Trial Outcomes & Findings for A Study to Evaluate Corrected QT Interval and Drug-Drug Interaction of Trastuzumab on Carboplatin in the Presence of Docetaxel in Patients With HER2-Positive Metastatic or Locally Advanced Inoperable Cancer (NCT NCT00927589)

Last Updated: 2015-12-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

59 participants

Primary outcome timeframe

Baseline, Cycle 1 Day 8 and Cycle 2 Day 1

Results posted on

2015-12-10

Participant Flow

Participant milestones

Participant milestones
Measure	Trastuzumab + Docetaxel + Carboplatin Trastuzumab was administered at an initial dose of 6 milligrams per kilogram (mg/kg) of body weight given by intravenous (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 milligrams per square meter (mg/m\^2) of body surface area (BSA) on Day 1 of each study treatment cycle. Carboplatin was administered as an IV dose at a target area under the concentration-versus-time curve (AUC) of 6 milligrams per milliliter per minute (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.
Overall Study STARTED	59
Overall Study COMPLETED	43
Overall Study NOT COMPLETED	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Trastuzumab + Docetaxel + Carboplatin Trastuzumab was administered at an initial dose of 6 milligrams per kilogram (mg/kg) of body weight given by intravenous (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 milligrams per square meter (mg/m\^2) of body surface area (BSA) on Day 1 of each study treatment cycle. Carboplatin was administered as an IV dose at a target area under the concentration-versus-time curve (AUC) of 6 milligrams per milliliter per minute (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.
Overall Study Death	1
Overall Study Physician Decision	1
Overall Study Withdrawal by Subject	3
Overall Study Adverse Event	2
Overall Study Disease Progression	8
Overall Study Non-compliance	1

Baseline Characteristics

A Study to Evaluate Corrected QT Interval and Drug-Drug Interaction of Trastuzumab on Carboplatin in the Presence of Docetaxel in Patients With HER2-Positive Metastatic or Locally Advanced Inoperable Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Trastuzumab + Docetaxel + Carboplatin n=59 Participants 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.
Age, Continuous	59.0 years STANDARD_DEVIATION 12.1 • n=5 Participants
Sex: Female, Male Female	33 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) at Trastuzumab Steady State	-8.4 milliseconds (msec) Interval -11.1 to -5.7

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=44 Participants 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.
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
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 outcome

Timeframe: 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

AUC0-6hr = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=44 Participants 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.
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 Hourmicrogram/milliliter (hrmcg/mL) Standard Deviation 28.63
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 Hourmicrogram/milliliter (hrmcg/mL) Standard Deviation 34.99

PRIMARY outcome

Timeframe: 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

Dose normalized Cmax is the maximum observed concentration of carboplatin in plasma normalized for different dose levels.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=44 Participants 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.
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
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 outcome

Timeframe: 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

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).

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=44 Participants 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.
Geometric Mean Ratio of Cmax/D of Carboplatin	1.02 ratio Interval 0.9 to 1.15

PRIMARY outcome

Timeframe: 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

AUC0-6hr/D = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion, normalized by carboplatin dose level.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=44 Participants 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.
Dose-Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin Cycle 1 Day 1 (in absence of trastuzumab)	19 (hrmcg/mL)/(minmg/mL) Standard Deviation 4.77
Dose-Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin Cycle 2 Day 1 (in presence of trastuzumab)	21 (hrmcg/mL)/(minmg/mL) Standard Deviation 5.83

PRIMARY outcome

Timeframe: 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

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).

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=44 Participants 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.
Geometric Mean Ratio of AUC0-6hr/D of Carboplatin	1.07 ratio Interval 0.96 to 1.18

PRIMARY outcome

Timeframe: 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.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=44 Participants 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.
Plasma Decay Half-Life (t1/2) of Carboplatin Cycle 1 Day 1 (in absence of trastuzumab) (n=44)	2 hr Standard Deviation 0.94
Plasma Decay Half-Life (t1/2) of Carboplatin Cycle 2 Day 1 (in presence of trastuzumab) (n=43)	2 hr Standard Deviation 1.12

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=57 Participants 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.
Maximum Observed Serum Concentration (Cmax) of Trastuzumab Cycle 1 Day 2 (n=57)	146.3 mcg/mL Interval 137.3 to 155.9
Maximum Observed Serum Concentration (Cmax) of Trastuzumab Cycle 1 Day 8 (n=51)	187.1 mcg/mL Interval 173.1 to 202.3
Maximum Observed Serum Concentration (Cmax) of Trastuzumab Cycle 2 Day 1 (n=48)	179.1 mcg/mL Interval 166.8 to 192.4
Maximum Observed Serum Concentration (Cmax) of Trastuzumab Cycle 3 Day 1 (n=42)	181.5 mcg/mL Interval 169.5 to 194.4

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=57 Participants 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.
Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab Cycle 1 Day 2 (n=57)	0.178 mcg/mL Interval 0.1 to 0.2
Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab Cycle 1 Day 8 (n=51)	38.8 mcg/mL Interval 30.7 to 49.2
Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab Cycle 2 Day 1 (n=48)	38.7 mcg/mL Interval 32.9 to 45.5
Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab Cycle 3 Day 1 (n=42)	29.7 mcg/mL Interval 24.5 to 36.1

SECONDARY outcome

Timeframe: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1

Population: ECG-evaluable participant population

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Change From Baseline in Corrected QT Interval Using Bazett's Correction (QTcB) at Trastuzumab Steady State	-5.9 msec Interval -9.2 to -2.6

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
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
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
Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration QTcF: Cycle 1 Day 8 (30 minutes postdose) (n=50)	-4.3 msec Standard Deviation 12.0
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
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
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
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
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
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
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
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
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
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
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
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
Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration QRS: Cycle 1 Day 2 (30 minutes postdose) (n=49)	-0.1 msec Standard Deviation 4.0
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
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
Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration QRS: Cycle 2 Day 1 (15 minutes predose) (n=48)	-0.5 msec Standard Deviation 5.0
Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration QRS: Cycle 2 Day 1 (30 minutes postdose) (n=48)	-0.3 msec Standard Deviation 6.0

SECONDARY outcome

Population: ECG-evaluable participant population. n=participants with available data at each timepoint.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Baseline-adjusted Heart Rate Cycle 1 Day 2 (30 minutes postdose) (n=49)	0.5 beats per minute (bpm) Standard Deviation 9.9
Baseline-adjusted Heart Rate Cycle 1 Day 8 (15 minutes predose) (n=50)	9.6 beats per minute (bpm) Standard Deviation 14.9
Baseline-adjusted Heart Rate Cycle 1 Day 8 (30 minutes postdose) (n=50)	6.2 beats per minute (bpm) Standard Deviation 13.7
Baseline-adjusted Heart Rate Cycle 2 Day 1 (15 minutes predose) (n=48)	3.1 beats per minute (bpm) Standard Deviation 12.7
Baseline-adjusted Heart Rate Cycle 2 Day 1 (30 minutes postdose) (n=48)	-0.7 beats per minute (bpm) Standard Deviation 12.1

SECONDARY outcome

Population: ECG-evaluable participant population. n=participants with available data at each timepoint.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Number of Participants Within Each Absolute QTc Interval Category QTcF<=450 msec: C1D2 30 min postdose (n=49)	44 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >450 to <=470 msec:C1D2 30min postdose (n=49)	4 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >470 to <=500 msec: C1D2 30min postdose(n=49)	1 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >500 msec: C1D2 30 min postdose (n=49)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF<=450 msec: C1D8 15 min predose (n=50)	49 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >450 to <=470 msec: C1D8 15 min predose(n=50)	1 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >470 to <=500 msec: C1D8 15 min predose(n=50)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >500 msec: C1D8 15 min predose (n=50)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF<=450 msec: C1D8 30 min postdose (n=50)	48 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >450 to <=470 msec: C1D8 30min postdose(n=50)	2 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >470 to <=500 msec: C1D8 30min postdose(n=50)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >500 msec: C1D8 30 min postdose (n=50)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF<=450 msec: C2D1 15 min predose (n=48)	48 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >450 to <=470 msec: C2D1 15 min predose(n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >470 to <=500 msec: C2D1 15 min predose(n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >500 msec: C2D1 15 min predose (n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF<=450 msec: C2D1 30 min postdose (n=48)	48 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >450 to <=470 msec: C2D1 30min postdose(n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >470 to <=500 msec: C2D1 30min postdose(n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcF >500 msec: C2D1 30 min postdose (n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB<=450 msec: C1D2 30 min postdose (n=49)	36 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >450 to <=470 msec:C1D2 30min postdose (n=49)	10 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >470 to <=500 msec: C1D2 30min postdose(n=49)	2 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >500 msec: C1D2 30 min postdose (n=49)	1 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB<=450 msec: C1D8 15 min predose (n=50)	41 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >450 to <=470 msec: C1D8 15 min predose(n=50)	7 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >470 to <=500 msec: C1D8 15 min predose(n=50)	2 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >500 msec: C1D8 15 min predose (n=50)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB<=450 msec: C1D8 30 min postdose (n=50)	39 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >450 to <=470 msec: C1D8 30min postdose(n=50)	9 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >470 to <=500 msec: C1D8 30min postdose(n=50)	2 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >500 msec: C1D8 30 min postdose (n=50)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB<=450 msec: C2D1 15 min predose (n=48)	43 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >450 to <=470 msec: C2D1 15 min predose(n=48)	4 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >470 to <=500 msec: C2D1 15 min predose(n=48)	1 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >500 msec: C2D1 15 min predose (n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB<=450 msec: C2D1 30 min postdose (n=48)	43 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >450 to <=470 msec: C2D1 30min postdose(n=48)	5 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >470 to <=500 msec: C2D1 30min postdose(n=48)	0 participants
Number of Participants Within Each Absolute QTc Interval Category QTcB >500 msec: C2D1 30 min postdose (n=48)	0 participants

SECONDARY outcome

Population: ECG-evaluable participant population. n=participants with available data at each timepoint.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Number of Participants With Increase From Baseline in QTc Interval QTcF<=30 msec: C1D2 30 min postdose (n=49)	49 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >30 to <=60 msec:C1D2 30 min postdose (n=49)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >60 msec: C1D2 30 min postdose (n=49)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF<=30 msec: C1D8 15 min predose (n=50)	50 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >30 to <=60 msec: C1D8 15 min predose (n=50)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >60 msec: C1D8 15 min predose (n=50)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF<=30 msec: C1D8 30 min postdose (n=50)	50 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >30 to <=60 msec: C1D8 30 min postdose (n=50)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >60 msec: C1D8 30 min postdose (n=50)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF<=30 msec: C2D1 15 min predose (n=48)	48 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >30 to <=60 msec: C2D1 15 min predose (n=48)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >60 msec: C2D1 15 min predose (n=48)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF<=30 msec: C2D1 30 min postdose (n=48)	48 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >30 to <=60 msec: C2D1 30min postdose (n=48)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcF >60 msec: C2D1 30 min postdose (n=48)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB<=30 msec: C1D2 30 min postdose (n=49)	49 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >30 to <=60 msec:C1D2 30 min postdose (n=49)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >60 msec: C1D2 30 min postdose (n=49)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB<=30 msec: C1D8 15 min predose (n=50)	50 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >30 to <=60 msec: C1D8 15 min predose (n=50)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >60 msec: C1D8 15 min predose (n=50)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB<=30 msec: C1D8 30 min postdose (n=50)	49 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >30 to <=60 msec: C1D8 30 min postdose (n=50)	1 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >60 msec: C1D8 30 min postdose (n=50)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB<=30 msec: C2D1 15 min predose (n=48)	48 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >30 to <=60 msec: C2D1 15 min predose (n=48)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >60 msec: C2D1 15 min predose (n=48)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB<=30 msec: C2D1 30 min postdose (n=48)	48 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >30 to <=60 msec: C2D1 30min postdose (n=48)	0 participants
Number of Participants With Increase From Baseline in QTc Interval QTcB >60 msec: C2D1 30 min postdose (n=48)	0 participants

SECONDARY outcome

Population: ECG-evaluable participant population. n=participants with available data at each timepoint.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Number of Participants With New Abnormal U Waves on ECG C2D1 30 min postdose (n=48)	0 participants
Number of Participants With New Abnormal U Waves on ECG C1D2 30 min postdose (n=49)	0 participants
Number of Participants With New Abnormal U Waves on ECG C1D8 15 min predose (n=50)	0 participants
Number of Participants With New Abnormal U Waves on ECG C1D8 30 min postdose (n=50)	0 participants
Number of Participants With New Abnormal U Waves on ECG C2D1 15 min predose (n=48)	0 participants

SECONDARY outcome

Population: ECG-evaluable participant population. n=participants with available data at each timepoint.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Number of Participants With New Abnormal T Waves on ECG C1D2 30 min postdose (n=49)	0 participants
Number of Participants With New Abnormal T Waves on ECG C1D8 15 min predose (n=50)	0 participants
Number of Participants With New Abnormal T Waves on ECG C1D8 30 min postdose (n=50)	0 participants
Number of Participants With New Abnormal T Waves on ECG C2D1 15 min predose (n=48)	0 participants
Number of Participants With New Abnormal T Waves on ECG C2D1 30 min postdose (n=48)	0 participants

SECONDARY outcome

Population: ECG-evaluable participant population. n=participants with available data at each timepoint.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Number of Participants With Abnormal Changes in PR Interval >=25% change: C1D2 30 min postdose (n=49)	0 participants
Number of Participants With Abnormal Changes in PR Interval Absolute value >200msec: C1D2 30min postdose(n=49)	2 participants
Number of Participants With Abnormal Changes in PR Interval >=25%change and >200msec:C1D2 30min postdose(n=49)	0 participants
Number of Participants With Abnormal Changes in PR Interval >=25% change: C1D8 15 min predose (n=50)	1 participants
Number of Participants With Abnormal Changes in PR Interval Absolute value >200msec: C1D8 15 min predose(n=50)	1 participants
Number of Participants With Abnormal Changes in PR Interval >=25%change and >200msec: C1D8 15min predose(n=50)	1 participants
Number of Participants With Abnormal Changes in PR Interval >=25% change: C1D8 30 min postdose (n=50)	0 participants
Number of Participants With Abnormal Changes in PR Interval Absolute value >200msec: C1D8 30min postdose(n=50)	1 participants
Number of Participants With Abnormal Changes in PR Interval >=25%change and >200msec:C1D8 30min postdose(n=50)	0 participants
Number of Participants With Abnormal Changes in PR Interval >=25% change: C2D1 15 min predose (n=48)	2 participants
Number of Participants With Abnormal Changes in PR Interval Absolute value >200msec: C2D1 15 min predose(n=48)	4 participants
Number of Participants With Abnormal Changes in PR Interval >=25%change and >200msec: C2D1 15min predose(n=48)	1 participants
Number of Participants With Abnormal Changes in PR Interval >=25% change: C2D1 30 min postdose (n=48)	2 participants
Number of Participants With Abnormal Changes in PR Interval Absolute value >200msec: C2D1 30min postdose(n=48)	4 participants
Number of Participants With Abnormal Changes in PR Interval >=25%change and >200msec:C2D1 30min postdose(n=48)	1 participants

SECONDARY outcome

Population: ECG-evaluable participant population. n=participants with available data at each timepoint.

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.

Outcome measures

Outcome measures
Measure	Trastuzumab + Docetaxel + Carboplatin n=53 Participants 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.
Number of Participants With Abnormal Changes in QRS Interval >=25% change: C1D2 30 min postdose (n=49)	0 participants
Number of Participants With Abnormal Changes in QRS Interval Absolute value >110msec: C1D2 30min postdose(n=49)	4 participants
Number of Participants With Abnormal Changes in QRS Interval >=25%change and >110msec:C1D2 30min postdose(n=49)	0 participants
Number of Participants With Abnormal Changes in QRS Interval >=25% change: C1D8 15 min predose (n=50)	0 participants
Number of Participants With Abnormal Changes in QRS Interval Absolute value >110msec: C1D8 15 min predose(n=50)	4 participants
Number of Participants With Abnormal Changes in QRS Interval >=25%change and >110msec: C1D8 15min predose(n=50)	0 participants
Number of Participants With Abnormal Changes in QRS Interval >=25% change: C1D8 30 min postdose (n=50)	0 participants
Number of Participants With Abnormal Changes in QRS Interval Absolute value >110msec: C1D8 30min postdose(n=50)	4 participants
Number of Participants With Abnormal Changes in QRS Interval >=25%change and >110msec:C1D8 30min postdose(n=50	0 participants
Number of Participants With Abnormal Changes in QRS Interval >=25% change: C2D1 15 min predose (n=48)	0 participants
Number of Participants With Abnormal Changes in QRS Interval Absolute value >110msec: C2D1 15 min predose(n=48)	4 participants
Number of Participants With Abnormal Changes in QRS Interval >=25%change and >110msec: C2D1 15min predose(n=48)	0 participants
Number of Participants With Abnormal Changes in QRS Interval >=25% change: C2D1 30 min postdose (n=48)	0 participants
Number of Participants With Abnormal Changes in QRS Interval Absolute value >110msec: C2D1 30min postdose(n=48)	4 participants
Number of Participants With Abnormal Changes in QRS Interval >=25%change and >110msec:C2D1 30min postdose(n=48)	0 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

Adverse Events

Trastuzumab + Docetaxel + Carboplatin

Serious events: 26 serious events

Other events: 56 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Trastuzumab + Docetaxel + Carboplatin n=58 participants at risk 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.
Gastrointestinal disorders Small intestinal obstruction	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Colitis	3.4% 2/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Constipation	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Diarrhoea	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Diverticular perforation	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Gastrointestinal haemorrhage	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Haematemesis	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Haemorrhoidal haemorrhage	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Nausea	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Oesophageal spasm	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Pancreatitis	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Vomiting	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Pneumonia	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Clostridium difficile colitis	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Peritonitis	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Urinary tract infection	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Urosepsis	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Blood and lymphatic system disorders Febrile neutropenia	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Dehydration	3.4% 2/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Diabetic ketoacidosis	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Hyperglycaemia	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Haemoglobin decreased	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations International normalised ratio increased	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Platelet count decreased	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Muscular weakness	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Pain in extremity	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Reproductive system and breast disorders Female genital tract fistula	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Reproductive system and breast disorders Vaginal haemorrhage	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Cardiac disorders Cardiac arrest	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Fatigue	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Injury, poisoning and procedural complications Electrical burn	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Nervous system disorders Haemorrhagic stroke	1.7% 1/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.

Other adverse events

Other adverse events
Measure	Trastuzumab + Docetaxel + Carboplatin n=58 participants at risk 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.
Investigations Neutrophil count decreased	63.8% 37/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Haemoglobin decreased	56.9% 33/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Platelet count decreased	39.7% 23/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations White blood cell count decreased	27.6% 16/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Weight decreased	12.1% 7/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Electrocardiogram QT prolonged	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Aspartate aminotransferase increased	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Blood alkaline phosphatase increased	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Investigations Gamma- glutamyltransferase increased	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Nausea	58.6% 34/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Diarrhoea	51.7% 30/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Vomiting	37.9% 22/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Constipation	19.0% 11/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Abdominal pain	17.2% 10/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Stomatitis	15.5% 9/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Dyspepsia	10.3% 6/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Abdominal distension	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Dry mouth	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Dysphagia	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Abdominal pain lower	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Abdominal pain upper	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Gastrooesophageal reflux disease	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Gastrointestinal disorders Haemorrhoidal haemorrhage	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Fatigue	53.4% 31/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Pyrexia	22.4% 13/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Oedema peripheral	17.2% 10/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Pain	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Chills	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Chest discomfort	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
General disorders Mucosal inflammation	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Decreased appetite	29.3% 17/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Dehydration	27.6% 16/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Hypomagnesaemia	24.1% 14/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Hypokalaemia	15.5% 9/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Hyponatraemia	15.5% 9/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Hypocalcaemia	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Hyperglycaemia	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Metabolism and nutrition disorders Iron deficiency	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Nervous system disorders Neuropathy peripheral	22.4% 13/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Nervous system disorders Dizziness	20.7% 12/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Nervous system disorders Dysgeusia	20.7% 12/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Nervous system disorders Headache	13.8% 8/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Nervous system disorders Peripheral sensory neuropathy	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Myalgia	20.7% 12/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Arthralgia	13.8% 8/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Back pain	12.1% 7/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Bone pain	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Pain in extremity	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Musculoskeletal and connective tissue disorders Muscular weakness	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Skin and subcutaneous tissue disorders Alopecia	31.0% 18/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Skin and subcutaneous tissue disorders Rash	13.8% 8/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Skin and subcutaneous tissue disorders Nail disorder	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Skin and subcutaneous tissue disorders Dry skin	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Skin and subcutaneous tissue disorders Pruritus	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Cough	15.5% 9/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.3% 6/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Epistaxis	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Hiccups	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Hypoxia	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Respiratory, thoracic and mediastinal disorders Nasal congestion	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Urinary tract infection	10.3% 6/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Sinusitis	8.6% 5/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Upper respiratory tract infection	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Candidiasis	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Infections and infestations Rhinitis	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Vascular disorders Hypotension	10.3% 6/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Vascular disorders Deep vein thrombosis	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Vascular disorders Flushing	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Vascular disorders Hypertension	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Eye disorders Lacrimation increased	15.5% 9/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Eye disorders Vision blurred	10.3% 6/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Psychiatric disorders Insomnia	10.3% 6/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Psychiatric disorders Anxiety	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Psychiatric disorders Depression	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Renal and urinary disorders Haematuria	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Renal and urinary disorders Proteinuria	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Injury, poisoning and procedural complications Infusion related reaction	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Blood and lymphatic system disorders Lymphopenia	6.9% 4/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.
Immune system disorders Drug hypersensitivity	5.2% 3/58 • Baseline up to study completion/early termination (28 to 42 days after the last administration of study treatment) (maximum treatment duration = 163 weeks) The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER