumab | 241 hours | Standard Deviation 48.1 |
| Part 2: Cohort B | Terminal Elimination Half-Life (T1/2) of Trastuzumab | 270 hours | Standard Deviation 80.1 |
Secondary
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.
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)
Population: PK Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 | Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 1.65 hours |
| Part 1: Cohort 2 | Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 3.00 hours |
| Part 1: Cohort 3 | Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 156.00 hours |
| Part 1: Cohort 4 | Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 132.12 hours |
| Part 1: Cohort 5 | Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 96.00 hours |
| Part 2: Cohort A | Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 97.13 hours |
| Part 2: Cohort B | Time to Maximum Serum Concentration (Tmax) of Trastuzumab | 96.05 hours |
Secondary
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
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 | Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | 25.6 μg/mL | Standard Deviation 12.1 |
| Part 1: Cohort 2 | Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | 27.5 μg/mL | Standard Deviation 7.5 |
| Part 1: Cohort 3 | Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | 31.6 μg/mL | Standard Deviation 12 |
| Part 1: Cohort 4 | Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | 51.4 μg/mL | Standard Deviation 15.8 |
| Part 1: Cohort 5 | Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | 39.4 μg/mL | Standard Deviation 5.5 |
| Part 2: Cohort A | Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | 37.8 μg/mL | Standard Deviation 10.4 |
| Part 2: Cohort B | Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab | 60.8 μg/mL | Standard Deviation 22 |