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

Genentech, Inc.59 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Solid Cancers

Interventions

carboplatin

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologic documentation of a HER2-positive solid malignancy in patients with metastatic or locally advanced inoperable disease * Left ventricular ejection fraction (LVEF) \>/= 50% by multiple-gated acquisition (MUGA) scan or two-dimensional echocardiography (ECHO) \</= 42 days prior to Cycle 1, Day 1 Exclusion Criteria: * History of trastuzumab treatment \</= 100 days prior to Cycle 1, Day 1 * Pretreatment QTcF interval \> 450 ms as determined by local assessment

Locations (20)

Unnamed facility

Scottsdale, Arizona, United States

Unnamed facility

Beverly Hills, California, United States

Unnamed facility

La Jolla, California, United States

Unnamed facility

San Diego, California, United States

Unnamed facility

Santa Rosa, California, United States

Unnamed facility

Whittier, California, United States

Unnamed facility

Miami, Florida, United States

Unnamed facility

Wichita, Kansas, United States

Unnamed facility

Billings, Montana, United States

Unnamed facility

Farmington, New Mexico, United States

...and 10 more locations

Outcomes

Primary Outcomes

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

Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 (C1D8) and Cycle 2 Day 1 (C2D1) after the trastuzumab infusion.

Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1

Maximum Observed Plasma Concentration (Cmax) of Carboplatin

Time frame: 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)

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

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

Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)

Dose-Normalized Cmax (Cmax/D) of Carboplatin

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

Time frame: 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)

Geometric Mean Ratio of Cmax/D of Carboplatin

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

Time frame: 0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)

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

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

Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)

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

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

Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)

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

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

Time frame: 0 to 5, 60 (±5), 120 (±10), 240 (±10), and 360 (±15) minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)

Maximum Observed Serum Concentration (Cmax) of Trastuzumab

Time frame: 30 (±15) minutes after the end of the infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1

Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab

Time frame: 15 (±15) minutes prior to the start of the trastuzumab infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1

Secondary Outcomes

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

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Bazette's formula (QTcB = QT divided by square root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 and Cycle 2 Day 1 after the trastuzumab infusion.

Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1

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

For each postbaseline timepoint, a participant's corresponding baseline measure was subtracted from his or her average of the triplicate ECG measure to create a "baseline-adjusted" corresponding ECG measure for each participant at each postbaseline timepoint.

Time frame: Baseline, Cycle 1 Day 2 (30 minutes postdose), Cycle 1 Day 8 (15 minutes predose), Cycle 1 Day 8 (30 minutes postdose), Cycle 2 Day 1 (15 minutes predose), and Cycle 2 Day 1 (30 minutes postdose)

Baseline-adjusted Heart Rate

For each postbaseline timepoint, a participant's corresponding baseline heart rate was subtracted from his or her average of the triplicate heart rate to create a "baseline-adjusted" corresponding heart rate for each participant at each postbaseline timepoint.

Number of Participants Within Each Absolute QTc Interval Category

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum QTc less than or equal to (\<=) 450 msec, greater than (\>) 450 to \<=470 msec, \>470 to \<= 500 msec, or \>500 msec were reported.

Number of Participants With Increase From Baseline in QTc Interval

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum increase from baseline of =\>30msec, 30 to \<60 msec (borderline) and \>=60 msec (prolonged) were summarized.

Number of Participants With New Abnormal U Waves on ECG

The incidence of abnormal U-wave changes from baseline was determined based on centrally read ECG tracings comparing each of the three triplicate readings from the post baseline ECG time points to the baseline ECG reading. At each time point, if at least one of the three triplicate readings was abnormal, the participant was counted as abnormal for that ECG timepoint as follows: a large U wave, inverted U wave, or T-U fusion compared with baseline was considered an abnormal significant change from baseline.

Number of Participants With New Abnormal T Waves on ECG

The incidence of abnormal T-wave changes from baseline was determined based on centrally read ECG tracings comparing each of the three triplicate readings from the post baseline ECG time points to the baseline ECG reading. At each time point, if at least one of the three triplicate readings was abnormal, the participant was counted as abnormal for that ECG timepoint as follows: an inverted T, flat T, or biphasic T compared with baseline was considered an abnormal significant change from baseline. Additionally, nonspecific T-wave changes from baseline were considered as abnormal nonsignificant changes from baseline. T-wave changes from baseline due to ventricular conduction or left ventricular hypertrophy strain were considered not evaluable.

Number of Participants With Abnormal Changes in PR Interval

Criteria for abnormal changes in PR interval were defined as: =\>25 percentage (%) change from baseline, an absolute value \>200 msec, or \>=25% change from baseline and an absolute value \>200 msec.

Number of Participants With Abnormal Changes in QRS Interval

Criteria for abnormal changes in QRS interval were defined as: \>=25% change from baseline, an absolute value \>110 msec, or \>=25% change from baseline and an absolute value \>110 msec.

Population Pharmacokinetics of Trastuzumab

As per planned analysis, separate population pharmacokinetic analysis results are not available for the current study as this analysis is based on pooled data from multiple studies.

Time frame: 15 (±15) minutes prior to the start of the trastuzumab infusion, and 30 (±15) minutes after the end of the infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1