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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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00927589
First received: June 24, 2009
Last updated: November 5, 2015
Last verified: November 2015
  Purpose

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.


Condition Intervention Phase
Solid Cancers
Drug: carboplatin
Drug: docetaxel
Drug: trastuzumab
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) at Trastuzumab Steady State [ Time Frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 ] [ Designated as safety issue: No ]
    Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 (C1D8) and Cycle 2 Day 1 (C2D1) after the trastuzumab infusion.

  • Maximum Observed Plasma Concentration (Cmax) of Carboplatin [ 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) ] [ Designated as safety issue: No ]
  • Area Under the Curve From Time Zero to 6 Hours Post Infusion (AUC0-6hr) of Carboplatin [ 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) ] [ Designated as safety issue: No ]
    AUC0-6hr = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion.

  • Dose-Normalized Cmax (Cmax/D) 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) ] [ Designated as safety issue: No ]
    Dose normalized Cmax is the maximum observed concentration of carboplatin in plasma normalized for different dose levels.

  • Geometric Mean Ratio of Cmax/D of Carboplatin [ 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) ] [ Designated as safety issue: No ]
    The geometric mean ratio of Cmax of carboplatin was defined as the Cmax/D of carboplatin on Cycle 1 Day 1 (in the absence of trastuzumab) divided by Cmax/D of carboplatin on Cycle 2 Day 1 (in the presence of trastuzumab).

  • Dose−Normalized AUC0-6hr (AUC0-6hr/D) of Carboplatin [ 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) ] [ Designated as safety issue: No ]
    AUC0-6hr/D = Area under the plasma concentration versus time curve from 0 to 6 hours post-infusion, normalized by carboplatin dose level.

  • Geometric Mean Ratio of AUC0-6hr/D of Carboplatin [ 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) ] [ Designated as safety issue: No ]
    The geometric mean ratio of AUC0-6hr/D of carboplatin was defined as the AUC0-6hr/D of carboplatin on Cycle 1 Day 1 (in the absence of trastuzumab) divided by AUC0-6hr/D of carboplatin on Cycle 2 Day 1 (in the presence of trastuzumab).

  • Plasma Decay Half-Life (t1/2) of Carboplatin [ 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) ] [ Designated as safety issue: No ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change From Baseline in Corrected QT Interval Using Bazett's Correction (QTcB) at Trastuzumab Steady State [ Time Frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 ] [ Designated as safety issue: No ]
    Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Bazette's formula (QTcB = QT divided by square root of RR). Trastuzumab steady state was defined as the average of the 2 ECG measurements collected on Cycle 1 Day 8 and Cycle 2 Day 1 after the trastuzumab infusion.

  • Baseline-adjusted QTcF, QTcB, PR Interval, and QRS Duration [ 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) ] [ Designated as safety issue: No ]
    For each postbaseline timepoint, a participant's corresponding baseline measure was subtracted from his or her average of the triplicate ECG measure to create a "baseline-adjusted" corresponding ECG measure for each participant at each postbaseline timepoint.

  • Baseline-adjusted Heart Rate [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 59
Study Start Date: July 2009
Study Completion Date: February 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: carboplatin
Intravenous repeating dose
Drug: docetaxel
Intravenous repeating dose
Drug: trastuzumab
Intravenous repeating dose

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00927589

Locations
United States, Arizona
Scottsdale, Arizona, United States, 85258
United States, 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
United States, Florida
Miami, Florida, United States, 33136
United States, Kansas
Wichita, Kansas, United States, 67214-3728
United States, Montana
Billings, Montana, United States, 59101
United States, New Mexico
Farmington, New Mexico, United States, 87401
United States, New York
Bronx, New York, United States, 10461
United States, Tennessee
Memphis, Tennessee, United States, 38120
Nashville, Tennessee, United States, 37232
United States, Texas
Dallas, Texas, United States, 75230
Galveston, Texas, United States, 77555
Houston, Texas, United States, 77024
Houston, Texas, United States, 77030
San Antonio, Texas, United States, 78229
Temple, Texas, United States, 76508
United States, Washington
Seattle, Washington, United States, 98101
Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Harald Weber, M.D. Genentech, Inc.
  More Information

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00927589     History of Changes
Other Study ID Numbers: H4613g  GO01305 
Study First Received: June 24, 2009
Results First Received: November 5, 2015
Last Updated: November 5, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Genentech, Inc.:
HER2+ Metastatic Cancer
HER2+ Locally Advanced Inoperable Cancer
HER2+ Solid Malignancy

Additional relevant MeSH terms:
Docetaxel
Carboplatin
Trastuzumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 05, 2016