Back to resultsCorrected 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
Primary Purpose
Metastatic Breast Cancer
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
pertuzumab
Trastuzumab emtansine [Kadcyla]
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Breast Cancer focused on measuring MBC, TDM1, Armed Herceptin, Herceptin, Trastuzumab emtansine
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
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
T-DM1 / T-DM1 + pertuzumab
Arm Description
Trastuzumab emtansine (T-DM1) was administered to participants by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg. From Cycle 4, participants with early progressive disease (demonstrated prior to the end of Cycle 6) could receive combined pertuzumab and trastuzumab emtansine. Pertuzumab was administered after trastuzumab emtansine by IV infusion at a loading dose of 840 mg on Day 1, starting at the cycle after tumor progression was determined, followed by 420 mg IV infusion every 3 weeks in subsequent cycles. Participants who met criteria for ongoing clinical benefit were allowed to continue study treatment in the absence of disease progression or unacceptable toxicity for up to 1 year.
Outcomes
Primary Outcome Measures
Change From Baseline in Mean Duration of the QTc Interval
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 corrected QT interval was calculated using Fridericia's correction (QTcF) from electrocardiogram (ECG) data. Each participant had triplicate QTcF intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTcF interval was subtracted from the average QTcF intervals to create a baseline-adjusted average QTcF interval.
Secondary Outcome Measures
Change From Baseline in Mean Duration of the QTc Interval Using Bazett's Correction
The corrected QT interval was calculated using Bazett's correction (QTcB) from electrocardiogram (ECG) data. Each participant had triplicate QTcB intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTcB interval was subtracted from the average QTcB intervals to create a baseline-adjusted average QTcB interval.
Change From Baseline in Uncorrected QT Interval
The uncorrected QT interval was calculated from electrocardiogram (ECG) data. Each participant had triplicate QT intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QT interval was subtracted from the average QT intervals to create a baseline-adjusted average QT interval.
Change From Baseline in PR Interval
The PR interval is the time in seconds from the beginning of the P wave to the beginning of the QRS complex, and was calculated from electrocardiogram (ECG) data. Each participant had triplicate PR intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline PR interval was subtracted from the average PR intervals to create a baseline-adjusted average PR interval.
Change From Baseline in QRS Duration
The QRS interval represents the time it takes for depolarization of the ventricles and was calculated from electrocardiogram (ECG) data. Each participant had triplicate QRS intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QRS interval was subtracted from the average QRS intervals to create a baseline-adjusted average QRS interval.
Change From Baseline in Heart Rate
Percentage of Participants Within Each Absolute QTc Interval Category
The corrected QT interval was calculated using Fridericia's correction (QTcF) and using Bazett's correction (QTcB) from electrocardiogram (ECG) data. Each participant had triplicate QTc intervals measured at each timepoint and the average was calculated for each patient at each timepoint. QTc interval categories are based off International Conference on Harmonisation (ICH) Tripartite Guideline E14.
Percentage of Participants Within Each Baseline-adjusted QTc Interval Category
The corrected QT interval was calculated using Fridericia's correction (QTcF) and using Bazett's correction (QTcB) from electrocardiogram (ECG) data. Each participant had triplicate QTc intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTc interval was subtracted from the average QTc intervals to create a baseline-adjusted average QTc interval.
QTc interval categories are based off International Conference on Harmonisation (ICH) Tripartite Guideline E14.
Percentage of Participants With New Abnormal U Waves
The incidence of abnormal U-wave changes from baseline was determined based on centrally read electrocardiogram (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.
Percentage of Participants With New Abnormal T Waves
The incidence of abnormal T-wave changes from baseline was determined based on centrally read electrocardiogram (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. C=Cycle; D=Day.
Percentage of Participants With an Objective Response During the Single-agent Trastuzumab Emtansine Treatment Period
Objective response was defined as a complete response (CR) or partial response (PR) determined on two consecutive assessments conducted by the investigator ≥ 4 weeks apart. Responses were assessed by physical examination and imaged-based evaluation using a modified version of the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0:
CR-the disappearance of all target lesions and the disappearance of all nontarget lesions and normalization of tumor marker level and no new lesions.
PR-either the disappearance of all target lesions with persistence of one or more nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter with no new lesions or unequivocal progression of existing nontarget lesions.
Duration of Objective Response Based on Investigator Assessment During the Single-agent Trastuzumab Emtansine Treatment Period
In patients with an objective response during the single-agent trastuzumab emtansine treatment period, duration of response was defined as the time from the first documented objective response to the time of first documented disease progression or death, whichever occurred first. Progressive disease was defined as either at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study with an absolute increase of at least 5 mm, or the appearance of one or more new lesions, or the unequivocal progression of existing nontarget lesions.
If a patient did not die or experience disease progression before the end of the study, duration of response was censored at the day of the last tumor assessment when the patient was known to be progression free.
Progression-free Survival During the Single-agent Trastuzumab Emtansine Treatment Period
Progression-free survival (PFS) was defined as the time from the first day of study treatment (Day 1) to first documented disease progression or death, whichever occurred first. If a patient did not experience disease progression or die, PFS was censored at the day of the last tumor assessment that a patient was known to be progression free.
Percentage of Participants With Clinical Benefit During the Single-agent Trastuzumab Emtansine Treatment Period
Participants were considered to have experienced clinical benefit if they had an objective response or maintained stable disease for at least 6 months from start of study treatment. Objective response was defined as a complete or partial response determined on two consecutive tumor assessments at least 4 weeks apart based on a modified version of RECIST.
Stable disease was defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started and no new lesions or unequivocal progression of existing nontarget lesions.
Number of Participants With Adverse Events (AEs)
An serious AE is any AE that is fatal, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s), or is considered a significant medical event by the investigator (e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above).
The severity of each AE was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0, or as follows: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Very severe; Grade 5 = Death related to AE.
Number of Participants With Decreased Ejection Fraction
Left ventricular ejection fraction (LVEF) was assessed on the basis of local assessments of echocardiogram or multigated acquisition scan (MUGA) data. A decrease in LVEF is defined as a decrease from Baseline of greater than or equal to 15%.
Grade 3 LVEF is an ejection fraction between 20 and 40%.
Maximum Observed Serum Concentration of T-DM1 and Total Trastuzumab
Serum samples were quantitated for T-DM1 (DM1 conjugated to trastuzumab) levels in a validated assay using an indirect sandwich enzyme-linked immunosorbent assay (ELISA). The minimum quantifiable concentration in human serum was 40 ng/mL. Serum samples were assayed for total trastuzumab (conjugated and unconjugated T-DM1) in a validated assay using an indirect sandwich ELISA method; the minimum quantifiable concentration in human serum was 40 ng/mL.
Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration for T-DM1 and Total Trastuzumab
Area under the serum concentration-time curve from Time zero to time of last measurable concentration (AUClast) for T-DM1 (conjugated trastuzumab) and Total Trastuzumab (conjugated and unconjugated T-DM1) at Cycle 1 and Cycle 3.
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity for T-DM1 and Total Trastuzumab
Area under the serum concentration-time curve from Time zero extrapolated to infinity (AUCinf) for T-DM1 (conjugated trastuzumab) and total trastuzumab (conjugated and unconjugated T-DM1) at Cycle 1.
Terminal Half-life for T-DM1 and Total Trastuzumab
Clearance T-DM1 and Total Trastuzumab
Volume of Distribution at Steady State for T-DM1 and Total Trastuzumab
Number of Participants With Anti-therapeutic Antibodies (ATAs) to Trastuzumab Emtansine
The number of participants with anti-T-DM1 antibodies was assessed using a validated bridging antibody enzyme-linked immunosorbent assay (ELISA).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00943670
Brief Title
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
2. Study Status
Record Verification Date
May 2013
Overall Recruitment Status
Completed
Study Start Date
July 2009 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
August 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Genentech, Inc.
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Breast Cancer
Keywords
MBC, TDM1, Armed Herceptin, Herceptin, Trastuzumab emtansine
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
51 (Actual)
8. Arms, Groups, and Interventions
Arm Title
T-DM1 / T-DM1 + pertuzumab
Arm Type
Experimental
Arm Description
Trastuzumab emtansine (T-DM1) was administered to participants by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.
From Cycle 4, participants with early progressive disease (demonstrated prior to the end of Cycle 6) could receive combined pertuzumab and trastuzumab emtansine. Pertuzumab was administered after trastuzumab emtansine by IV infusion at a loading dose of 840 mg on Day 1, starting at the cycle after tumor progression was determined, followed by 420 mg IV infusion every 3 weeks in subsequent cycles.
Participants who met criteria for ongoing clinical benefit were allowed to continue study treatment in the absence of disease progression or unacceptable toxicity for up to 1 year.
Intervention Type
Biological
Intervention Name(s)
pertuzumab
Other Intervention Name(s)
PERJETA™
Intervention Description
Intravenous repeating dose
Intervention Type
Biological
Intervention Name(s)
Trastuzumab emtansine [Kadcyla]
Other Intervention Name(s)
trastuzumab-MCC-DM1, T-DM1
Intervention Description
Intravenous repeating dose
Primary Outcome Measure Information:
Title
Change From Baseline in Mean Duration of the QTc Interval
Description
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 corrected QT interval was calculated using Fridericia's correction (QTcF) from electrocardiogram (ECG) data. Each participant had triplicate QTcF intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTcF interval was subtracted from the average QTcF intervals to create a baseline-adjusted average QTcF interval.
Time Frame
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 Outcome Measure Information:
Title
Change From Baseline in Mean Duration of the QTc Interval Using Bazett's Correction
Description
The corrected QT interval was calculated using Bazett's correction (QTcB) from electrocardiogram (ECG) data. Each participant had triplicate QTcB intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTcB interval was subtracted from the average QTcB intervals to create a baseline-adjusted average QTcB interval.
Time Frame
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.
Title
Change From Baseline in Uncorrected QT Interval
Description
The uncorrected QT interval was calculated from electrocardiogram (ECG) data. Each participant had triplicate QT intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QT interval was subtracted from the average QT intervals to create a baseline-adjusted average QT interval.
Time Frame
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.
Title
Change From Baseline in PR Interval
Description
The PR interval is the time in seconds from the beginning of the P wave to the beginning of the QRS complex, and was calculated from electrocardiogram (ECG) data. Each participant had triplicate PR intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline PR interval was subtracted from the average PR intervals to create a baseline-adjusted average PR interval.
Time Frame
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.
Title
Change From Baseline in QRS Duration
Description
The QRS interval represents the time it takes for depolarization of the ventricles and was calculated from electrocardiogram (ECG) data. Each participant had triplicate QRS intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QRS interval was subtracted from the average QRS intervals to create a baseline-adjusted average QRS interval.
Time Frame
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.
Title
Change From Baseline in Heart Rate
Time Frame
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.
Title
Percentage of Participants Within Each Absolute QTc Interval Category
Description
The corrected QT interval was calculated using Fridericia's correction (QTcF) and using Bazett's correction (QTcB) from electrocardiogram (ECG) data. Each participant had triplicate QTc intervals measured at each timepoint and the average was calculated for each patient at each timepoint. QTc interval categories are based off International Conference on Harmonisation (ICH) Tripartite Guideline E14.
Time Frame
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.
Title
Percentage of Participants Within Each Baseline-adjusted QTc Interval Category
Description
The corrected QT interval was calculated using Fridericia's correction (QTcF) and using Bazett's correction (QTcB) from electrocardiogram (ECG) data. Each participant had triplicate QTc intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTc interval was subtracted from the average QTc intervals to create a baseline-adjusted average QTc interval.
QTc interval categories are based off International Conference on Harmonisation (ICH) Tripartite Guideline E14.
Time Frame
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.
Title
Percentage of Participants With New Abnormal U Waves
Description
The incidence of abnormal U-wave changes from baseline was determined based on centrally read electrocardiogram (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.
Time Frame
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.
Title
Percentage of Participants With New Abnormal T Waves
Description
The incidence of abnormal T-wave changes from baseline was determined based on centrally read electrocardiogram (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. C=Cycle; D=Day.
Time Frame
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.
Title
Percentage of Participants With an Objective Response During the Single-agent Trastuzumab Emtansine Treatment Period
Description
Objective response was defined as a complete response (CR) or partial response (PR) determined on two consecutive assessments conducted by the investigator ≥ 4 weeks apart. Responses were assessed by physical examination and imaged-based evaluation using a modified version of the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0:
CR-the disappearance of all target lesions and the disappearance of all nontarget lesions and normalization of tumor marker level and no new lesions.
PR-either the disappearance of all target lesions with persistence of one or more nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter with no new lesions or unequivocal progression of existing nontarget lesions.
Time Frame
Tumor assessments were performed after every three cycles until study termination or progressive disease (up to a maximum of one year).
Title
Duration of Objective Response Based on Investigator Assessment During the Single-agent Trastuzumab Emtansine Treatment Period
Description
In patients with an objective response during the single-agent trastuzumab emtansine treatment period, duration of response was defined as the time from the first documented objective response to the time of first documented disease progression or death, whichever occurred first. Progressive disease was defined as either at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study with an absolute increase of at least 5 mm, or the appearance of one or more new lesions, or the unequivocal progression of existing nontarget lesions.
If a patient did not die or experience disease progression before the end of the study, duration of response was censored at the day of the last tumor assessment when the patient was known to be progression free.
Time Frame
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.
Title
Progression-free Survival During the Single-agent Trastuzumab Emtansine Treatment Period
Description
Progression-free survival (PFS) was defined as the time from the first day of study treatment (Day 1) to first documented disease progression or death, whichever occurred first. If a patient did not experience disease progression or die, PFS was censored at the day of the last tumor assessment that a patient was known to be progression free.
Time Frame
From the first day of study treatment to the first documented disease progression or death, up to a maximum time period of one year.
Title
Percentage of Participants With Clinical Benefit During the Single-agent Trastuzumab Emtansine Treatment Period
Description
Participants were considered to have experienced clinical benefit if they had an objective response or maintained stable disease for at least 6 months from start of study treatment. Objective response was defined as a complete or partial response determined on two consecutive tumor assessments at least 4 weeks apart based on a modified version of RECIST.
Stable disease was defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started and no new lesions or unequivocal progression of existing nontarget lesions.
Time Frame
Tumor assessments were performed after every three cycles until study termination or progressive disease (up to a maximum of one year).
Title
Number of Participants With Adverse Events (AEs)
Description
An serious AE is any AE that is fatal, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s), or is considered a significant medical event by the investigator (e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above).
The severity of each AE was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0, or as follows: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Very severe; Grade 5 = Death related to AE.
Time Frame
From first dose until 30 days after last dose (up to 1 year).
Title
Number of Participants With Decreased Ejection Fraction
Description
Left ventricular ejection fraction (LVEF) was assessed on the basis of local assessments of echocardiogram or multigated acquisition scan (MUGA) data. A decrease in LVEF is defined as a decrease from Baseline of greater than or equal to 15%.
Grade 3 LVEF is an ejection fraction between 20 and 40%.
Time Frame
Assessed at Baseline and after every 3 cycles, up to 1 year.
Title
Maximum Observed Serum Concentration of T-DM1 and Total Trastuzumab
Description
Serum samples were quantitated for T-DM1 (DM1 conjugated to trastuzumab) levels in a validated assay using an indirect sandwich enzyme-linked immunosorbent assay (ELISA). The minimum quantifiable concentration in human serum was 40 ng/mL. Serum samples were assayed for total trastuzumab (conjugated and unconjugated T-DM1) in a validated assay using an indirect sandwich ELISA method; the minimum quantifiable concentration in human serum was 40 ng/mL.
Time Frame
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.
Title
Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration for T-DM1 and Total Trastuzumab
Description
Area under the serum concentration-time curve from Time zero to time of last measurable concentration (AUClast) for T-DM1 (conjugated trastuzumab) and Total Trastuzumab (conjugated and unconjugated T-DM1) at Cycle 1 and Cycle 3.
Time Frame
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.
Title
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity for T-DM1 and Total Trastuzumab
Description
Area under the serum concentration-time curve from Time zero extrapolated to infinity (AUCinf) for T-DM1 (conjugated trastuzumab) and total trastuzumab (conjugated and unconjugated T-DM1) at Cycle 1.
Time Frame
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.
Title
Terminal Half-life for T-DM1 and Total Trastuzumab
Time Frame
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.
Title
Clearance T-DM1 and Total Trastuzumab
Time Frame
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.
Title
Volume of Distribution at Steady State for T-DM1 and Total Trastuzumab
Time Frame
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.
Title
Number of Participants With Anti-therapeutic Antibodies (ATAs) to Trastuzumab Emtansine
Description
The number of participants with anti-T-DM1 antibodies was assessed using a validated bridging antibody enzyme-linked immunosorbent assay (ELISA).
Time Frame
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steve Olsen, M.D.
Organizational Affiliation
Genentech, Inc.
Official's Role
Study Director
12. IPD Sharing Statement
Learn more about this trial
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