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

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 Overview

• Status: Completed
• Conditions: Solid Cancers
• Intervention / Treatment: Drug: carboplatin; Drug: docetaxel; Drug: trastuzumab

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
  • California
    • Beverly Hills, California, United States, 90211
    • La Jolla, California, United States, 92093
    • San Diego, California, United States, 92123
    • Santa Rosa, California, United States, 95403
    • Whittier, California, United States, 90603
  • Florida
    • Miami, Florida, United States, 33136
  • Kansas
    • Wichita, Kansas, United States, 67214-3728
  • Montana
    • Billings, Montana, United States, 59101
  • New Mexico
    • Farmington, New Mexico, United States, 87401
  • New York
    • Bronx, New York, United States, 10461
  • Tennessee
    • Memphis, Tennessee, United States, 38120
    • Nashville, Tennessee, United States, 37232
  • Texas
    • Dallas, Texas, United States, 75230
    • Galveston, Texas, United States, 77555
    • Houston, Texas, United States, 77030
    • Houston, Texas, United States, 77024
    • San Antonio, Texas, United States, 78229
    • Temple, Texas, United States, 76508
  • Washington
    • Seattle, Washington, United States, 98101

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: carboplatin; Intravenous repeating dose; Drug: docetaxel; Intravenous repeating dose; Drug: trastuzumab; Intravenous repeating dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Maximum Observed Plasma Concentration (Cmax) of Carboplatin		0 to 5 minutes after end of infusion on Cycle 1 Day 1 (in absence of trastuzumab) and Cycle 2 Day 1 (in presence of trastuzumab)
Area Under the Curve From Time Zero to 6 Hours Post Infusion (AUC0-6hr) of Carboplatin	AUC0-6hr = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion.	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.	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).	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.	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).	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.	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		30 (±15) minutes after the end of the infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1
Minimum Observed Serum Trough Concentration (Cmin) of Trastuzumab		15 (±15) minutes prior to the start of the trastuzumab infusion on Cycle 1 Day 2, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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)
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.	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)
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.	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)
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.	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)
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.	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)
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.	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)
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.	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 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.	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

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Harald Weber, M.D., Genentech, Inc.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: June 24, 2009
• First Submitted That Met QC Criteria: June 24, 2009
• First Posted (Estimate): June 25, 2009

Study Record Updates

• Last Update Posted (Estimate): December 10, 2015
• Last Update Submitted That Met QC Criteria: November 5, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: HER2+ Metastatic Cancer; HER2+ Locally Advanced Inoperable Cancer; HER2+ Solid Malignancy
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Docetaxel; Carboplatin; Trastuzumab
• Other Study ID Numbers: H4613g; GO01305 (Other Identifier: Hoffmann-La Roche)