A Phase 2 interventional study of pertuzumab and Trastuzumab emtansine [Kadcyla] in Metastatic Breast Cancer, sponsored by Genentech, Inc.. Completed. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2013-05-27.
Sponsored by Genentech, Inc. · Phase 2, Interventional, and Treatment
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.
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Exclusion Criteria:
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.
Biological: pertuzumab · Biological: Trastuzumab emtansine [Kadcyla]
Intravenous repeating dose
Also known as: PERJETA™
Intravenous repeating dose
Also known as: trastuzumab-MCC-DM1, T-DM1
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Time frame: Tumor assessments were performed after every three cycles until study termination or progressive disease (up to a maximum of one year).
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.
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.
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.
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.
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.
Time frame: Tumor assessments were performed after every three cycles until study termination or progressive disease (up to a maximum of one year).
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.
Time frame: From first dose until 30 days after last dose (up to 1 year).
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%.
Time frame: Assessed at Baseline and after every 3 cycles, up to 1 year.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
Between 14 July 2009 and 4 December 2009, 51 patients from 13 study sites in the United States were enrolled and initiated treatment in the study.
| Milestone | T-DM1 / T-DM1 + Pertuzumab |
|---|---|
| Started | 51 |
| Treated | 51 |
| Completed | 9 |
| Not completed | 42 |
| Withdrew: Physician decision | 2 |
| Withdrew: Withdrawal by subject | 3 |
| Withdrew: Systemic progression | 15 |
| Withdrew: Adverse event | 2 |
| Withdrew: Early progressive disease | 20 |
| Milestone | T-DM1 / T-DM1 + Pertuzumab |
|---|---|
| Started | 20 |
| Completed | 2 |
| Not completed | 18 |
| Withdrew: Physician decision | 1 |
| Withdrew: Withdrawal by subject | 4 |
| Withdrew: Systemic progression | 6 |
| Withdrew: Progression of brain metastases | 2 |
| Withdrew: Adverse event | 5 |
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.
| milliseconds | T-DM1 |
|---|---|
| Cycle 1, Day 1, 15 minutes post-dose [N=44] | 1.2 ± 8.3 |
| Cycle 1, Day 1, 60 minutes post-dose [N=45] | -1.0 ± 6.3 |
| Cycle 1, Day 8 [N=43] | -4.0 ± 13.4 |
| Cycle 3, Day 1, 15 minutes pre-dose [N=35] | -0.1 ± 10.1 |
| Cycle 3, Day 1, 15 minutes post-dose [N=37] | 4.7 ± 9.6 |
| Cycle 3, Day 1, 60 minutes post-dose [N=37] | 4.7 ± 10.9 |
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.
| milliseconds | T-DM1 |
|---|---|
| Cycle 1, Day 1, 15 minutes post-dose [N=44] | 3.6 ± 9.1 |
| Cycle 1, Day 1, 60 minutes post-dose [N=45] | 2.6 ± 7.4 |
| Cycle 1, Day 8 [N=43] | 0.7 ± 13.1 |
| Cycle 3, Day 1, 15 minutes pre-dose [N=35] | 3.7 ± 14.5 |
| Cycle 3, Day 1, 15 minutes post-dose [N=37] | 6.0 ± 13.2 |
| Cycle 3, Day 1, 60 minutes post-dose [N=37] | 7.3 ± 12.2 |
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.
| milliseconds | T-DM1 |
|---|---|
| Cycle 1 Day 1, 15 minutes post-dose [N=44] | -2.6 ± 17.4 |
| Cycle 1 Day 1, 60 minutes post-dose [N=45] | -7.0 ± 14.9 |
| Cycle 1 Day 8 [N=43] | 12.2 ± 22.1 |
| Cycle 3 Day 1, 15 minutes pre-dose [N=35] | -7.0 ± 14.9 |
| Cycle 3 Day 1, 15 minutes post-dose [N=37] | 2.4 ± 16.4 |
| Cycle 3 Day 1, 60 minutes post-dose [N=37] | 0.1 ± 19.6 |
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.
| milliseconds | T-DM1 |
|---|---|
| Cycle 1 Day 1, 15 minutes post-dose [N=44] | 2.3 ± 7.5 |
| Cycle 1 Day 1, 60 minutes post-dose [N=45] | 2.5 ± 8.7 |
| Cycle 1 Day 8 [N=43] | -0.7 ± 10.7 |
| Cycle 3 Day 1, 15 minutes pre-dose [N=35] | 1.8 ± 11.0 |
| Cycle 3 Day 1, 15 minutes post-dose [N=37] | 6.7 ± 9.8 |
| Cycle 3 Day 1, 60 minutes post-dose [N=37] | 5.3 ± 8.6 |
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.
| milliseconds | T-DM1 |
|---|---|
| Cycle 1 Day 1, 15 minutes post-dose [N=44] | 1.2 ± 3.1 |
| Cycle 1 Day 1, 60 minutes post-dose [N=45] | 0.4 ± 3.0 |
| Cycle 1 Day 8 [N=43] | 1.1 ± 4.8 |
| Cycle 3 Day 1, 15 minutes pre-dose [N=35] | 0.5 ± 4.5 |
| Cycle 3 Day 1, 15 minutes post-dose [N=37] | 1.9 ± 4.0 |
| Cycle 3 Day 1, 60 minutes post-dose [N=37] | 1.5 ± 3.8 |
| beats per minute | T-DM1 |
|---|---|
| Cycle 1 Day 1, 15 minutes post-dose [N=44] | 2.9 ± 8.3 |
| Cycle 1 Day 1, 60 minutes post-dose [N=45] | 4.4 ± 7.9 |
| Cycle 1 Day 8 [N=43] | 5.4 ± 8.8 |
| Cycle 3 Day 1, 15 minutes pre-dose [N=35] | 4.1 ± 7.9 |
| Cycle 3 Day 1, 15 minutes post-dose [N=37] | 0.8 ± 7.6 |
| Cycle 3 Day 1, 60 minutes post-dose [N=37] | 2.4 ± 7.8 |
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 | Average QTc Interval ≤ 450 ms | Average QTc Interval > 450 to ≤ 480 ms | Average QTc Interval > 480 to ≤ 500 ms | Average QTc Interval > 500 ms |
|---|---|---|---|---|
| QTcF: Cycle 1, Day 1, 15 minutes post-dose [N=44] | 100 | 0 | 0 | 0 |
| QTcF: Cycle 1, Day 1, 60 minutes post-dose [N=45] | 100 | 0 | 0 | 0 |
| QTcF: Cycle 1, Day 8 [N=43] | 100 | 0 | 0 | 0 |
| QTcF: Cycle 3, Day 1, 15 minutes pre-dose [N=35] | 97.1 | 2.9 | 0 | 0 |
| QTcF: Cycle 3, Day 1, 15 minutes post-dose [N=37] | 94.6 | 5.4 | 0 | 0 |
| QTcF: Cycle 3, Day 1, 60 minutes post-dose [N=37] | 97.3 | 2.7 | 0 | 0 |
| QTcB: Cycle 1, Day 1, 15 minutes post-dose [N=44] | 79.5 | 20.5 | 0 | 0 |
| QTcB: Cycle 1, Day 1, 60 minutes post-dose [N=45] | 73.3 | 26.7 | 0 | 0 |
| QTcB: Cycle 1, Day 8 [N=43] | 79.1 | 20.9 | 0 | 0 |
| QTcB: Cycle 3, Day 1, 15 minutes pre-dose [N=35] | 82.9 | 17.1 | 0 | 0 |
| QTcB: Cycle 3, Day 1, 15 minutes post-dose [N=37] | 70.3 | 29.7 | 0 | 0 |
| QTcB: Cycle 3, Day 1, 60 minutes post-dose [N=37] | 70.3 | 29.7 | 0 | 0 |
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 | Baseline-adjusted QTc Interval ≤ 30 ms | Baseline-adjusted QTc Interval > 30 to ≤ 60 ms | Baseline-adjusted QTc Interval > 60 ms |
|---|---|---|---|
| QTcF: Cycle 1, Day 1, 15 minutes post-dose [N=44] | 100 | 0 | 0 |
| QTcF: Cycle 1, Day 1, 60 minutes post-dose [N=45] | 100 | 0 | 0 |
| QTcF: Cycle 1, Day 8 [N=43] | 100 | 0 | 0 |
| QTcF: Cycle 3, Day 1, 15 minutes pre-dose [N=35] | 100 | 0 | 0 |
| QTcF: Cycle 3, Day 1, 15 minutes post-dose [N=37] | 100 | 0 | 0 |
| QTcF: Cycle 3, Day 1, 60 minutes post-dose [N=37] | 100 | 0 | 0 |
| QTcB: Cycle 1, Day 1, 15 minutes post-dose [N=44] | 100 | 0 | 0 |
| QTcB: Cycle 1, Day 1, 60 minutes post-dose [N=45] | 100 | 0 | 0 |
| QTcB: Cycle 1, Day 8 [N=43] | 100 | 0 | 0 |
| QTcB: Cycle 3, Day 1, 15 minutes pre-dose [N=35] | 94.3 | 5.7 | 0 |
| QTcB: Cycle 3, Day 1, 15 minutes post-dose [N=37] | 94.6 | 5.4 | 0 |
| QTcB: Cycle 3, Day 1, 60 minutes post-dose [N=37] | 97.3 | 2.7 | 0 |
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 | T-DM1 |
|---|---|
| Cycle 1, Day 1, 15 minutes post-dose [N=44] | 0 |
| Cycle 1, Day 1, 60 minutes post-dose [N=45] | 0 |
| Cycle 1, Day 8 [N=43] | 0 |
| Cycle 3, Day 1, 15 minutes pre-dose [N=35] | 0 |
| Cycle 3, Day 1, 15 minutes post-dose [N=36] | 0 |
| Cycle 3, Day 1, 60 minutes post-dose [N=37] | 0 |
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 | T-DM1 |
|---|---|
| Significant: C1D1, 15 minutes post-dose [N=44] | 0 |
| Significant: C1D1, 60 minutes post-dose [N=45] | 0 |
| Significant: C1D8 [N=43] | 2.3 |
| Significant: C3D1, 15 minutes pre-dose [N=35] | 0 |
| Significant: C3D1, 15 minutes post-dose [N=36] | 0 |
| Significant: C3D1, 60 minutes post-dose [N=37] | 0 |
| Non-Significant: C1D1, 15 minutes post-dose [N=44] | 13.6 |
| Non-Significant: C1D1, 60 minutes post-dose [N=45] | 11.1 |
| Non-Significant: C1D8 [N=43] | 20.9 |
| Non-Significant: C3D1, 15 minutes pre-dose [N=35] | 17.1 |
| Non-Significant: C3D1, 15 minutes post-dose [N=36] | 13.9 |
| Non-Significant: C3D1, 60 minutes post-dose [N=37] | 27.0 |
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.
| percentage of participants | T-DM1 |
|---|---|
| Percentage of Participants With an Objective Response During the Single-agent Trastuzumab Emtansine Treatment Period | 25.5 (15.2 to 38.5) |
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.
| months | T-DM1 |
|---|---|
| Duration of Objective Response Based on Investigator Assessment During the Single-agent Trastuzumab Emtansine Treatment Period | 9.3 (4.7 to NA) |
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.
| months | T-DM1 |
|---|---|
| Progression-free Survival During the Single-agent Trastuzumab Emtansine Treatment Period | 4.3 (4.0 to 6.7) |
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.
| percentage of participants | T-DM1 |
|---|---|
| Percentage of Participants With Clinical Benefit During the Single-agent Trastuzumab Emtansine Treatment Period | 39.2 (25.8 to 53.1) |
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.
| participants | T-DM1 | T-DM1 + Pertuzumab |
|---|---|---|
| Any adverse event | 51 | 18 |
| Grade ≥ 3 adverse events | 17 | 12 |
| Serious adverse events | 4 | 5 |
| Adverse events leading to treatment discontinuatio | 2 | 5 |
| Deaths | 0 | 0 |
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%.
| participants | T-DM1 | T-DM1 + Pertuzumab |
|---|---|---|
| Grade 3 | 1 | 0 |
| Overall | 1 | 1 |
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.
| μg/mL | Single-Agent T-DM1 Treatment |
|---|---|
| Cycle 1: T-DM1 [N=51] | 75.6 ± 21.9 |
| Cycle 1: Total trastuzumab [N=51] | 95.9 ± 32.3 |
| Cycle 3: T-Dm1 [N=47] | 80.7 ± 18.1 |
| Cycle 3: Total trastuzumab [N=47] | 98.6 ± 26.1 |
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.
| μg * day/mL | Single-Agent T-DM1 Treatment |
|---|---|
| Cycle 1: T-DM1 [N=51] | 418 ± 121 |
| Cycle 1: Total trastuzumab [N=51] | 929 ± 564 |
| Cycle 3: T-Dm1 [N=47] | 475 ± 150 |
| Cycle 3: Total trastuzumab [N=47] | 958 ± 394 |
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.
| μg * day/mL | Single-Agent T-DM1 Treatment |
|---|---|
| T-DM1 | 431 ± 126 |
| Total trastuzumab | 1420 ± 1390 |
| days | Single-Agent T-DM1 Treatment |
|---|---|
| Cycle 1: T-DM1 [N=51] | 4.02 ± 0.938 |
| Cycle 1: Total trastuzumab [N=51] | 10.3 ± 6.81 |
| Cycle 3: T-Dm1 [N=47] | 4.46 ± 0.926 |
| Cycle 3: Total trastuzumab [N=47] | 12.0 ± 6.24 |
| mL/day/kg | Single-Agent T-DM1 Treatment |
|---|---|
| Cycle 1: T-DM1 [N=51] | 9.17 ± 3.03 |
| Cycle 1: Total trastuzumab [N=51] | 4.21 ± 2.43 |
| Cycle 3: T-Dm1 [N=47] | 7.91 ± 3.30 |
| Cycle 3: Total trastuzumab [N=47] | 3.12 ± 1.71 |
| mL/kg | Single-Agent T-DM1 Treatment |
|---|---|
| Cycle 1: T-DM1 [N=51] | 41.2 ± 24.5 |
| Cycle 1: Total trastuzumab [N=51] | 41.9 ± 16.2 |
| Cycle 3: T-Dm1 [N=47] | 43.6 ± 40.7 |
| Cycle 3: Total trastuzumab [N=47] | 43.7 ± 15.4 |
The number of participants with anti-T-DM1 antibodies was assessed using a validated bridging antibody enzyme-linked immunosorbent assay (ELISA).
| participants | Single-Agent T-DM1 Treatment |
|---|---|
| Pre-dose (Baseline) | 2 |
| Post-dose | 0 |
Collected over 1 year. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Single-Agent T-DM1 Treatment | — | 4/51 (7.8%) | 51/51 (100%) |
| T-DM1 + Pertuzumab | — | 5/20 (25%) | 18/20 (90%) |
| Event | Single-Agent T-DM1 Treatment | T-DM1 + Pertuzumab |
|---|---|---|
| AnaemiaBlood and lymphatic system disorders | 0/51 | 2/20 |
| ThrombocytopeniaBlood and lymphatic system disorders | 2/51 | 1/20 |
| Cardiac arrestCardiac disorders | 0/51 | 1/20 |
| Gastrointestinal haemorrhageGastrointestinal disorders | 0/51 | 1/20 |
| Aspartate aminotransferase increasedInvestigations | 0/51 | 1/20 |
| HypokalaemiaMetabolism and nutrition disorders | 0/51 | 1/20 |
| Skin haemorrhageSkin and subcutaneous tissue disorders | 0/51 | 1/20 |
| Generalised oedemaGeneral disorders | 1/51 | 0/20 |
| ConvulsionNervous system disorders | 1/51 | 0/20 |
| Renal failureRenal and urinary disorders | 1/51 | 0/20 |
| Event | Single-Agent T-DM1 Treatment | T-DM1 + Pertuzumab |
|---|---|---|
| NauseaGastrointestinal disorders | 33/51 | 3/20 |
| FatigueGeneral disorders | 33/51 | 4/20 |
| Dry mouthGastrointestinal disorders | 25/51 | 2/20 |
| ThrombocytopeniaBlood and lymphatic system disorders | 17/51 | 2/20 |
| Aspartate aminotransferase increasedInvestigations | 17/51 | 4/20 |
| VomitingGastrointestinal disorders | 16/51 | 4/20 |
| AnaemiaBlood and lymphatic system disorders | 7/51 | 6/20 |
| ConstipationGastrointestinal disorders | 12/51 | 1/20 |
| PyrexiaGeneral disorders | 12/51 | 2/20 |
| Decreased appetiteMetabolism and nutrition disorders | 12/51 | 3/20 |
| Age Continuous(years) | T-DM1 / T-DM1 + Pertuzumab |
|---|---|
| Mean | 53.5 ± 11.4 |
| Sex: Female, Male(Participants) | T-DM1 / T-DM1 + Pertuzumab |
|---|---|
| Female | 51 |
| Male | 0 |
| Region of Enrollment(participants) | T-DM1 / T-DM1 + Pertuzumab |
|---|---|
| United States | 51 |
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