Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Breast Neoplasms

Disease Progression

Breast Diseases

Skin Diseases

Disease Attributes

Myotonic Dystrophy Type 1

Antineoplastic Agents

All Drugs and Chemicals

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Ado-Trastuzumab Emtansine

Trastuzumab

Pertuzumab

Mitogens

Adenosine

Maytansine

Antineoplastic Agents, Immunological

Tubulin Modulators

Antimitotic Agents

Immunotoxins

Immunoconjugates

Immunologic Factors

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.

pertuzumab

Trastuzumab emtansine [Kadcyla]

Steve Olsen, M.D.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 (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.

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.

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.

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%.

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 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 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.

The number of participants with anti-T-DM1 antibodies was assessed using a validated bridging antibody enzyme-linked immunosorbent assay (ELISA).

Genentech, Inc.

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.

Single-Agent T-DM1 Treatment

Participants who received combined pertuzumab and trastuzumab emtansine. Pertuzumab was administered after trastuzumab emtansine by IV infusion at a loading dose of 840 mg on Day 1, followed by 420 mg IV infusion every 3 weeks in subsequent cycles.

T-DM1 + Pertuzumab

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.

T-DM1 / T-DM1 + Pertuzumab

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Medical Communications

Cycle 1, Day 1, 15 minutes post-dose [N=44]

Cycle 1, Day 1, 60 minutes post-dose [N=45]

Cycle 1, Day 8 [N=43]

Cycle 3, Day 1, 15 minutes pre-dose [N=35]

Cycle 3, Day 1, 15 minutes post-dose [N=37]

Cycle 3, Day 1, 60 minutes post-dose [N=37]

T-DM1

ECG-evaluable population consisted of patients who received T-DM1, had at least 1 interpretable pre-T-DM1 ECG measurement recorded on Cycle 1 Day 1, had at least 1 interpretable post-T-DM1 ECG measurement and who were not treated with medications that may have altered cardiac conduction. N indicates the ECG-evaluable population at each time point.

Change From Baseline in Mean Duration of the QTc Interval

ECG-Evaluable population; N indicates the ECG-evaluable population with available data at each time point.

Change From Baseline in Mean Duration of the QTc Interval Using Bazett's Correction

Cycle 1 Day 1, 15 minutes post-dose [N=44]

Cycle 1 Day 1, 60 minutes post-dose [N=45]

Cycle 1 Day 8 [N=43]

Cycle 3 Day 1, 15 minutes pre-dose [N=35]

Cycle 3 Day 1, 15 minutes post-dose [N=37]

Cycle 3 Day 1, 60 minutes post-dose [N=37]

Change From Baseline in Uncorrected QT Interval

Change From Baseline in PR Interval

Change From Baseline in QRS Duration

ECG-evaluable population; N indicates the ECG-evaluable population with available data at each time point.

Change From Baseline in Heart Rate

QTcF: Cycle 1, Day 1, 15 minutes post-dose [N=44]

QTcF: Cycle 1, Day 1, 60 minutes post-dose [N=45]

QTcF: Cycle 1, Day 8 [N=43]

QTcF: Cycle 3, Day 1, 15 minutes pre-dose [N=35]

QTcF: Cycle 3, Day 1, 15 minutes post-dose [N=37]

QTcF: Cycle 3, Day 1, 60 minutes post-dose [N=37]

QTcB: Cycle 1, Day 1, 15 minutes post-dose [N=44]

QTcB: Cycle 1, Day 1, 60 minutes post-dose [N=45]

QTcB: Cycle 1, Day 8 [N=43]

QTcB: Cycle 3, Day 1, 15 minutes pre-dose [N=35]

QTcB: Cycle 3, Day 1, 15 minutes post-dose [N=37]

QTcB: Cycle 3, Day 1, 60 minutes post-dose [N=37]

Participants with an average QTc interval less than or equal to 450 ms who received trastuzumab emtansine (T-DM1) by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.

Average QTc Interval ≤ 450 ms

Participants with an average QTc interval greater than 450 and less than or equal to 480 ms who received trastuzumab emtansine (T-DM1) by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.

Average QTc Interval > 450 to ≤ 480 ms

Participants with an average QTc interval greater than 480 and less than or equal to 500 ms who received trastuzumab emtansine (T-DM1) by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.

Average QTc Interval > 480 to ≤ 500 ms

Participants with an average QTc interval greater than 500 ms who received trastuzumab emtansine (T-DM1) by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.

Average QTc Interval > 500 ms

The number of participants analyzed for each QTc interval category represents the total treated population. N indicates the ECG-evaluable population with available data at each time point.

Percentage of Participants Within Each Absolute QTc Interval Category

Participants with an average Baseline-adjusted QTc interval less than or equal to 30 ms who received trastuzumab emtansine (T-DM1) by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.

Baseline-adjusted QTc Interval ≤ 30 ms

Participants with an average Baseline-adjusted QTc interval greater than 30 and less than or equal to 60 ms who received trastuzumab emtansine (T-DM1) by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.

Baseline-adjusted QTc Interval > 30 to ≤ 60 ms

Participants with an average Baseline-adjusted QTc interval greater than 60 ms who received trastuzumab emtansine (T-DM1) by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg.

Baseline-adjusted QTc Interval > 60 ms

Percentage of Participants Within Each Baseline-adjusted QTc Interval Category

Cycle 3, Day 1, 15 minutes post-dose [N=36]

Percentage of Participants With New Abnormal U Waves

Significant: C1D1, 15 minutes post-dose [N=44]

Significant: C1D1, 60 minutes post-dose [N=45]

Significant: C1D8 [N=43]

Significant: C3D1, 15 minutes pre-dose [N=35]

Significant: C3D1, 15 minutes post-dose [N=36]

Significant: C3D1, 60 minutes post-dose [N=37]

Non-Significant: C1D1, 15 minutes post-dose [N=44]

Non-Significant: C1D1, 60 minutes post-dose [N=45]

Non-Significant: C1D8 [N=43]

Non-Significant: C3D1, 15 minutes pre-dose [N=35]

Non-Significant: C3D1, 15 minutes post-dose [N=36]

Non-Significant: C3D1, 60 minutes post-dose [N=37]

Percentage of Participants With New Abnormal T Waves

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.

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.

The efficacy-evaluable population was defined as patients who received at least one dose of study drug. Patients with missing or no post-baseline response assessments were classified as non-responders.

Percentage of Participants With an Objective Response During the Single-agent Trastuzumab Emtansine Treatment Period

Efficacy evaluable patients who achieved an objective response.

Duration of Objective Response Based on Investigator Assessment During the Single-agent Trastuzumab Emtansine Treatment Period

Progression-free Survival During the Single-agent Trastuzumab Emtansine Treatment Period

The efficacy-evaluable population was defined as patients who received at least one dose of study drug.

Percentage of Participants With Clinical Benefit During the Single-agent Trastuzumab Emtansine Treatment Period

Any adverse event

Grade ≥ 3 adverse events

Serious adverse events

Adverse events leading to treatment discontinuatio

Deaths

Safety-Evaluable Patients (i.e., the treated population).

Number of Participants With Adverse Events (AEs)

Grade 3

Overall

Number of Participants With Decreased Ejection Fraction

Cycle 1: T-DM1 [N=51]

Cycle 1: Total trastuzumab [N=51]

Cycle 3: T-Dm1 [N=47]

Cycle 3: Total trastuzumab [N=47]

Pharmacokinetic (PK)-evaluable patients were defined as patients who had adequate concentration-time data to estimate at least one PK parameter. "N" refers to the number of PK-evaluable patients in that cycle.

Maximum Observed Serum Concentration of T-DM1 and Total Trastuzumab

PK-evaluable patients were defined as patients who had adequate concentration-time data to estimate at least one PK parameter. "N" refers to the number of PK-evaluable patients in that cycle.

Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration for T-DM1 and Total Trastuzumab

Total trastuzumab

Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity for T-DM1 and Total Trastuzumab

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

Pre-dose (Baseline)

Post-dose

Evaluable patients, defined as patients who had at least one ATA measurement available for analysis at Baseline (pre-dose in Cycle 1) and post-baseline.

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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