Clinical trial NCT00943670: Corrected QT Interval Effects of Trastuzumab Emtansine (T-DM1) in Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Locally Advanced or Metastatic Breast Cancer and the Safety and Tolerability of Combined T-DM1 and Pertuzumab in Patients With Early Disease Progression
Official title: A Phase II, Open-Label Study to Evaluate Corrected QT Interval Effects of Trastuzumab-MCC-DM1 (T-DM1) in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer and to Evaluate the Safety and Tolerability of Combined T-DM1 and Pertuzumab in Patients With Early Disease Progression While Receiving T-DM1 Alone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: MBC
TDM1
Armed Herceptin
Herceptin
Trastuzumab emtansine
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2009-07-22
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a multicenter, open-label, single-arm Phase II study designed to evaluate the effect of T-DM1 on the duration of corrected QT (QTc) interval in patients with HER2-positive locally advanced or metastatic breast cancer and to make preliminary assessments regarding the safety, tolerability, and efficacy of combined T-DM1 and pertuzumab in patients with early disease progression.

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.


Eligibility criteria: Inclusion Criteria:

* Histologically documented, locally advanced, or metastatic breast cancer; measurable and/or non-measureable but evaluable disease is permitted
* HER2-positive disease
* History of prior trastuzumab therapy
* Life expectancy ≥ 90 days as assessed by the investigator
* Negative urine pregnancy test ≤ 72 hours prior to Cycle 1 Day 1 for all women of childbearing potential
* For patients of childbearing potential, agreement to use one highly effective form of contraception or two effective forms of contraception for the duration of the study treatment(s) and for 4 months after the last dose of T-DM1 or 6 months after the last dose of pertuzumab, if applicable

Exclusion Criteria:

* Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy for the treatment of breast cancer within 2 weeks of the first study treatment
* Prior T-DM1 or pertuzumab therapy
* History of intolerance (such as Grade 3-4 infusion reaction) and/or adverse events related to trastuzumab
* Grade ≥ 2 (based on National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v3) peripheral neuropathy at the time of or within 3 weeks prior to the first study treatment
* Brain metastases that are untreated or progressive or have required any type of therapy, including radiation, surgery, and/or steroids, to control symptoms from brain metastases within 60 days prior to the first study treatment
* History of cardiac disease, unstable angina, symptomatic congestive heart failure (CHF) (Class ≥ II per the New York Heart Associate \[NYHA\] guidelines), myocardial infarction, or ventricular arrhythmia ≤ 6 months prior to Cycle 1, Day 1
* Implantable pacemaker or automatic implantable cardioverter defibrillator
* Congenital long QT syndrome or family history of long QT syndrome
* Current uncontrolled hypertension
* Current treatment with medications that alter cardiac conduction (e.g., digitalis, beta-blockers, or calcium channel blockers) or medications that are generally accepted to have a risk of causing torsades de pointes (TdP)
* Current known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
* Major surgical procedure or significant traumatic injury within 28 days prior to first study treatment, or anticipation of the need for major surgery during the course of study treatment

Primary outcomes:
measure: Change From Baseline in Mean Duration of the QTc Interval
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
Secondary outcomes:
measure: Change From Baseline in Mean Duration of the QTc Interval Using Bazett's Correction
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Change From Baseline in Uncorrected QT Interval
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Change From Baseline in PR Interval
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Change From Baseline in QRS Duration
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Change From Baseline in Heart Rate
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Percentage of Participants Within Each Absolute QTc Interval Category
timeFrame: Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Percentage of Participants Within Each Baseline-adjusted QTc Interval Category
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Percentage of Participants With New Abnormal U Waves
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Percentage of Participants With New Abnormal T Waves
timeFrame: Cycle 1 Day 1, pre-dose (Baseline); Cycle 1 Day 1, 15 and 60 minutes post-dose; Cycle 1 Day 8; and Cycle 3 Day 1, 15 minutes pre-dose and 15 and 60 minutes post-dose.
measure: Percentage of Participants With an Objective Response During the Single-agent Trastuzumab Emtansine Treatment Period
timeFrame: Tumor assessments were performed after every three cycles until study termination or progressive disease (up to a maximum of one year).
measure: Duration of Objective Response Based on Investigator Assessment During the Single-agent Trastuzumab Emtansine Treatment Period
timeFrame: Time from the first documented objective response to the time of first documented disease progression or death, up to a maximum time period of one year.
measure: Progression-free Survival During the Single-agent Trastuzumab Emtansine Treatment Period
timeFrame: From the first day of study treatment to the first documented disease progression or death, up to a maximum time period of one year.
measure: Percentage of Participants With Clinical Benefit During the Single-agent Trastuzumab Emtansine Treatment Period
timeFrame: Tumor assessments were performed after every three cycles until study termination or progressive disease (up to a maximum of one year).
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From first dose until 30 days after last dose (up to 1 year).
measure: Number of Participants With Decreased Ejection Fraction
timeFrame: Assessed at Baseline and after every 3 cycles, up to 1 year.
measure: Maximum Observed Serum Concentration of T-DM1 and Total Trastuzumab
timeFrame: Blood samples were collected prior to dosing, 15 and 60 minutes after the end of infusion, and anytime on Days 8 and 15 in Cycles 1 and 3, and pre-dose in Cycle 4.
measure: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration for T-DM1 and Total Trastuzumab
timeFrame: Blood samples were collected prior to T-DM1 dosing, 15 and 60 minutes after the end of infusion, and anytime on Days 8 and 15 in Cycles 1 and 3, and pre-dose in Cycle 4.
measure: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity for T-DM1 and Total Trastuzumab
timeFrame: Blood samples were collected prior to T-DM1 dosing, 15 and 60 minutes after the end of infusion, and anytime on Days 8 and 15 in Cycle 1.
measure: Terminal Half-life for T-DM1 and Total Trastuzumab
timeFrame: Blood samples were collected prior to T-DM1 dosing, 15 and 60 minutes after the end of infusion, and anytime on Days 8 and 15 in Cycles 1 and 3, and pre-dose in Cycle 4.
measure: Clearance T-DM1 and Total Trastuzumab
timeFrame: Blood samples were collected prior to T-DM1 dosing, 15 and 60 minutes after the end of infusion, and anytime on Days 8 and 15 in Cycles 1 and 3, and pre-dose in Cycle 4.
measure: Volume of Distribution at Steady State for T-DM1 and Total Trastuzumab
timeFrame: Blood samples were collected prior to T-DM1 dosing, 15 and 60 minutes after the end of infusion, and anytime on Days 8 and 15 in Cycles 1 and 3, and pre-dose in Cycle 4.
measure: Number of Participants With Anti-therapeutic Antibodies (ATAs) to Trastuzumab Emtansine
timeFrame: Blood samples were collected prior to T-DM1 dosing, 15 and 60 minutes after the end of infusion, and anytime on Days 8 and 15 in Cycles 1 and 3, and pre-dose in Cycle 4.
Other outcomes:
Locations:
Study officials:
affiliation: Genentech, Inc.
name: Steve Olsen, M.D.
role: STUDY_DIRECTOR
References: