Solid Cancers
Conditions
Keywords
HER2+ Metastatic Cancer, HER2+ Locally Advanced Inoperable Cancer, HER2+ Solid Malignancy
Brief summary
This Phase Ib, multicenter, single-arm, open-label study is designed to evaluate the effect of trastuzumab on QTcF interval and to characterize the effects of trastuzumab on carboplatin pharmacokinetics in patients with HER2-positive metastatic or locally advanced inoperable cancer. The QT interval is a measure of time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QTcF interval is the QT interval as calculated using Fridericia's correction; the QTcB interval is the QT interval as calculated using Bazett's correction.
Interventions
DRUGcarboplatin
Intravenous repeating dose
DRUGdocetaxel
Intravenous repeating dose
DRUGtrastuzumab
Intravenous repeating dose
Sponsors
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic documentation of a HER2-positive solid malignancy in patients with metastatic or locally advanced inoperable disease * Left ventricular ejection fraction (LVEF) \>/= 50% by multiple-gated acquisition (MUGA) scan or two-dimensional echocardiography (ECHO) \</= 42 days prior to Cycle 1, Day 1
Exclusion criteria
* History of trastuzumab treatment \</= 100 days prior to Cycle 1, Day 1 * Pretreatment QTcF interval \> 450 ms as determined by local assessment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Serum Concentration (Cmax) of Trastuzumab | 30 (±15) minutes after the end of the infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1 | — |
| Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab | 15 (±15) minutes prior to the start of the trastuzumab infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1 | — |
| Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) at Trastuzumab Steady State | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 (C1D8) and Cycle 2 Day 1 (C2D1) after the trastuzumab infusion. |
| Maximum Observed Plasma Concentration (Cmax) of Carboplatin | 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab) | — |
| Area Under the Curve From Time Zero to 6 Hours Post Infusion (AUC0-6hr) of Carboplatin | 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab) | AUC0-6hr = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion. |
| Dose-Normalized Cmax (Cmax/D) of Carboplatin | 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab) | Dose normalized Cmax is the maximum observed concentration of carboplatin in plasma normalized for different dose levels. |
| Geometric Mean Ratio of Cmax/D of Carboplatin | 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab) | The geometric mean ratio of Cmax of carboplatin was defined as the Cmax/D of carboplatin on Cycle 1 Day 1 (in the absence of trastuzumab) divided by Cmax/D of carboplatin on Cycle 2 Day 1 (in the presence of trastuzumab). |
| Dose-Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin | 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab) | AUC0-6hr/D = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion, normalized by carboplatin dose level. |
| Geometric Mean Ratio of AUC0-6hr/D of Carboplatin | 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab) | The geometric mean ratio of AUC0-6hr/D of carboplatin was defined as the AUC0-6hr/D of carboplatin on Cycle 1 Day 1 (in the absence of trastuzumab) divided by AUC0-6hr/D of carboplatin on Cycle 2 Day 1 (in the presence of trastuzumab). |
| Plasma Decay Half-Life (t1/2) of Carboplatin | 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Corrected QT Interval Using Bazett's Correction (QTcB) at Trastuzumab Steady State | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Bazette's formula (QTcB = QT divided by square root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 and Cycle 2 Day 1 after the trastuzumab infusion. |
| Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | For each postbaseline timepoint, a participant's corresponding baseline measure was subtracted from his or her average of the triplicate ECG measure to create a baseline-adjusted corresponding ECG measure for each participant at each postbaseline timepoint. |
| Baseline-adjusted Heart Rate | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | For each postbaseline timepoint, a participant's corresponding baseline heart rate was subtracted from his or her average of the triplicate heart rate to create a baseline-adjusted corresponding heart rate for each participant at each postbaseline timepoint. |
| Number of Participants Within Each Absolute QTc Interval Category | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum QTc less than or equal to (\<=) 450 msec, greater than (\>) 450 to \<=470 msec, \>470 to \<= 500 msec, or \>500 msec were reported. |
| Number of Participants With Increase From Baseline in QTc Interval | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum increase from baseline of =\>30msec, 30 to \<60 msec (borderline) and \>=60 msec (prolonged) were summarized. |
| Number of Participants With New Abnormal U Waves on ECG | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | The incidence of abnormal U-wave changes from baseline was determined based on centrally read ECG tracings comparing each of the three triplicate readings from the post baseline ECG time points to the baseline ECG reading. At each time point, if at least one of the three triplicate readings was abnormal, the participant was counted as abnormal for that ECG timepoint as follows: a large U wave, inverted U wave, or T-U fusion compared with baseline was considered an abnormal significant change from baseline. |
| Number of Participants With New Abnormal T Waves on ECG | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | The incidence of abnormal T-wave changes from baseline was determined based on centrally read ECG tracings comparing each of the three triplicate readings from the post baseline ECG time points to the baseline ECG reading. At each time point, if at least one of the three triplicate readings was abnormal, the participant was counted as abnormal for that ECG timepoint as follows: an inverted T, flat T, or biphasic T compared with baseline was considered an abnormal significant change from baseline. Additionally, nonspecific T-wave changes from baseline were considered as abnormal nonsignificant changes from baseline. T-wave changes from baseline due to ventricular conduction or left ventricular hypertrophy strain were considered not evaluable. |
| Number of Participants With Abnormal Changes in PR Interval | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | Criteria for abnormal changes in PR interval were defined as: =\>25 percentage (%) change from baseline, an absolute value \>200 msec, or \>=25% change from baseline and an absolute value \>200 msec. |
| Number of Participants With Abnormal Changes in QRS Interval | Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose) | Criteria for abnormal changes in QRS interval were defined as: \>=25% change from baseline, an absolute value \>110 msec, or \>=25% change from baseline and an absolute value \>110 msec. |
| Population Pharmacokinetics of Trastuzumab | 15 (±15) minutes prior to the start of the trastuzumab infusion, and 30 (±15) minutes after the end of the infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1 | As per planned analysis, separate population pharmacokinetic analysis results are not available for the current study as this analysis is based on pooled data from multiple studies. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab + Docetaxel + Carboplatin Trastuzumab was administered at an initial dose of 6 mg/kg of body weight given by IV infusion over 90 (±10) minutes on Cycle 1 Day 2 and Cycle 1 Day 8, followed by a maintenance dose of 6 mg/kg given by IV infusion on Day 1 of each subsequent treatment cycle (every 21 \[±3\] days). Docetaxel was administered as an IV dose of 75 mg/m\^2 of BSA on Day 1 of each study treatment cycle. Carboplatin was administered as an IV dose at a target AUC of 6 mg/mL/min on Day 1 of each study treatment cycle. Study treatment continued until the Investigator decided to discontinue study therapy or for up to 12 months after the last participant was enrolled in the study, whichever came first. | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 1 |
| Overall Study | Disease Progression | 8 |
| Overall Study | Non-compliance | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Trastuzumab + Docetaxel + Carboplatin |
|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 56 / 58 |
| serious Total, serious adverse events | 26 / 58 |
Outcome results
Primary
Area Under the Curve From Time Zero to 6 Hours Post Infusion (AUC0-6hr) of Carboplatin
AUC0-6hr = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion.
Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Population: The PK analysis population for carboplatin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Area Under the Curve From Time Zero to 6 Hours Post Infusion (AUC0-6hr) of Carboplatin | Cycle 1 Day 1 (in absence of trastuzumab) | 115 Hour*microgram/milliliter (hr*mcg/mL) | Standard Deviation 28.63 |
| Trastuzumab + Docetaxel + Carboplatin | Area Under the Curve From Time Zero to 6 Hours Post Infusion (AUC0-6hr) of Carboplatin | Cycle 2 Day 1 (in presence of trastuzumab) | 123 Hour*microgram/milliliter (hr*mcg/mL) | Standard Deviation 34.99 |
Primary
Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) at Trastuzumab Steady State
Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 (C1D8) and Cycle 2 Day 1 (C2D1) after the trastuzumab infusion.
Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Population: ECG-evaluable participant population: received any trastuzumab, had at least 1 interpretable baseline ECG measurement recorded on C1D2 prior trastuzumab exposure, had at least 1 interpretable ECG measurement recorded on C1D8 or C2D1 corresponding to time of steady-state trastuzumab concentration, and no infusion reaction requiring drug treatments.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) at Trastuzumab Steady State | -8.4 milliseconds (msec) |
Primary
Dose-Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin
AUC0-6hr/D = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion, normalized by carboplatin dose level.
Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Population: The PK analysis population for carboplatin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Dose-Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin | Cycle 2 Day 1 (in presence of trastuzumab) | 21 (hr*mcg/mL)/(min*mg/mL) | Standard Deviation 5.83 |
| Trastuzumab + Docetaxel + Carboplatin | Dose-Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin | Cycle 1 Day 1 (in absence of trastuzumab) | 19 (hr*mcg/mL)/(min*mg/mL) | Standard Deviation 4.77 |
Primary
Dose-Normalized Cmax (Cmax/D) of Carboplatin
Dose normalized Cmax is the maximum observed concentration of carboplatin in plasma normalized for different dose levels.
Time frame: 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Population: The PK analysis population for carboplatin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Dose-Normalized Cmax (Cmax/D) of Carboplatin | Cycle 1 Day 1 (in absence of trastuzumab) | 9 (mcg/mL)/(min*mg/mL) | Standard Deviation 2.52 |
| Trastuzumab + Docetaxel + Carboplatin | Dose-Normalized Cmax (Cmax/D) of Carboplatin | Cycle 2 Day 1 (in presence of trastuzumab) | 9 (mcg/mL)/(min*mg/mL) | Standard Deviation 2.76 |
Primary
Geometric Mean Ratio of AUC0-6hr/D of Carboplatin
The geometric mean ratio of AUC0-6hr/D of carboplatin was defined as the AUC0-6hr/D of carboplatin on Cycle 1 Day 1 (in the absence of trastuzumab) divided by AUC0-6hr/D of carboplatin on Cycle 2 Day 1 (in the presence of trastuzumab).
Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Population: The PK analysis population for carboplatin
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Geometric Mean Ratio of AUC0-6hr/D of Carboplatin | 1.07 ratio |
Primary
Geometric Mean Ratio of Cmax/D of Carboplatin
The geometric mean ratio of Cmax of carboplatin was defined as the Cmax/D of carboplatin on Cycle 1 Day 1 (in the absence of trastuzumab) divided by Cmax/D of carboplatin on Cycle 2 Day 1 (in the presence of trastuzumab).
Time frame: 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Population: The PK analysis population for carboplatin
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Geometric Mean Ratio of Cmax/D of Carboplatin | 1.02 ratio |
Primary
Maximum Observed Plasma Concentration (Cmax) of Carboplatin
Time frame: 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Population: The pharmacokinetic (PK) analysis population for carboplatin included all participants who had a measurable ultrafiltrate or plasma carboplatin concentration at all nominal sampling time points. Participants for whom a full set of carboplatin PK samples in both Cycle 1 and Cycle 2 was not reported were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Maximum Observed Plasma Concentration (Cmax) of Carboplatin | Cycle 1 Day 1 (in absence of trastuzumab) | 51 Microgram per milliliter (mcg/mL) | Standard Deviation 15.13 |
| Trastuzumab + Docetaxel + Carboplatin | Maximum Observed Plasma Concentration (Cmax) of Carboplatin | Cycle 2 Day 1 (in presence of trastuzumab) | 52 Microgram per milliliter (mcg/mL) | Standard Deviation 16.58 |
Primary
Maximum Observed Serum Concentration (Cmax) of Trastuzumab
Time frame: 30 (±15) minutes after the end of the infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1
Population: The PK analysis population for trastuzumab included all participants who had at least 1 measurable serum trastuzumab concentration collected at a nominal sampling timepoint. Participants who did not receive a trastuzumab dose or for whom no trastuzumab PK samples were reported were excluded. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Maximum Observed Serum Concentration (Cmax) of Trastuzumab | Cycle 1 Day 2 (n=57) | 146.3 mcg/mL |
| Trastuzumab + Docetaxel + Carboplatin | Maximum Observed Serum Concentration (Cmax) of Trastuzumab | Cycle 1 Day 8 (n=51) | 187.1 mcg/mL |
| Trastuzumab + Docetaxel + Carboplatin | Maximum Observed Serum Concentration (Cmax) of Trastuzumab | Cycle 2 Day 1 (n=48) | 179.1 mcg/mL |
| Trastuzumab + Docetaxel + Carboplatin | Maximum Observed Serum Concentration (Cmax) of Trastuzumab | Cycle 3 Day 1 (n=42) | 181.5 mcg/mL |
Primary
Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab
Time frame: 15 (±15) minutes prior to the start of the trastuzumab infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1
Population: PK analysis population for trastuzumab. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab | Cycle 1 Day 2 (n=57) | 0.178 mcg/mL |
| Trastuzumab + Docetaxel + Carboplatin | Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab | Cycle 1 Day 8 (n=51) | 38.8 mcg/mL |
| Trastuzumab + Docetaxel + Carboplatin | Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab | Cycle 2 Day 1 (n=48) | 38.7 mcg/mL |
| Trastuzumab + Docetaxel + Carboplatin | Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab | Cycle 3 Day 1 (n=42) | 29.7 mcg/mL |
Primary
Plasma Decay Half-Life (t1/2) of Carboplatin
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Population: The PK analysis population for carboplatin. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Plasma Decay Half-Life (t1/2) of Carboplatin | Cycle 1 Day 1 (in absence of trastuzumab) (n=44) | 2 hr | Standard Deviation 0.94 |
| Trastuzumab + Docetaxel + Carboplatin | Plasma Decay Half-Life (t1/2) of Carboplatin | Cycle 2 Day 1 (in presence of trastuzumab) (n=43) | 2 hr | Standard Deviation 1.12 |
Secondary
Baseline-adjusted Heart Rate
For each postbaseline timepoint, a participant's corresponding baseline heart rate was subtracted from his or her average of the triplicate heart rate to create a baseline-adjusted corresponding heart rate for each participant at each postbaseline timepoint.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted Heart Rate | Cycle 1 Day 2 (30 minutes postdose) (n=49) | 0.5 beats per minute (bpm) | Standard Deviation 9.9 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted Heart Rate | Cycle 1 Day 8 (15 minutes predose) (n=50) | 9.6 beats per minute (bpm) | Standard Deviation 14.9 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted Heart Rate | Cycle 1 Day 8 (30 minutes postdose) (n=50) | 6.2 beats per minute (bpm) | Standard Deviation 13.7 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted Heart Rate | Cycle 2 Day 1 (15 minutes predose) (n=48) | 3.1 beats per minute (bpm) | Standard Deviation 12.7 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted Heart Rate | Cycle 2 Day 1 (30 minutes postdose) (n=48) | -0.7 beats per minute (bpm) | Standard Deviation 12.1 |
Secondary
Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration
For each postbaseline timepoint, a participant's corresponding baseline measure was subtracted from his or her average of the triplicate ECG measure to create a baseline-adjusted corresponding ECG measure for each participant at each postbaseline timepoint.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcF: Cycle 1 Day 2 (30 minutes postdose) (n=49) | 3.5 msec | Standard Deviation 11.8 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcF: Cycle 1 Day 8 (15 minutes predose) (n=50) | -9.3 msec | Standard Deviation 12.1 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcF: Cycle 1 Day 8 (30 minutes postdose) (n=50) | -4.3 msec | Standard Deviation 12 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcF: Cycle 2 Day 1 (15 minutes predose) (n=48) | -15.6 msec | Standard Deviation 13.3 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcF: Cycle 2 Day 1 (30 minutes postdose) (n=48) | -13.4 msec | Standard Deviation 14.6 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcB: Cycle 1 Day 2 (30 minutes postdose) (n=49) | 3.9 msec | Standard Deviation 9.7 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcB: Cycle 1 Day 8 (15 minutes predose) (n=50) | -0.8 msec | Standard Deviation 14.5 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcB: Cycle 1 Day 8 (30 minutes postdose) (n=50) | 1.4 msec | Standard Deviation 14.6 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcB: Cycle 2 Day 1 (15 minutes predose) (n=48) | -13.2 msec | Standard Deviation 16.6 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QTcB: Cycle 2 Day 1 (30 minutes postdose) (n=48) | -14.2 msec | Standard Deviation 18.6 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | PR: Cycle 1 Day 2 (30 minutes postdose) (n=49) | -0.1 msec | Standard Deviation 9.4 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | PR: Cycle 1 Day 8 (15 minutes predose) (n=50) | 1.4 msec | Standard Deviation 14.6 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | PR: Cycle 1 Day 8 (30 minutes postdose) (n=50) | 4.2 msec | Standard Deviation 11.8 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | PR: Cycle 2 Day 1 (15 minutes predose) (n=48) | 9.7 msec | Standard Deviation 13.1 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | PR: Cycle 2 Day 1 (30 minutes postdose) (n=48) | 13.7 msec | Standard Deviation 16.1 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QRS: Cycle 1 Day 2 (30 minutes postdose) (n=49) | -0.1 msec | Standard Deviation 4 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QRS: Cycle 1 Day 8 (15 minutes predose) (n=50) | -1.8 msec | Standard Deviation 5.5 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QRS: Cycle 1 Day 8 (30 minutes postdose) (n=50) | -1.8 msec | Standard Deviation 5.8 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QRS: Cycle 2 Day 1 (15 minutes predose) (n=48) | -0.5 msec | Standard Deviation 5 |
| Trastuzumab + Docetaxel + Carboplatin | Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration | QRS: Cycle 2 Day 1 (30 minutes postdose) (n=48) | -0.3 msec | Standard Deviation 6 |
Secondary
Change From Baseline in Corrected QT Interval Using Bazett's Correction (QTcB) at Trastuzumab Steady State
Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Bazette's formula (QTcB = QT divided by square root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 and Cycle 2 Day 1 after the trastuzumab infusion.
Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Population: ECG-evaluable participant population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Change From Baseline in Corrected QT Interval Using Bazett's Correction (QTcB) at Trastuzumab Steady State | -5.9 msec |
Secondary
Number of Participants With Abnormal Changes in PR Interval
Criteria for abnormal changes in PR interval were defined as: =\>25 percentage (%) change from baseline, an absolute value \>200 msec, or \>=25% change from baseline and an absolute value \>200 msec.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25% change: C1D8 15 min predose (n=50) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25% change: C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | Absolute value >200msec: C1D2 30min postdose(n=49) | 2 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25%change and >200msec:C1D2 30min postdose(n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | Absolute value >200msec: C1D8 15 min predose(n=50) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25%change and >200msec: C1D8 15min predose(n=50) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25% change: C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | Absolute value >200msec: C1D8 30min postdose(n=50) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25%change and >200msec:C1D8 30min postdose(n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25% change: C2D1 15 min predose (n=48) | 2 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | Absolute value >200msec: C2D1 15 min predose(n=48) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25%change and >200msec: C2D1 15min predose(n=48) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25% change: C2D1 30 min postdose (n=48) | 2 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | Absolute value >200msec: C2D1 30min postdose(n=48) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in PR Interval | >=25%change and >200msec:C2D1 30min postdose(n=48) | 1 participants |
Secondary
Number of Participants With Abnormal Changes in QRS Interval
Criteria for abnormal changes in QRS interval were defined as: \>=25% change from baseline, an absolute value \>110 msec, or \>=25% change from baseline and an absolute value \>110 msec.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25% change: C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | Absolute value >110msec: C1D2 30min postdose(n=49) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25%change and >110msec:C1D2 30min postdose(n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25% change: C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | Absolute value >110msec: C1D8 15 min predose(n=50) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25%change and >110msec: C1D8 15min predose(n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25% change: C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | Absolute value >110msec: C1D8 30min postdose(n=50) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25%change and >110msec:C1D8 30min postdose(n=50 | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25% change: C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | Absolute value >110msec: C2D1 15 min predose(n=48) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25%change and >110msec: C2D1 15min predose(n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25% change: C2D1 30 min postdose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | Absolute value >110msec: C2D1 30min postdose(n=48) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Abnormal Changes in QRS Interval | >=25%change and >110msec:C2D1 30min postdose(n=48) | 0 participants |
Secondary
Number of Participants With Increase From Baseline in QTc Interval
Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum increase from baseline of =\>30msec, 30 to \<60 msec (borderline) and \>=60 msec (prolonged) were summarized.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF<=30 msec: C1D2 30 min postdose (n=49) | 49 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >30 to <=60 msec:C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >60 msec: C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF<=30 msec: C1D8 15 min predose (n=50) | 50 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >30 to <=60 msec: C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >60 msec: C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF<=30 msec: C1D8 30 min postdose (n=50) | 50 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >30 to <=60 msec: C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >60 msec: C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF<=30 msec: C2D1 15 min predose (n=48) | 48 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >30 to <=60 msec: C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >60 msec: C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF<=30 msec: C2D1 30 min postdose (n=48) | 48 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >30 to <=60 msec: C2D1 30min postdose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcF >60 msec: C2D1 30 min postdose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB<=30 msec: C1D2 30 min postdose (n=49) | 49 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >30 to <=60 msec:C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >60 msec: C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB<=30 msec: C1D8 15 min predose (n=50) | 50 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >30 to <=60 msec: C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >60 msec: C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB<=30 msec: C1D8 30 min postdose (n=50) | 49 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >30 to <=60 msec: C1D8 30 min postdose (n=50) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >60 msec: C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB<=30 msec: C2D1 15 min predose (n=48) | 48 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >30 to <=60 msec: C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >60 msec: C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB<=30 msec: C2D1 30 min postdose (n=48) | 48 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >30 to <=60 msec: C2D1 30min postdose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With Increase From Baseline in QTc Interval | QTcB >60 msec: C2D1 30 min postdose (n=48) | 0 participants |
Secondary
Number of Participants Within Each Absolute QTc Interval Category
Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum QTc less than or equal to (\<=) 450 msec, greater than (\>) 450 to \<=470 msec, \>470 to \<= 500 msec, or \>500 msec were reported.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF<=450 msec: C1D2 30 min postdose (n=49) | 44 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >450 to <=470 msec:C1D2 30min postdose (n=49) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >470 to <=500 msec: C1D2 30min postdose(n=49) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >500 msec: C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF<=450 msec: C1D8 15 min predose (n=50) | 49 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >450 to <=470 msec: C1D8 15 min predose(n=50) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >470 to <=500 msec: C1D8 15 min predose(n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >500 msec: C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF<=450 msec: C1D8 30 min postdose (n=50) | 48 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >450 to <=470 msec: C1D8 30min postdose(n=50) | 2 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >470 to <=500 msec: C1D8 30min postdose(n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >500 msec: C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF<=450 msec: C2D1 15 min predose (n=48) | 48 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >450 to <=470 msec: C2D1 15 min predose(n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >470 to <=500 msec: C2D1 15 min predose(n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >500 msec: C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF<=450 msec: C2D1 30 min postdose (n=48) | 48 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >450 to <=470 msec: C2D1 30min postdose(n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >470 to <=500 msec: C2D1 30min postdose(n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcF >500 msec: C2D1 30 min postdose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB<=450 msec: C1D2 30 min postdose (n=49) | 36 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >450 to <=470 msec:C1D2 30min postdose (n=49) | 10 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >470 to <=500 msec: C1D2 30min postdose(n=49) | 2 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >500 msec: C1D2 30 min postdose (n=49) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB<=450 msec: C1D8 15 min predose (n=50) | 41 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >450 to <=470 msec: C1D8 15 min predose(n=50) | 7 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >470 to <=500 msec: C1D8 15 min predose(n=50) | 2 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >500 msec: C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB<=450 msec: C1D8 30 min postdose (n=50) | 39 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >450 to <=470 msec: C1D8 30min postdose(n=50) | 9 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >470 to <=500 msec: C1D8 30min postdose(n=50) | 2 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >500 msec: C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB<=450 msec: C2D1 15 min predose (n=48) | 43 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >450 to <=470 msec: C2D1 15 min predose(n=48) | 4 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >470 to <=500 msec: C2D1 15 min predose(n=48) | 1 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >500 msec: C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB<=450 msec: C2D1 30 min postdose (n=48) | 43 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >450 to <=470 msec: C2D1 30min postdose(n=48) | 5 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >470 to <=500 msec: C2D1 30min postdose(n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants Within Each Absolute QTc Interval Category | QTcB >500 msec: C2D1 30 min postdose (n=48) | 0 participants |
Secondary
Number of Participants With New Abnormal T Waves on ECG
The incidence of abnormal T-wave changes from baseline was determined based on centrally read ECG tracings comparing each of the three triplicate readings from the post baseline ECG time points to the baseline ECG reading. At each time point, if at least one of the three triplicate readings was abnormal, the participant was counted as abnormal for that ECG timepoint as follows: an inverted T, flat T, or biphasic T compared with baseline was considered an abnormal significant change from baseline. Additionally, nonspecific T-wave changes from baseline were considered as abnormal nonsignificant changes from baseline. T-wave changes from baseline due to ventricular conduction or left ventricular hypertrophy strain were considered not evaluable.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal T Waves on ECG | C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal T Waves on ECG | C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal T Waves on ECG | C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal T Waves on ECG | C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal T Waves on ECG | C2D1 30 min postdose (n=48) | 0 participants |
Secondary
Number of Participants With New Abnormal U Waves on ECG
The incidence of abnormal U-wave changes from baseline was determined based on centrally read ECG tracings comparing each of the three triplicate readings from the post baseline ECG time points to the baseline ECG reading. At each time point, if at least one of the three triplicate readings was abnormal, the participant was counted as abnormal for that ECG timepoint as follows: a large U wave, inverted U wave, or T-U fusion compared with baseline was considered an abnormal significant change from baseline.
Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)
Population: ECG-evaluable participant population. n=participants with available data at each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal U Waves on ECG | C1D2 30 min postdose (n=49) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal U Waves on ECG | C1D8 15 min predose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal U Waves on ECG | C1D8 30 min postdose (n=50) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal U Waves on ECG | C2D1 15 min predose (n=48) | 0 participants |
| Trastuzumab + Docetaxel + Carboplatin | Number of Participants With New Abnormal U Waves on ECG | C2D1 30 min postdose (n=48) | 0 participants |
Secondary
Population Pharmacokinetics of Trastuzumab
As per planned analysis, separate population pharmacokinetic analysis results are not available for the current study as this analysis is based on pooled data from multiple studies.
Time frame: 15 (±15) minutes prior to the start of the trastuzumab infusion, and 30 (±15) minutes after the end of the infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1