A Study of Pertuzumab With High-Dose Trastuzumab for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (MBC) With Central Nervous System (CNS) Progression Post-Radiotherapy
Study Details
Study Description
Brief Summary
This study will examine the safety and efficacy of pertuzumab in combination with high-dose trastuzumab in adult participants with HER2-positive MBC with CNS metastases and disease progression in the brain following radiotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Pertuzumab + Trastuzumab Participants with CNS metastases secondary to HER2-positive MBC will receive pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. |
Drug: Pertuzumab
Participants will receive 840 milligrams (mg) loading dose of pertuzumab, followed every 3 weeks thereafter by a dose of 420 mg via intravenous (IV) infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.
Other Names:
Drug: Trastuzumab
Participants will receive trastuzumab at a dose of 6 milligrams per kilogram (mg/kg) of body weight once weekly via IV infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria [From Baseline until disease progression (assessed every 6 weeks for first 2 scans, followed by every 8 weeks for 2 scans, then every 12 weeks until disease progression; up to approximately 3.5 years)]
Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. An objective response in the central nervous system (CNS) was a complete response (CR) or partial response (PR) confirmed by repeat assessment, according to RANO-BM criteria. A CR was defined as the disappearance of all CNS target lesions sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically; for non-target lesions, a CR was the disappearance of all enhancing CNS non-target lesions and no new CNS lesions. A PR was defined as at least a 30% decrease in the sum longest diameter (LD) of CNS target lesions, taking as reference the baseline sum LD sustained for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; and stable or improved clinically. The 95% Clopper-Pearson exact confidence intervals were calculated for responses.
Secondary Outcome Measures
- Median Duration of Response in the CNS, Assessed Using RANO-BM Criteria [From documentation of first complete response (CR) or partial response (PR) to the time of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 3.5 years)]
Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. An objective response in the central nervous system (CNS) was a complete response (CR) or partial response (PR) confirmed by repeat assessment, according to RANO-BM criteria. Among participants who achieved an objective response, duration of response in the CNS was defined as the time from documentation of the first CR or PR to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of response was censored on the last date the participant was known to be progression free. Duration of response was estimated by the Kaplan-Meier method.
- Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria [From Baseline until disease progression (assessed every 6 weeks for first 2 scans, followed by every 8 weeks for 2 scans, then every 12 weeks until disease progression; up to approximately 5 years)]
Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 4 months, confirmed by repeat assessment according to RANO-BM criteria. A CR or PR were defined in the same way as for objective response in the CNS. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter (LD) while on study. The 95% Clopper-Pearson exact confidence intervals were calculated for responses.
- Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria [From documentation of first complete response (CR), partial response (PR), or stable disease (SD) ≥4 months to the date of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 5 years)]
Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 4 months, confirmed by repeat assessment according to RANO-BM criteria. Among participants who achieved clinical benefit, duration of clinical benefit in the CNS was defined as the time from documentation of the first CR, PR, or SD ≥4 months to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of clinical benefit was censored on the last date the participant was known to be progression free. Duration of clinical benefit was estimated by the Kaplan-Meier method.
- Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria [From Baseline until disease progression (assessed every 6 weeks for first 2 scans, followed by every 8 weeks for 2 scans, then every 12 weeks until disease progression; up to approximately 5 years)]
Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months, confirmed by repeat assessment according to RANO-BM criteria. A CR or PR were defined in the same way as for objective response in the CNS. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter (LD) while on study. The 95% Clopper-Pearson exact confidence intervals were calculated for responses.
- Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria [From documentation of first complete response (CR), partial response (PR), or stable disease (SD) ≥6 months to the date of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 5 years)]
Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months, confirmed by repeat assessment according to RANO-BM criteria. Among participants who achieved clinical benefit, duration of clinical benefit in the CNS was defined as the time from documentation of the first CR, PR, or SD ≥6 months to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of clinical benefit was censored on the last date the participant was known to be progression free. Duration of clinical benefit was estimated by the Kaplan-Meier method.
- Progression-Free Survival (CNS), Assessed Using RANO-BM Criteria [From the date of first dose to disease progression in the CNS or death from any cause, whichever occurred first (up to approximately 5 years)]
Progression-free survival (CNS) was defined as the time from the date of first dose to disease progression in the CNS or death from any cause. If no progressive disease in the CNS and no death occurred, progression-free survival (CNS) was censored on the date of the last CNS tumor assessment. If a post-baseline assessment was not available, progression-free survival (CNS) was censored on Day 1.
- Progression-Free Survival (Systemic), Assessed Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) [From the date of first dose to systemic disease progression or death from any cause, whichever occurred first (up to approximately 5 years)]
Progression-free survival (systemic) was defined as the time from the date of first dose to systemic disease progression or death from any cause. If no systemic disease progression and no death occurred, progression-free survival (systemic) was censored on the date of the last systemic tumor assessment. If a post-baseline assessment was not available, progression-free survival (systemic) was censored on Day 1.
- Progression-Free Survival (CNS or Systemic), Assessed Using RANO-BM Criteria and RECIST v1.1 [From the date of first dose to CNS or systemic disease progression or death from any cause, whichever occurred first (up to approximately 5 years)]
Progression-free survival (CNS or systemic) was defined as the time from the date of first dose to CNS or systemic disease progression or death from any cause. If no CNS or systemic disease progression and no death occurred, data was censored on the date of the last CNS or systemic tumor assessment, whichever occurred first. If a post-baseline assessment was not available, data was censored on Day 1.
- Overall Survival [From the date of first dose until death due to any cause (up to approximately 5 years)]
Overall survival was defined as the period from the date of first dose until the date of death from any cause. If no death occurred, overall survival was censored on the last date the participant was known to be alive.
- Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death [From date of first dose until death due to any cause (up to approximately 5 years)]
- Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) by Highest Grade of Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) [From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)]
Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.
- Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 [From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)]
Treatment-emergent serious adverse events (SAEs) were defined as all adverse events that met seriousness criteria (as defined in the protocol; same as the ClinicalTrials.gov definition) occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All SAEs were graded for severity using the NCI-CTCAE v4.0; any SAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe or medically significant, but not immediately life-threatening; Grade 4 = life-threatening consequences or urgent intervention indicated; and Grade 5 = death related to adverse event. The terms "severe" and "serious" are not synonymous and are independently assessed for each adverse event. Multiple occurrences of SAEs were counted only once per participant at the highest (worst) grade.
- Number of Participants With at Least One TEAE Leading to Withdrawal of Any Study Drug, Pertuzumab Only, or Both Pertuzumab and Trastuzumab, by Highest Grade of Severity According to NCI-CTCAE v4.0 [From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)]
Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.
- Number of Participants With at Least One TEAE Leading to Pertuzumab Infusion Delay, Slow Down, or Interruption, by Highest Grade of Severity According to NCI-CTCAE v4.0 [From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)]
Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.
- Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 [From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)]
Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.
- Percentage of Participants With at Least One TEAE of Special Interest by Highest Grade of Severity, According to NCI-CTCAE v4.0 [From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)]
Protocol-defined TEAEs of special interest, occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment, included the following: An elevated ALT or AST (>3 times baseline value) in combination with either an elevated total bilirubin (>2 times the upper limit of normal) or clinical jaundice; Suspected transmission of an infectious agent by the study treatment; Congestive heart failure; An asymptomatic decline in LVEF (a value 10 percentage points below baseline or lower, and <45%) that requires treatment or that leads to discontinuation of study treatment. All TEAEs of special interest were graded for severity using the NCI-CTCAE v4.0. Multiple occurrences of TEAEs of special interest were counted only once per participant at the highest (worst) grade.
- Median Left Ventricular Ejection Fraction (LVEF) Values Over Time [Baseline, Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 132 (Treatment Period); and every 3 months during Survival Follow-Up (up to approximately 5 years)]
Left ventricular ejection fraction (LVEF) is the measurement of the percentage of blood that is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. All participants were required to have had a baseline LVEF of at least 50% to participate in this study. Measurements were done by either echocardiogram (ECHO) or mulitple-gated acquisition (MUGA) scan (with ECHO as the preferred method). Participants were to be reassessed with the same technique used for baseline cardiac evaluation throughout the study.
- Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time [Baseline, Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 132 (Treatment Period); and every 3 months during Survival Follow-Up (up to approximately 5 years)]
Left ventricular ejection fraction (LVEF) is the measurement of the percentage of blood that is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. All participants were required to have had a baseline LVEF of at least (≥)50% to participate in this study. Measurements were done by either echocardiogram (ECHO) or mulitple-gated acquisition (MUGA) scan (with ECHO as the preferred method). Participants were to be reassessed with the same technique used for baseline cardiac evaluation throughout the study. The following are definitions for the three categories of LVEF findings: 'Normal' was defined as LVEF >45% or LVEF 40-45% with less than (<)10% points drop below baseline; 'Abnormal' was defined as LVEF <40% or LVEF ≥10% points drop below baseline, and clinically significant versus non-clinically significant was subject to the investigator's assessment of whether symptoms were present or absent.
- Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time [Baseline, Weeks 18, 36, and 60 (up to approximately 5 years)]
Clinical laboratory tests for hematology parameters were performed every 6 weeks and any abnormal values (High or Low) were based on NCI-CTCAE v4.0 grades. Laboratory abnormalities of NCI-CTCAE v4.0 Grades 3 and 4 are presented. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. For the overall category, multiple occurrences of the same laboratory abnormality over time in one participant were only counted once.
- Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time [Weeks 6, 12, and 18, and Unscheduled Visits (up to approximately 5 years)]
Clinical laboratory tests for blood chemistry parameters were performed every 6 weeks and any abnormal values (High or Low) were based on NCI-CTCAE v4.0 grades. Laboratory abnormalities of NCI-CTCAE v4.0 Grades 3 and 4 are presented. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. For the overall category, multiple occurrences of the same laboratory abnormality over time in one participant were only counted once.
- Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints [Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16]
Per protocol eligibility criteria, participants were not required to be pertuzumab naïve; therefore pertuzumab was detectable in some participants pre-dose at Week 1.
- Maximum Serum Concentrations (Cmax) of Pertuzumab at Specified Timepoints [Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16]
- Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints [Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16]
Per protocol eligibility criteria, participants were not required to be trastuzumab naïve; therefore trastuzumab was detectable in some participants pre-dose at Week 1.
- Maximum Serum Concentrations (Cmax) of Trastuzumab at Specified Timepoints [Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16]
- Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire [Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64]
The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related symptoms (Cleeland et al. 2000) that are sensitive to disease and treatment changes. The MDASI-BT is composed of the symptom severity scale and the symptom interference scale. In the symptom severity scale, participants rate the severity of their symptoms in the last 24 hours on 0-10 numeric scales, ranging from 0 = "not present" to 10 = "as bad as you can imagine." The MDASI-BT symptom severity scale score will be calculated by (sum of total scores of non-missing items) divided by (total number of non-missing items), if participants answered at least 12 of the 22 severity scale items. The score will be considered missing if less than 12 items are completed.
- Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire [Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64]
The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related symptoms that are sensitive to disease and treatment changes. The MDASI-BT is composed of the symptom severity scale and the symptom interference scale. In the symptom interference scale, participants rate interference with daily activities caused by their symptoms on 0-10 numeric scales ranging from 0 = "did not interfere" to 10 = "interfered completely." The MDASI-BT symptom interference scale score will be calculated by (sum of total scores of non-missing items) divided by (total number of non-missing items), if participants answered at least 4 of the 6 interference scale items. The score will be considered missing if less than 4 items are completed.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Pathologically confirmed HER2-positive MBC
-
Progression of or new brain metastases after completion of whole-brain radiotherapy or stereotactic radiosurgery
-
Completion of whole-brain radiotherapy or stereotactic radiosurgery more than 60 days prior to enrollment
-
Stable systemic disease
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
-
LVEF at least 50%
-
Adequate hematologic, renal, and hepatic function
-
Life expectancy more than 12 weeks
Exclusion Criteria:
-
Progression of systemic disease at Screening
-
Leptomeningeal disease
-
History of intolerance or hypersensitivity to study drug
-
Use of certain investigational therapies within 21 days prior to enrollment
-
Current anthracycline use
-
Unwillingness to discontinue ado-trastuzumab emtansine or lapatinib use
-
Active infection
-
Pregnant or lactating women
-
Significant history or risk of cardiac disease
-
Symptomatic intrinsic lung disease or lung involvement
-
History of other malignancy within the last 5 years
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Arizona Cancer Center | Tucson | Arizona | United States | 85719 |
| 2 | City of Hope National Medical Center | Duarte | California | United States | 91010 |
| 3 | Stanford Cancer Institute | Stanford | California | United States | 94305 |
| 4 | University of Miami Hospital & Clinics | Miami | Florida | United States | 33136 |
| 5 | H. Lee Moffitt Cancer Center and Research Inst. | Tampa | Florida | United States | 33612 |
| 6 | Northwestern University | Chicago | Illinois | United States | 60611-2987 |
| 7 | University of Maryland Medical Center; Department of Neurology | Baltimore | Maryland | United States | 21201 |
| 8 | Associates in Oncology-Hematology, PC | Bethesda | Maryland | United States | 20817 |
| 9 | Dana Farber Cancer Inst. | Boston | Massachusetts | United States | 02115 |
| 10 | Allina Health System | Saint Paul | Minnesota | United States | 55102 |
| 11 | Stony Brook University Medical Center | Stony Brook | New York | United States | 11794 |
| 12 | Mid Ohio Oncology Hematology;ZangMeister Center (West) | Columbus | Ohio | United States | 43213 |
| 13 | Temple Cancer Center; Oncology | Philadelphia | Pennsylvania | United States | 19140 |
| 14 | Methodist Hospital Research Institute | Houston | Texas | United States | 77030 |
| 15 | Huntsman Cancer Institute; University of Utah | Salt Lake City | Utah | United States | 84112 |
| 16 | Northwest Medical Specialties, PLLC | Tacoma | Washington | United States | 98405 |
Sponsors and Collaborators
- Genentech, Inc.
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
More Information
Publications
None provided.- ML29366
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Period Title: Overall Study | |
| STARTED | 40 |
| Received at Least One Dose of Study Drug | 39 |
| Efficacy-Evaluable Population | 37 |
| COMPLETED | 12 |
| NOT COMPLETED | 28 |
Baseline Characteristics
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Overall Participants | 40 |
| Age (Years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [Years] |
50.0
(9.78)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
40
100%
|
| Male |
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
6
15%
|
| Not Hispanic or Latino |
33
82.5%
|
| Unknown or Not Reported |
1
2.5%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| White |
36
90%
|
| Asian |
2
5%
|
| Other Race |
1
2.5%
|
| Not Reported |
1
2.5%
|
| Women of Childbearing Potential Status (Count of Participants) | |
| Childbearing Potential |
12
30%
|
| Non-Childbearing Potential - Postmenopausal |
21
52.5%
|
| Non-Childbearing Potential - Surgically Sterile |
7
17.5%
|
| Left Ventricular Ejection Fraction (LVEF) Value at Baseline (Percentage Points of LVEF (%)) [Median (Full Range) ] | |
| Median (Full Range) [Percentage Points of LVEF (%)] |
60.00
|
Outcome Measures
| Title | Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria |
|---|---|
| Description | Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. An objective response in the central nervous system (CNS) was a complete response (CR) or partial response (PR) confirmed by repeat assessment, according to RANO-BM criteria. A CR was defined as the disappearance of all CNS target lesions sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically; for non-target lesions, a CR was the disappearance of all enhancing CNS non-target lesions and no new CNS lesions. A PR was defined as at least a 30% decrease in the sum longest diameter (LD) of CNS target lesions, taking as reference the baseline sum LD sustained for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; and stable or improved clinically. The 95% Clopper-Pearson exact confidence intervals were calculated for responses. |
| Time Frame | From Baseline until disease progression (assessed every 6 weeks for first 2 scans, followed by every 8 weeks for 2 scans, then every 12 weeks until disease progression; up to approximately 3.5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 37 |
| With Objective Response (Confirmed CR or PR) |
10.8
27%
|
| Confirmed Complete Response (CR) |
0.0
0%
|
| Confirmed Partial Response (PR) |
10.8
27%
|
| Without Objective Response |
89.2
223%
|
| Title | Median Duration of Response in the CNS, Assessed Using RANO-BM Criteria |
|---|---|
| Description | Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. An objective response in the central nervous system (CNS) was a complete response (CR) or partial response (PR) confirmed by repeat assessment, according to RANO-BM criteria. Among participants who achieved an objective response, duration of response in the CNS was defined as the time from documentation of the first CR or PR to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of response was censored on the last date the participant was known to be progression free. Duration of response was estimated by the Kaplan-Meier method. |
| Time Frame | From documentation of first complete response (CR) or partial response (PR) to the time of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 3.5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. Only participants who had a confirmed CR or PR in the CNS were included in this analysis. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 4 |
| Median (Full Range) [Months] |
4.60
|
| Title | Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria |
|---|---|
| Description | Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 4 months, confirmed by repeat assessment according to RANO-BM criteria. A CR or PR were defined in the same way as for objective response in the CNS. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter (LD) while on study. The 95% Clopper-Pearson exact confidence intervals were calculated for responses. |
| Time Frame | From Baseline until disease progression (assessed every 6 weeks for first 2 scans, followed by every 8 weeks for 2 scans, then every 12 weeks until disease progression; up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 37 |
| With Clinical Benefit (Confirmed CR,PR,or SD≥4mos) |
67.6
169%
|
| Confirmed Complete Response (CR) |
0.0
0%
|
| Confirmed Partial Response (PR) |
10.8
27%
|
| Confirmed Stable Disease (SD) ≥4 Months |
56.8
142%
|
| Without Clinical Benefit |
32.4
81%
|
| Title | Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria |
|---|---|
| Description | Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 4 months, confirmed by repeat assessment according to RANO-BM criteria. Among participants who achieved clinical benefit, duration of clinical benefit in the CNS was defined as the time from documentation of the first CR, PR, or SD ≥4 months to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of clinical benefit was censored on the last date the participant was known to be progression free. Duration of clinical benefit was estimated by the Kaplan-Meier method. |
| Time Frame | From documentation of first complete response (CR), partial response (PR), or stable disease (SD) ≥4 months to the date of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. Only those with confirmed CR, PR, or SD ≥4 months in the CNS were included in this analysis. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 25 |
| Median (Full Range) [Months] |
6.64
|
| Title | Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria |
|---|---|
| Description | Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months, confirmed by repeat assessment according to RANO-BM criteria. A CR or PR were defined in the same way as for objective response in the CNS. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter (LD) while on study. The 95% Clopper-Pearson exact confidence intervals were calculated for responses. |
| Time Frame | From Baseline until disease progression (assessed every 6 weeks for first 2 scans, followed by every 8 weeks for 2 scans, then every 12 weeks until disease progression; up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 37 |
| With Clinical Benefit (Confirmed CR,PR,or SD≥6mos) |
51.4
128.5%
|
| Confirmed Complete Response (CR) |
0.0
0%
|
| Confirmed Partial Response (PR) |
10.8
27%
|
| Confirmed Stable Disease (SD) ≥6 Months |
40.5
101.3%
|
| Without Clinical Benefit |
48.6
121.5%
|
| Title | Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria |
|---|---|
| Description | Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months, confirmed by repeat assessment according to RANO-BM criteria. Among participants who achieved clinical benefit, duration of clinical benefit in the CNS was defined as the time from documentation of the first CR, PR, or SD ≥6 months to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of clinical benefit was censored on the last date the participant was known to be progression free. Duration of clinical benefit was estimated by the Kaplan-Meier method. |
| Time Frame | From documentation of first complete response (CR), partial response (PR), or stable disease (SD) ≥6 months to the date of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. Only those with confirmed CR, PR, or SD ≥6 months in the CNS were included in this analysis. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 19 |
| Median (Full Range) [Months] |
9.23
|
| Title | Progression-Free Survival (CNS), Assessed Using RANO-BM Criteria |
|---|---|
| Description | Progression-free survival (CNS) was defined as the time from the date of first dose to disease progression in the CNS or death from any cause. If no progressive disease in the CNS and no death occurred, progression-free survival (CNS) was censored on the date of the last CNS tumor assessment. If a post-baseline assessment was not available, progression-free survival (CNS) was censored on Day 1. |
| Time Frame | From the date of first dose to disease progression in the CNS or death from any cause, whichever occurred first (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 37 |
| Median (Full Range) [Months] |
4.63
|
| Title | Progression-Free Survival (Systemic), Assessed Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) |
|---|---|
| Description | Progression-free survival (systemic) was defined as the time from the date of first dose to systemic disease progression or death from any cause. If no systemic disease progression and no death occurred, progression-free survival (systemic) was censored on the date of the last systemic tumor assessment. If a post-baseline assessment was not available, progression-free survival (systemic) was censored on Day 1. |
| Time Frame | From the date of first dose to systemic disease progression or death from any cause, whichever occurred first (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 37 |
| Median (Full Range) [Months] |
16.26
|
| Title | Progression-Free Survival (CNS or Systemic), Assessed Using RANO-BM Criteria and RECIST v1.1 |
|---|---|
| Description | Progression-free survival (CNS or systemic) was defined as the time from the date of first dose to CNS or systemic disease progression or death from any cause. If no CNS or systemic disease progression and no death occurred, data was censored on the date of the last CNS or systemic tumor assessment, whichever occurred first. If a post-baseline assessment was not available, data was censored on Day 1. |
| Time Frame | From the date of first dose to CNS or systemic disease progression or death from any cause, whichever occurred first (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 37 |
| Median (Full Range) [Months] |
4.63
|
| Title | Overall Survival |
|---|---|
| Description | Overall survival was defined as the period from the date of first dose until the date of death from any cause. If no death occurred, overall survival was censored on the last date the participant was known to be alive. |
| Time Frame | From the date of first dose until death due to any cause (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy-Evaluable Population: all participants who received any dose of study treatment and had at least one follow-up CNS tumor assessment or died without follow-up tumor assessment within 30 days from the last dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 37 |
| Median (Full Range) [Months] |
27.17
|
| Title | Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death |
|---|---|
| Description | |
| Time Frame | From date of first dose until death due to any cause (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| All Deaths |
20
50%
|
| Deaths ≤30 Days From Last Dose of Study Drug |
1
2.5%
|
| Deaths >30 Days From Last Dose of Study Drug |
19
47.5%
|
| Primary Cause of Death: Progressive Disease |
16
40%
|
| Primary Cause of Death: Other Cause (and Cancer) |
1
2.5%
|
| Primary Cause of Death: Unknown |
3
7.5%
|
| Title | Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) by Highest Grade of Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) |
|---|---|
| Description | Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade. |
| Time Frame | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Any TEAE - Any Grade |
38
95%
|
| Any TEAE - Grade 1 |
5
12.5%
|
| Any TEAE - Grade 2 |
16
40%
|
| Any TEAE - Grade 3 |
14
35%
|
| Any TEAE - Grade 4 |
3
7.5%
|
| Any TEAE - Grade 5 |
0
0%
|
| Title | Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 |
|---|---|
| Description | Treatment-emergent serious adverse events (SAEs) were defined as all adverse events that met seriousness criteria (as defined in the protocol; same as the ClinicalTrials.gov definition) occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All SAEs were graded for severity using the NCI-CTCAE v4.0; any SAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe or medically significant, but not immediately life-threatening; Grade 4 = life-threatening consequences or urgent intervention indicated; and Grade 5 = death related to adverse event. The terms "severe" and "serious" are not synonymous and are independently assessed for each adverse event. Multiple occurrences of SAEs were counted only once per participant at the highest (worst) grade. |
| Time Frame | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Any SAE - Any Grade |
7
17.5%
|
| Any SAE - Grade 1 |
0
0%
|
| Any SAE - Grade 2 |
1
2.5%
|
| Any SAE - Grade 3 |
5
12.5%
|
| Any SAE - Grade 4 |
2
5%
|
| Any SAE - Grade 5 |
0
0%
|
| Title | Number of Participants With at Least One TEAE Leading to Withdrawal of Any Study Drug, Pertuzumab Only, or Both Pertuzumab and Trastuzumab, by Highest Grade of Severity According to NCI-CTCAE v4.0 |
|---|---|
| Description | Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade. |
| Time Frame | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Withdrawal of Any Study Drug - Any Grade TEAE |
2
5%
|
| Withdrawal of Any Study Drug - Grade 3 TEAE |
2
5%
|
| Withdrawal of Pertuzumab Only - Any Grade TEAE |
0
0%
|
| Withdrawal of Both Study Drugs - Any Grade TEAE |
2
5%
|
| Withdrawal of Both Study Drugs - Grade 3 TEAE |
2
5%
|
| Title | Number of Participants With at Least One TEAE Leading to Pertuzumab Infusion Delay, Slow Down, or Interruption, by Highest Grade of Severity According to NCI-CTCAE v4.0 |
|---|---|
| Description | Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade. |
| Time Frame | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Any TEAE - Any Grade |
7
17.5%
|
| Any TEAE - Grade 1 |
1
2.5%
|
| Any TEAE - Grade 2 |
4
10%
|
| Any TEAE - Grade 3 |
1
2.5%
|
| Any TEAE - Grade 4 |
1
2.5%
|
| Any TEAE - Grade 5 |
0
0%
|
| Title | Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 |
|---|---|
| Description | Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade. |
| Time Frame | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Any TEAE - Any Grade |
12
30%
|
| Any TEAE - Grade 1 |
2
5%
|
| Any TEAE - Grade 2 |
4
10%
|
| Any TEAE - Grade 3 |
5
12.5%
|
| Any TEAE - Grade 4 |
1
2.5%
|
| Any TEAE - Grade 5 |
0
0%
|
| Title | Percentage of Participants With at Least One TEAE of Special Interest by Highest Grade of Severity, According to NCI-CTCAE v4.0 |
|---|---|
| Description | Protocol-defined TEAEs of special interest, occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment, included the following: An elevated ALT or AST (>3 times baseline value) in combination with either an elevated total bilirubin (>2 times the upper limit of normal) or clinical jaundice; Suspected transmission of an infectious agent by the study treatment; Congestive heart failure; An asymptomatic decline in LVEF (a value 10 percentage points below baseline or lower, and <45%) that requires treatment or that leads to discontinuation of study treatment. All TEAEs of special interest were graded for severity using the NCI-CTCAE v4.0. Multiple occurrences of TEAEs of special interest were counted only once per participant at the highest (worst) grade. |
| Time Frame | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Any TEAE of Special Interest - Any Grade |
2.6
6.5%
|
| Asymptomatic Decline in LVEF - Grade 3 |
2.6
6.5%
|
| Title | Median Left Ventricular Ejection Fraction (LVEF) Values Over Time |
|---|---|
| Description | Left ventricular ejection fraction (LVEF) is the measurement of the percentage of blood that is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. All participants were required to have had a baseline LVEF of at least 50% to participate in this study. Measurements were done by either echocardiogram (ECHO) or mulitple-gated acquisition (MUGA) scan (with ECHO as the preferred method). Participants were to be reassessed with the same technique used for baseline cardiac evaluation throughout the study. |
| Time Frame | Baseline, Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 132 (Treatment Period); and every 3 months during Survival Follow-Up (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. Only participants with evaluable assessments at each visit were included in the analysis. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Baseline |
60.00
|
| Week 6 |
60.00
|
| Week 12 |
60.00
|
| Week 24 |
60.00
|
| Week 36 |
60.00
|
| Week 48 |
60.00
|
| Week 60 |
62.00
|
| Week 72 |
55.50
|
| Week 84 |
60.00
|
| Week 96 |
63.00
|
| Week 108 |
62.00
|
| Week 120 |
64.00
|
| Week 132 |
64.00
|
| Survival Follow-Up 1 |
60.00
|
| Survival Follow-Up 2 |
59.00
|
| Survival Follow-Up 3 |
60.00
|
| Survival Follow-Up 4 |
69.00
|
| Survival Follow-Up 5 |
67.00
|
| Survival Follow-Up 6 |
57.00
|
| Survival Follow-Up 7 |
57.50
|
| Survival Follow-Up 8 |
57.00
|
| Title | Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time |
|---|---|
| Description | Left ventricular ejection fraction (LVEF) is the measurement of the percentage of blood that is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. All participants were required to have had a baseline LVEF of at least (≥)50% to participate in this study. Measurements were done by either echocardiogram (ECHO) or mulitple-gated acquisition (MUGA) scan (with ECHO as the preferred method). Participants were to be reassessed with the same technique used for baseline cardiac evaluation throughout the study. The following are definitions for the three categories of LVEF findings: 'Normal' was defined as LVEF >45% or LVEF 40-45% with less than (<)10% points drop below baseline; 'Abnormal' was defined as LVEF <40% or LVEF ≥10% points drop below baseline, and clinically significant versus non-clinically significant was subject to the investigator's assessment of whether symptoms were present or absent. |
| Time Frame | Baseline, Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 132 (Treatment Period); and every 3 months during Survival Follow-Up (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. Only participants with evaluable assessments at each visit were included in the analysis. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Normal |
39
97.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
33
82.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
1
2.5%
|
| Normal |
30
75%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
14
35%
|
| Abnormal, Not Clinically Significant |
1
2.5%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
9
22.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
6
15%
|
| Abnormal, Not Clinically Significant |
1
2.5%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
6
15%
|
| Abnormal, Not Clinically Significant |
1
2.5%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
4
10%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
3
7.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
3
7.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
2
5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
1
2.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
1
2.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
5
12.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
12
30%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
5
12.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
1
2.5%
|
| Abnormal, Not Clinically Significant |
1
2.5%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
3
7.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
3
7.5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
2
5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Normal |
2
5%
|
| Abnormal, Not Clinically Significant |
0
0%
|
| Abnormal, Clinically Significant |
0
0%
|
| Title | Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time |
|---|---|
| Description | Clinical laboratory tests for hematology parameters were performed every 6 weeks and any abnormal values (High or Low) were based on NCI-CTCAE v4.0 grades. Laboratory abnormalities of NCI-CTCAE v4.0 Grades 3 and 4 are presented. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. For the overall category, multiple occurrences of the same laboratory abnormality over time in one participant were only counted once. |
| Time Frame | Baseline, Weeks 18, 36, and 60 (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. Only participants with evaluable assessments at each visit were included in the analysis. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Overall: Lymphocytes (10^9/L), Low - Grade 3 |
3
7.5%
|
| Overall: Lymphocytes (10^9/L), High - Grade 3 |
0
0%
|
| Overall: Lymphocytes (10^9/L), Low - Grade 4 |
1
2.5%
|
| Overall: Lymphocytes (10^9/L), High - Grade 4 |
0
0%
|
| Baseline: Lymphocytes (10^9/L), Low - Grade 3 |
2
5%
|
| Baseline: Lymphocytes (10^9/L), Low - Grade 4 |
0
0%
|
| Week 18: Lymphocytes (10^9/L), Low - Grade 3 |
1
2.5%
|
| Week 18: Lymphocytes (10^9/L), Low - Grade 4 |
0
0%
|
| Week 36: Lymphocytes (10^9/L), Low - Grade 3 |
1
2.5%
|
| Week 36: Lymphocytes (10^9/L), Low - Grade 4 |
0
0%
|
| Week 60: Lymphocytes (10^9/L), Low - Grade 3 |
0
0%
|
| Week 60: Lymphocytes (10^9/L), Low - Grade 4 |
1
2.5%
|
| Title | Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time |
|---|---|
| Description | Clinical laboratory tests for blood chemistry parameters were performed every 6 weeks and any abnormal values (High or Low) were based on NCI-CTCAE v4.0 grades. Laboratory abnormalities of NCI-CTCAE v4.0 Grades 3 and 4 are presented. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. For the overall category, multiple occurrences of the same laboratory abnormality over time in one participant were only counted once. |
| Time Frame | Weeks 6, 12, and 18, and Unscheduled Visits (up to approximately 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: all participants who received at least one dose of study treatment. Only participants with evaluable assessments at each visit were included in the analysis. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Overall: Glucose (mmol/L), Low - Grade 3 |
0
0%
|
| Overall: Glucose (mmol/L), High - Grade 3 |
2
5%
|
| Overall: Glucose (mmol/L), Low - Grade 4 |
0
0%
|
| Overall: Glucose (mmol/L), High - Grade 4 |
0
0%
|
| Week 6: Glucose (mmol/L), High - Grade 3 |
1
2.5%
|
| Week 12: Glucose (mmol/L), High - Grade 3 |
1
2.5%
|
| Week 18: Glucose (mmol/L), High - Grade 3 |
1
2.5%
|
| Overall: Potassium (mmol/L), Low - Grade 3 |
0
0%
|
| Overall: Potassium (mmol/L), High - Grade 3 |
0
0%
|
| Overall: Potassium (mmol/L), Low - Grade 4 |
1
2.5%
|
| Overall: Potassium (mmol/L), High - Grade 4 |
0
0%
|
| Unscheduled Visit: Potassium (mmol/L),Low -Grade 4 |
1
2.5%
|
| Title | Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints |
|---|---|
| Description | Per protocol eligibility criteria, participants were not required to be pertuzumab naïve; therefore pertuzumab was detectable in some participants pre-dose at Week 1. |
| Time Frame | Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetics (PK)-Evaluable Population: all participants who received any dose of study treatment and had at least one PK assessment unless there were major protocol deviations or if information impacting PK evaluation (e.g., exact blood sampling time, labeling error, technical failure in sample analysis) were unavailable. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Week 1 Day 1 |
43.12
(101.45)
|
| Week 4 Day 1 |
88.03
(29.91)
|
| Week 10 Day 1 |
94.46
(38.47)
|
| Week 16 Day 1 |
101.99
(41.59)
|
| Title | Maximum Serum Concentrations (Cmax) of Pertuzumab at Specified Timepoints |
|---|---|
| Description | |
| Time Frame | Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetics (PK)-Evaluable Population: all participants who received any dose of study treatment and had at least one PK assessment unless there were major protocol deviations or if information impacting PK evaluation (e.g., exact blood sampling time, labeling error, technical failure in sample analysis) were unavailable. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Week 1 Day 1 |
275.94
(88.80)
|
| Week 16 Day 1 |
225.55
(56.22)
|
| Title | Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints |
|---|---|
| Description | Per protocol eligibility criteria, participants were not required to be trastuzumab naïve; therefore trastuzumab was detectable in some participants pre-dose at Week 1. |
| Time Frame | Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetics (PK)-Evaluable Population: all participants who received any dose of study treatment and had at least one PK assessment unless there were major protocol deviations or if information impacting PK evaluation (e.g., exact blood sampling time, labeling error, technical failure in sample analysis) were unavailable. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Week 1 Day 1 |
57.00
(52.73)
|
| Week 4 Day 1 |
190.82
(52.22)
|
| Week 10 Day 1 |
294.50
(70.33)
|
| Week 16 Day 1 |
306.14
(90.22)
|
| Title | Maximum Serum Concentrations (Cmax) of Trastuzumab at Specified Timepoints |
|---|---|
| Description | |
| Time Frame | Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetics (PK)-Evaluable Population: all participants who received any dose of study treatment and had at least one PK assessment unless there were major protocol deviations or if information impacting PK evaluation (e.g., exact blood sampling time, labeling error, technical failure in sample analysis) were unavailable. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 39 |
| Week 1 Day 1 |
181.43
(72.49)
|
| Week 16 Day 1 |
394.14
(94.09)
|
| Title | Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire |
|---|---|
| Description | The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related symptoms (Cleeland et al. 2000) that are sensitive to disease and treatment changes. The MDASI-BT is composed of the symptom severity scale and the symptom interference scale. In the symptom severity scale, participants rate the severity of their symptoms in the last 24 hours on 0-10 numeric scales, ranging from 0 = "not present" to 10 = "as bad as you can imagine." The MDASI-BT symptom severity scale score will be calculated by (sum of total scores of non-missing items) divided by (total number of non-missing items), if participants answered at least 12 of the 22 severity scale items. The score will be considered missing if less than 12 items are completed. |
| Time Frame | Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patient-Reported Outcome (PRO)-Evaluable Population: all treated participants who had both a nonmissing baseline and at least one post-baseline PRO assessment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 36 |
| Baseline |
1.65
(1.618)
|
| Week 6 |
1.97
(1.822)
|
| Week 12 |
2.24
(2.141)
|
| Week 20 |
2.09
(2.111)
|
| Week 28 |
1.94
(2.547)
|
| Week 40 |
2.78
(2.856)
|
| Week 52 |
3.53
(3.018)
|
| Week 64 |
3.12
(2.500)
|
| Title | Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire |
|---|---|
| Description | The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related symptoms that are sensitive to disease and treatment changes. The MDASI-BT is composed of the symptom severity scale and the symptom interference scale. In the symptom interference scale, participants rate interference with daily activities caused by their symptoms on 0-10 numeric scales ranging from 0 = "did not interfere" to 10 = "interfered completely." The MDASI-BT symptom interference scale score will be calculated by (sum of total scores of non-missing items) divided by (total number of non-missing items), if participants answered at least 4 of the 6 interference scale items. The score will be considered missing if less than 4 items are completed. |
| Time Frame | Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patient-Reported Outcome (PRO)-Evaluable Population: all treated participants who had both a nonmissing baseline and at least one post-baseline PRO assessment. |
| Arm/Group Title | Pertuzumab + Trastuzumab |
|---|---|
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. |
| Measure Participants | 36 |
| Baseline |
2.51
(2.629)
|
| Week 6 |
2.23
(2.787)
|
| Week 12 |
2.81
(3.391)
|
| Week 20 |
2.11
(2.858)
|
| Week 28 |
1.76
(2.427)
|
| Week 40 |
3.24
(3.548)
|
| Week 52 |
4.25
(3.522)
|
| Week 64 |
3.93
(3.570)
|
Adverse Events
| Time Frame | From first dose of study drug until 30 days after last dose of study drug (except for serious AEs related to treatment; up to approximately 5 years) | |
|---|---|---|
| Adverse Event Reporting Description | Investigators seek information on adverse events (AEs) at each patient contact. All AEs were recorded, regardless of who reported them. After informed consent but prior to initiation of study drug, only serious AEs caused by protocol-mandated intervention were to be reported. After initiation of study drug, all AEs were to be reported until 30 days after the last dose of study drug. After this period, only serious AEs believed to be related to prior study drug treatment were to be reported. | |
| Arm/Group Title | Pertuzumab + Trastuzumab | |
| Arm/Group Description | Participants with CNS metastases secondary to HER2-positive MBC, who had disease progression in the brain following previous treatment with radiotherapy (whole-brain radiation therapy or stereotactic radiosurgery) for brain metastases, received treatment with pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor, whichever occurred first. | |
All Cause Mortality |
||
| Pertuzumab + Trastuzumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 20/39 (51.3%) | |
Serious Adverse Events |
||
| Pertuzumab + Trastuzumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 7/39 (17.9%) | |
| Infections and infestations | ||
| Gastroenteritis viral | 1/39 (2.6%) | 1 |
| Parainfluenzae virus infection | 1/39 (2.6%) | 1 |
| Nervous system disorders | ||
| Seizure | 4/39 (10.3%) | 4 |
| Headache | 1/39 (2.6%) | 1 |
| Hydrocephalus | 1/39 (2.6%) | 1 |
| Vascular disorders | ||
| Hypertension | 1/39 (2.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Pertuzumab + Trastuzumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 38/39 (97.4%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 3/39 (7.7%) | 3 |
| Ear and labyrinth disorders | ||
| Ear pain | 2/39 (5.1%) | 2 |
| Eye disorders | ||
| Vision blurred | 4/39 (10.3%) | 6 |
| Dry eye | 2/39 (5.1%) | 2 |
| Gastrointestinal disorders | ||
| Diarrhoea | 23/39 (59%) | 30 |
| Nausea | 12/39 (30.8%) | 21 |
| Vomiting | 12/39 (30.8%) | 16 |
| Constipation | 7/39 (17.9%) | 9 |
| Dry mouth | 3/39 (7.7%) | 4 |
| Dysphagia | 4/39 (10.3%) | 4 |
| Abdominal distension | 2/39 (5.1%) | 6 |
| Abdominal pain | 2/39 (5.1%) | 5 |
| Dyspepsia | 3/39 (7.7%) | 5 |
| Stomatitis | 2/39 (5.1%) | 2 |
| Abdominal pain upper | 2/39 (5.1%) | 2 |
| Rectal haemorrhage | 2/39 (5.1%) | 2 |
| General disorders | ||
| Fatigue | 17/39 (43.6%) | 21 |
| Asthenia | 6/39 (15.4%) | 6 |
| Gait disturbance | 5/39 (12.8%) | 5 |
| Pain | 4/39 (10.3%) | 4 |
| Mucosal inflammation | 3/39 (7.7%) | 3 |
| Oedema peripheral | 2/39 (5.1%) | 5 |
| Pyrexia | 2/39 (5.1%) | 2 |
| Swelling face | 2/39 (5.1%) | 2 |
| Infections and infestations | ||
| Upper respiratory tract infection | 6/39 (15.4%) | 10 |
| Urinary tract infection | 5/39 (12.8%) | 11 |
| Gastroenteritis viral | 2/39 (5.1%) | 2 |
| Nasopharyngitis | 2/39 (5.1%) | 2 |
| Sinusitis | 2/39 (5.1%) | 2 |
| Injury, poisoning and procedural complications | ||
| Fall | 4/39 (10.3%) | 7 |
| Contusion | 3/39 (7.7%) | 3 |
| Infusion related reaction | 3/39 (7.7%) | 3 |
| Investigations | ||
| Alanine aminotransferase increased | 3/39 (7.7%) | 3 |
| Aspartate aminotransferase increased | 3/39 (7.7%) | 3 |
| Blood alkaline phosphatase increased | 2/39 (5.1%) | 2 |
| Neutrophil count decreased | 2/39 (5.1%) | 5 |
| Platelet count decreased | 2/39 (5.1%) | 2 |
| Weight increased | 2/39 (5.1%) | 3 |
| White blood cell count decreased | 2/39 (5.1%) | 4 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 6/39 (15.4%) | 6 |
| Hypokalaemia | 6/39 (15.4%) | 7 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 4/39 (10.3%) | 7 |
| Arthralgia | 4/39 (10.3%) | 8 |
| Muscle spasms | 4/39 (10.3%) | 5 |
| Muscular weakness | 3/39 (7.7%) | 4 |
| Pain in extremity | 4/39 (10.3%) | 5 |
| Musculoskeletal chest pain | 2/39 (5.1%) | 2 |
| Myalgia | 3/39 (7.7%) | 3 |
| Bone pain | 2/39 (5.1%) | 2 |
| Neck pain | 2/39 (5.1%) | 2 |
| Nervous system disorders | ||
| Dizziness | 7/39 (17.9%) | 10 |
| Headache | 6/39 (15.4%) | 15 |
| Paraesthesia | 4/39 (10.3%) | 7 |
| Dysarthria | 3/39 (7.7%) | 3 |
| Neuropathy peripheral | 3/39 (7.7%) | 3 |
| Syncope | 2/39 (5.1%) | 2 |
| Memory impairment | 2/39 (5.1%) | 3 |
| Peripheral sensory neuropathy | 2/39 (5.1%) | 2 |
| Taste disorder | 2/39 (5.1%) | 4 |
| Seizure | 2/39 (5.1%) | 2 |
| Psychiatric disorders | ||
| Insomnia | 7/39 (17.9%) | 7 |
| Anxiety | 5/39 (12.8%) | 5 |
| Depression | 2/39 (5.1%) | 4 |
| Reproductive system and breast disorders | ||
| Vaginal haemorrhage | 2/39 (5.1%) | 2 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 5/39 (12.8%) | 6 |
| Nasal congestion | 5/39 (12.8%) | 5 |
| Dyspnoea | 2/39 (5.1%) | 5 |
| Epistaxis | 2/39 (5.1%) | 5 |
| Oropharyngeal pain | 3/39 (7.7%) | 4 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 6/39 (15.4%) | 7 |
| Pruritus | 5/39 (12.8%) | 7 |
| Dry skin | 2/39 (5.1%) | 2 |
| Rash maculo-papular | 2/39 (5.1%) | 2 |
| Rash papular | 2/39 (5.1%) | 2 |
| Onychoclasis | 2/39 (5.1%) | 2 |
| Vascular disorders | ||
| Hypertension | 3/39 (7.7%) | 4 |
| Hot flush | 2/39 (5.1%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Genentech, Inc. |
| Phone | 800-821-8590 |
| genentech@druginfo.com |
- ML29366