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Trastuzumab

Carboplatin

Docetaxel

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carboplatin

docetaxel

trastuzumab

Harald Weber, M.D.

This Phase Ib, multicenter, single-arm, open-label study is designed to evaluate the effect of trastuzumab on QTcF interval and to characterize the effects of trastuzumab on carboplatin pharmacokinetics in patients with HER2-positive metastatic or locally advanced inoperable cancer.

The QT interval is a measure of time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QTcF interval is the QT interval as calculated using Fridericia's correction; the QTcB interval is the QT interval as calculated using Bazett's correction.

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

A Phase 1b, Single-arm, Open-label Clinical Trial to Evaluate Corrected QT Interval and Drug-drug Interaction of Trastuzumab on Carboplatin in the Presence of Docetaxel in Patients With Metastatic Cancer

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.

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

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

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).

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

The geometric mean ratio of AUC0-6hr/D of carboplatin was defined as the AUC0-6hr/D of carboplatin on Cycle 1 Day 1 (in the absence of trastuzumab) divided by AUC0-6hr/D of carboplatin on Cycle 2 Day 1 (in the presence of trastuzumab).

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Genentech, Inc.

The safety-evaluable participant analysis population included all participants who were treated with at least one dose of any treatment of the study regimen.

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.

Trastuzumab + Docetaxel + Carboplatin

Age, Continuous

Sex: Female, Male

Medical Communications

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.

Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) at Trastuzumab Steady State

Cycle 1 Day 1 (in absence of trastuzumab)

Cycle 2 Day 1 (in presence of trastuzumab)

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.

Maximum Observed Plasma Concentration (Cmax) of Carboplatin

The PK analysis population for carboplatin

Area Under the Curve From Time Zero to 6 Hours Post Infusion (AUC0-6hr) of Carboplatin

Dose-Normalized Cmax (Cmax/D) of Carboplatin

Change From Baseline in Corrected QT Interval Using Bazett's Correction (QTcB) at Trastuzumab Steady State

QTcF: Cycle 1 Day 2 (30 minutes postdose) (n=49)

QTcF: Cycle 1 Day 8 (15 minutes predose) (n=50)

QTcF: Cycle 1 Day 8 (30 minutes postdose) (n=50)

QTcF: Cycle 2 Day 1 (15 minutes predose) (n=48)

QTcF: Cycle 2 Day 1 (30 minutes postdose) (n=48)

QTcB: Cycle 1 Day 2 (30 minutes postdose) (n=49)

QTcB: Cycle 1 Day 8 (15 minutes predose) (n=50)

QTcB: Cycle 1 Day 8 (30 minutes postdose) (n=50)

QTcB: Cycle 2 Day 1 (15 minutes predose) (n=48)

QTcB: Cycle 2 Day 1 (30 minutes postdose) (n=48)

PR: Cycle 1 Day 2 (30 minutes postdose) (n=49)

PR: Cycle 1 Day 8 (15 minutes predose) (n=50)

PR: Cycle 1 Day 8 (30 minutes postdose) (n=50)

PR: Cycle 2 Day 1 (15 minutes predose) (n=48)

PR: Cycle 2 Day 1 (30 minutes postdose) (n=48)

QRS: Cycle 1 Day 2 (30 minutes postdose) (n=49)

QRS: Cycle 1 Day 8 (15 minutes predose) (n=50)

QRS: Cycle 1 Day 8 (30 minutes postdose) (n=50)

QRS: Cycle 2 Day 1 (15 minutes predose) (n=48)

QRS: Cycle 2 Day 1 (30 minutes postdose) (n=48)

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

Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration

Cycle 1 Day 2 (30 minutes postdose) (n=49)

Cycle 1 Day 8 (15 minutes predose) (n=50)

Cycle 1 Day 8 (30 minutes postdose) (n=50)

Cycle 2 Day 1 (15 minutes predose) (n=48)

Cycle 2 Day 1 (30 minutes postdose) (n=48)

Baseline-adjusted Heart Rate

QTcF<=450 msec: C1D2 30 min postdose (n=49)

QTcF >450 to <=470 msec:C1D2 30min postdose (n=49)

QTcF >470 to <=500 msec: C1D2 30min postdose(n=49)

QTcF >500 msec: C1D2 30 min postdose (n=49)

QTcF<=450 msec: C1D8 15 min predose (n=50)

QTcF >450 to <=470 msec: C1D8 15 min predose(n=50)

QTcF >470 to <=500 msec: C1D8 15 min predose(n=50)

QTcF >500 msec: C1D8 15 min predose (n=50)

QTcF<=450 msec: C1D8 30 min postdose (n=50)

QTcF >450 to <=470 msec: C1D8 30min postdose(n=50)

QTcF >470 to <=500 msec: C1D8 30min postdose(n=50)

QTcF >500 msec: C1D8 30 min postdose (n=50)

QTcF<=450 msec: C2D1 15 min predose (n=48)

QTcF >450 to <=470 msec: C2D1 15 min predose(n=48)

QTcF >470 to <=500 msec: C2D1 15 min predose(n=48)

QTcF >500 msec: C2D1 15 min predose (n=48)

QTcF<=450 msec: C2D1 30 min postdose (n=48)

QTcF >450 to <=470 msec: C2D1 30min postdose(n=48)

QTcF >470 to <=500 msec: C2D1 30min postdose(n=48)

QTcF >500 msec: C2D1 30 min postdose (n=48)

QTcB<=450 msec: C1D2 30 min postdose (n=49)

QTcB >450 to <=470 msec:C1D2 30min postdose (n=49)

QTcB >470 to <=500 msec: C1D2 30min postdose(n=49)

QTcB >500 msec: C1D2 30 min postdose (n=49)

QTcB<=450 msec: C1D8 15 min predose (n=50)

QTcB >450 to <=470 msec: C1D8 15 min predose(n=50)

QTcB >470 to <=500 msec: C1D8 15 min predose(n=50)

QTcB >500 msec: C1D8 15 min predose (n=50)

QTcB<=450 msec: C1D8 30 min postdose (n=50)

QTcB >450 to <=470 msec: C1D8 30min postdose(n=50)

QTcB >470 to <=500 msec: C1D8 30min postdose(n=50)

QTcB >500 msec: C1D8 30 min postdose (n=50)

QTcB<=450 msec: C2D1 15 min predose (n=48)

QTcB >450 to <=470 msec: C2D1 15 min predose(n=48)

QTcB >470 to <=500 msec: C2D1 15 min predose(n=48)

QTcB >500 msec: C2D1 15 min predose (n=48)

QTcB<=450 msec: C2D1 30 min postdose (n=48)

QTcB >450 to <=470 msec: C2D1 30min postdose(n=48)

QTcB >470 to <=500 msec: C2D1 30min postdose(n=48)

QTcB >500 msec: C2D1 30 min postdose (n=48)

Number of Participants Within Each Absolute QTc Interval Category

QTcF<=30 msec: C1D2 30 min postdose (n=49)

QTcF >30 to <=60 msec:C1D2 30 min postdose (n=49)

QTcF >60 msec: C1D2 30 min postdose (n=49)

QTcF<=30 msec: C1D8 15 min predose (n=50)

QTcF >30 to <=60 msec: C1D8 15 min predose (n=50)

QTcF >60 msec: C1D8 15 min predose (n=50)

QTcF<=30 msec: C1D8 30 min postdose (n=50)

QTcF >30 to <=60 msec: C1D8 30 min postdose (n=50)

QTcF >60 msec: C1D8 30 min postdose (n=50)

QTcF<=30 msec: C2D1 15 min predose (n=48)

QTcF >30 to <=60 msec: C2D1 15 min predose (n=48)

QTcF >60 msec: C2D1 15 min predose (n=48)

QTcF<=30 msec: C2D1 30 min postdose (n=48)

QTcF >30 to <=60 msec: C2D1 30min postdose (n=48)

QTcF >60 msec: C2D1 30 min postdose (n=48)

QTcB<=30 msec: C1D2 30 min postdose (n=49)

QTcB >30 to <=60 msec:C1D2 30 min postdose (n=49)

QTcB >60 msec: C1D2 30 min postdose (n=49)

QTcB<=30 msec: C1D8 15 min predose (n=50)

QTcB >30 to <=60 msec: C1D8 15 min predose (n=50)

QTcB >60 msec: C1D8 15 min predose (n=50)

QTcB<=30 msec: C1D8 30 min postdose (n=50)

QTcB >30 to <=60 msec: C1D8 30 min postdose (n=50)

QTcB >60 msec: C1D8 30 min postdose (n=50)

QTcB<=30 msec: C2D1 15 min predose (n=48)

QTcB >30 to <=60 msec: C2D1 15 min predose (n=48)

QTcB >60 msec: C2D1 15 min predose (n=48)

QTcB<=30 msec: C2D1 30 min postdose (n=48)

QTcB >30 to <=60 msec: C2D1 30min postdose (n=48)

QTcB >60 msec: C2D1 30 min postdose (n=48)

Number of Participants With Increase From Baseline in QTc Interval

C1D2 30 min postdose (n=49)

C1D8 15 min predose (n=50)

C1D8 30 min postdose (n=50)

C2D1 15 min predose (n=48)

C2D1 30 min postdose (n=48)

Number of Participants With New Abnormal U Waves on ECG

Number of Participants With New Abnormal T Waves on ECG

>=25% change: C1D2 30 min postdose (n=49)

Absolute value >200msec: C1D2 30min postdose(n=49)

>=25%change and >200msec:C1D2 30min postdose(n=49)

>=25% change: C1D8 15 min predose (n=50)

Absolute value >200msec: C1D8 15 min predose(n=50)

>=25%change and >200msec: C1D8 15min predose(n=50)

>=25% change: C1D8 30 min postdose (n=50)

Absolute value >200msec: C1D8 30min postdose(n=50)

>=25%change and >200msec:C1D8 30min postdose(n=50)

>=25% change: C2D1 15 min predose (n=48)

Absolute value >200msec: C2D1 15 min predose(n=48)

>=25%change and >200msec: C2D1 15min predose(n=48)

>=25% change: C2D1 30 min postdose (n=48)

Absolute value >200msec: C2D1 30min postdose(n=48)

>=25%change and >200msec:C2D1 30min postdose(n=48)

Number of Participants With Abnormal Changes in PR Interval

Absolute value >110msec: C1D2 30min postdose(n=49)

>=25%change and >110msec:C1D2 30min postdose(n=49)

Absolute value >110msec: C1D8 15 min predose(n=50)

>=25%change and >110msec: C1D8 15min predose(n=50)

Absolute value >110msec: C1D8 30min postdose(n=50)

>=25%change and >110msec:C1D8 30min postdose(n=50

Absolute value >110msec: C2D1 15 min predose(n=48)

>=25%change and >110msec: C2D1 15min predose(n=48)

Absolute value >110msec: C2D1 30min postdose(n=48)

>=25%change and >110msec:C2D1 30min postdose(n=48)

Number of Participants With Abnormal Changes in QRS Interval

Population Pharmacokinetics of Trastuzumab

Geometric Mean Ratio of Cmax/D of Carboplatin

Dose-Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin

Geometric Mean Ratio of AUC0-6hr/D of Carboplatin

Cycle 1 Day 1 (in absence of trastuzumab) (n=44)

Cycle 2 Day 1 (in presence of trastuzumab) (n=43)

The PK analysis population for carboplatin. n=participants with available data at each timepoint.

Plasma Decay Half-Life (t1/2) of Carboplatin

Cycle 1 Day 2 (n=57)

Cycle 1 Day 8 (n=51)

Cycle 2 Day 1 (n=48)

Cycle 3 Day 1 (n=42)

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.

Maximum Observed Serum Concentration (Cmax) of Trastuzumab

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT00927589	Solid Cancers	carboplatin docetaxel trastuzumab	18 Years -	Genentech, Inc.
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	NCT00927589	Solid Cancers	carboplatin docetaxel trastuzumab	18 Years -	Genentech, Inc.

Spots Global Cancer Trial Database for her2+ locally advanced inoperable cancer