Trial Outcomes & Findings for 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 (NCT NCT02536339)

NCT ID: NCT02536339

Last Updated: 2021-12-07

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 40 participants
• Primary outcome timeframe: 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)
• Results posted on: 2021-12-07

Participant Flow

Participant milestones

Measure	Pertuzumab + Trastuzumab 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 Study STARTED	40
Overall Study Received at Least One Dose of Study Drug	39
Overall Study Efficacy-Evaluable Population	37
Overall Study COMPLETED	12
Overall Study NOT COMPLETED	28

Reasons for withdrawal

Measure	Pertuzumab + Trastuzumab 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 Study Death	20
Overall Study Withdrawal by Subject	3
Overall Study Lost to Follow-up	2
Overall Study Treatment discontinued	2
Overall Study Physician Decision	1

Baseline Characteristics

The LVEF analysis was performed on the safety analysis population, which included all participants who received at least one dose of study treatment. One participant who did not receive any study drug was excluded from the analysis.

Baseline characteristics by cohort

Measure	Pertuzumab + Trastuzumab n=40 Participants 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.
Age, Continuous	50.0 Years STANDARD_DEVIATION 9.78 • n=40 Participants
Sex: Female, Male Female	40 Participants n=40 Participants
Sex: Female, Male Male	0 Participants n=40 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=40 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	33 Participants n=40 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=40 Participants
Race/Ethnicity, Customized White	36 Participants n=40 Participants
Race/Ethnicity, Customized Asian	2 Participants n=40 Participants
Race/Ethnicity, Customized Other Race	1 Participants n=40 Participants
Race/Ethnicity, Customized Not Reported	1 Participants n=40 Participants
Women of Childbearing Potential Status Childbearing Potential	12 Participants n=40 Participants
Women of Childbearing Potential Status Non-Childbearing Potential - Postmenopausal	21 Participants n=40 Participants
Women of Childbearing Potential Status Non-Childbearing Potential - Surgically Sterile	7 Participants n=40 Participants
Left Ventricular Ejection Fraction (LVEF) Value at Baseline	60.00 Percentage Points of LVEF (%) n=39 Participants • The LVEF analysis was performed on the safety analysis population, which included all participants who received at least one dose of study treatment. One participant who did not receive any study drug was excluded from the analysis.

PRIMARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=37 Participants 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.
Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria With Objective Response (Confirmed CR or PR)	10.8 Percentage of Participants Interval 3.03 to 25.42
Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria Confirmed Complete Response (CR)	0.0 Percentage of Participants Interval 0.0 to 9.49
Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria Confirmed Partial Response (PR)	10.8 Percentage of Participants Interval 3.03 to 25.42
Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria Without Objective Response	89.2 Percentage of Participants The 95% confidence intervals were only calculated for objective responses.

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure

Pertuzumab + Trastuzumab n=4 Participants 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.

Median Duration of Response in the CNS, Assessed Using RANO-BM Criteria

4.60 Months Interval 3.19 to 5.59

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=37 Participants 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.
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria With Clinical Benefit (Confirmed CR,PR,or SD≥4mos)	67.6 Percentage of Participants Interval 50.21 to 81.99
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria Confirmed Complete Response (CR)	0.0 Percentage of Participants Interval 0.0 to 9.49
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria Confirmed Partial Response (PR)	10.8 Percentage of Participants Interval 3.03 to 25.42
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria Confirmed Stable Disease (SD) ≥4 Months	56.8 Percentage of Participants Interval 39.49 to 72.9
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria Without Clinical Benefit	32.4 Percentage of Participants The 95% confidence intervals were only calculated for clinical benefit responses.

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure

Pertuzumab + Trastuzumab n=25 Participants 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.

Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria

6.64 Months Interval 3.2 to 56.1

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=37 Participants 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.
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria With Clinical Benefit (Confirmed CR,PR,or SD≥6mos)	51.4 Percentage of Participants Interval 34.4 to 68.08
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria Confirmed Complete Response (CR)	0.0 Percentage of Participants Interval 0.0 to 9.49
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria Confirmed Partial Response (PR)	10.8 Percentage of Participants Interval 3.03 to 25.42
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria Confirmed Stable Disease (SD) ≥6 Months	40.5 Percentage of Participants Interval 24.75 to 57.9
Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria Without Clinical Benefit	48.6 Percentage of Participants The 95% confidence intervals were only calculated for clinical benefit responses.

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure

Pertuzumab + Trastuzumab n=19 Participants 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.

Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria

9.23 Months Interval 3.2 to 56.1

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure

Pertuzumab + Trastuzumab n=37 Participants 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.

Progression-Free Survival (CNS), Assessed Using RANO-BM Criteria

4.63 Months Interval 0.82 to 56.11

SECONDARY outcome

Timeframe: From the date of first dose to systemic disease progression or death from any cause, whichever occurred first (up to approximately 5 years)

Population: 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.

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.

Outcome measures

Measure

Pertuzumab + Trastuzumab n=37 Participants 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.

Progression-Free Survival (Systemic), Assessed Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

16.26 Months Interval 0.03 to 55.2

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure

Pertuzumab + Trastuzumab n=37 Participants 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.

Progression-Free Survival (CNS or Systemic), Assessed Using RANO-BM Criteria and RECIST v1.1

4.63 Months Interval 0.03 to 55.2

SECONDARY outcome

Timeframe: From the date of first dose until death due to any cause (up to approximately 5 years)

Population: 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.

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.

Outcome measures

Measure

Pertuzumab + Trastuzumab n=37 Participants 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 Survival

27.17 Months Interval 0.82 to 57.49

SECONDARY outcome

Timeframe: From date of first dose until death due to any cause (up to approximately 5 years)

Population: Safety Population: all participants who received at least one dose of study treatment.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death All Deaths	20 Participants
Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death Deaths ≤30 Days From Last Dose of Study Drug	1 Participants
Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death Deaths >30 Days From Last Dose of Study Drug	19 Participants
Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death Primary Cause of Death: Progressive Disease	16 Participants
Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death Primary Cause of Death: Other Cause (and Cancer)	1 Participants
Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death Primary Cause of Death: Unknown	3 Participants

SECONDARY outcome

Timeframe: From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)

Population: Safety Population: all participants who received at least one dose of study treatment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
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) Any TEAE - Any Grade	38 Participants
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) Any TEAE - Grade 1	5 Participants
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) Any TEAE - Grade 2	16 Participants
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) Any TEAE - Grade 3	14 Participants
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) Any TEAE - Grade 4	3 Participants
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) Any TEAE - Grade 5	0 Participants

SECONDARY outcome

Timeframe: From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)

Population: Safety Population: all participants who received at least one dose of study treatment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 Any SAE - Any Grade	7 Participants
Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 Any SAE - Grade 1	0 Participants
Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 Any SAE - Grade 2	1 Participants
Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 Any SAE - Grade 3	5 Participants
Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 Any SAE - Grade 4	2 Participants
Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 Any SAE - Grade 5	0 Participants

SECONDARY outcome

Timeframe: From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)

Population: Safety Population: all participants who received at least one dose of study treatment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
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 Withdrawal of Any Study Drug - Any Grade TEAE	2 Participants
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 Withdrawal of Any Study Drug - Grade 3 TEAE	2 Participants
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 Withdrawal of Pertuzumab Only - Any Grade TEAE	0 Participants
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 Withdrawal of Both Study Drugs - Any Grade TEAE	2 Participants
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 Withdrawal of Both Study Drugs - Grade 3 TEAE	2 Participants

SECONDARY outcome

Timeframe: From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)

Population: Safety Population: all participants who received at least one dose of study treatment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
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 Any TEAE - Any Grade	7 Participants
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 Any TEAE - Grade 1	1 Participants
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 Any TEAE - Grade 2	4 Participants
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 Any TEAE - Grade 3	1 Participants
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 Any TEAE - Grade 4	1 Participants
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 Any TEAE - Grade 5	0 Participants

SECONDARY outcome

Timeframe: From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)

Population: Safety Population: all participants who received at least one dose of study treatment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 Any TEAE - Any Grade	12 Participants
Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 Any TEAE - Grade 1	2 Participants
Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 Any TEAE - Grade 2	4 Participants
Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 Any TEAE - Grade 3	5 Participants
Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 Any TEAE - Grade 4	1 Participants
Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 Any TEAE - Grade 5	0 Participants

SECONDARY outcome

Timeframe: From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years)

Population: Safety Population: all participants who received at least one dose of study treatment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Percentage of Participants With at Least One TEAE of Special Interest by Highest Grade of Severity, According to NCI-CTCAE v4.0 Any TEAE of Special Interest - Any Grade	2.6 Percentage of Participants Interval 0.06 to 13.48
Percentage of Participants With at Least One TEAE of Special Interest by Highest Grade of Severity, According to NCI-CTCAE v4.0 Asymptomatic Decline in LVEF - Grade 3	2.6 Percentage of Participants Interval 0.06 to 13.48

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 12	60.00 Percentage Points of LVEF (%) Interval 51.0 to 73.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 24	60.00 Percentage Points of LVEF (%) Interval 50.0 to 67.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 5	67.00 Percentage Points of LVEF (%) Interval 60.0 to 72.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Baseline	60.00 Percentage Points of LVEF (%) Interval 50.0 to 75.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 6	60.00 Percentage Points of LVEF (%) Interval 30.0 to 69.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 36	60.00 Percentage Points of LVEF (%) Interval 50.0 to 65.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 48	60.00 Percentage Points of LVEF (%) Interval 48.0 to 64.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 60	62.00 Percentage Points of LVEF (%) Interval 49.0 to 70.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 72	55.50 Percentage Points of LVEF (%) Interval 53.0 to 65.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 84	60.00 Percentage Points of LVEF (%) Interval 55.0 to 62.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 96	63.00 Percentage Points of LVEF (%) Interval 60.0 to 65.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 108	62.00 Percentage Points of LVEF (%) Interval 60.0 to 64.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 120	64.00 Percentage Points of LVEF (%) Interval 64.0 to 64.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Week 132	64.00 Percentage Points of LVEF (%) Interval 64.0 to 64.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 1	60.00 Percentage Points of LVEF (%) Interval 50.0 to 68.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 2	59.00 Percentage Points of LVEF (%) Interval 53.0 to 75.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 3	60.00 Percentage Points of LVEF (%) Interval 55.0 to 65.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 4	69.00 Percentage Points of LVEF (%) Interval 66.0 to 72.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 6	57.00 Percentage Points of LVEF (%) Interval 55.0 to 58.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 7	57.50 Percentage Points of LVEF (%) Interval 55.0 to 60.0
Median Left Ventricular Ejection Fraction (LVEF) Values Over Time Survival Follow-Up 8	57.00 Percentage Points of LVEF (%) Interval 55.0 to 59.0

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Baseline · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 12 · Normal	30 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 24 · Normal	14 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 24 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 48 · Abnormal, Not Clinically Significant	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 48 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 60 · Abnormal, Not Clinically Significant	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 96 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 132 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 1 · Normal	5 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 1 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 3 · Normal	5 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 3 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 4 · Abnormal, Not Clinically Significant	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 4 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Baseline · Normal	39 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Baseline · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 6 · Normal	33 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 6 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 6 · Abnormal, Clinically Significant	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 12 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 12 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 24 · Abnormal, Not Clinically Significant	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 36 · Normal	9 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 36 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 36 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 48 · Normal	6 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 60 · Normal	6 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 60 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 72 · Normal	4 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 72 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 72 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 84 · Normal	3 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 84 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 84 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 96 · Normal	3 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 96 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 108 · Normal	2 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 108 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 108 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 120 · Normal	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 120 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 120 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 132 · Normal	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Week 132 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 1 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 2 · Normal	12 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 2 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 2 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 3 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 4 · Normal	1 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 5 · Normal	3 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 5 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 5 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 6 · Normal	3 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 6 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 6 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 7 · Normal	2 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 7 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 7 · Abnormal, Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 8 · Normal	2 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 8 · Abnormal, Not Clinically Significant	0 Participants
Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time Survival Follow-Up 8 · Abnormal, Clinically Significant	0 Participants

SECONDARY outcome

Timeframe: Baseline, Weeks 18, 36, and 60 (up to approximately 5 years)

Population: 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.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Week 36: Lymphocytes (10^9/L), Low - Grade 3	1 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Overall: Lymphocytes (10^9/L), Low - Grade 3	3 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Overall: Lymphocytes (10^9/L), High - Grade 3	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Overall: Lymphocytes (10^9/L), Low - Grade 4	1 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Overall: Lymphocytes (10^9/L), High - Grade 4	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Baseline: Lymphocytes (10^9/L), Low - Grade 3	2 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Baseline: Lymphocytes (10^9/L), Low - Grade 4	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Week 18: Lymphocytes (10^9/L), Low - Grade 3	1 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Week 18: Lymphocytes (10^9/L), Low - Grade 4	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Week 36: Lymphocytes (10^9/L), Low - Grade 4	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Week 60: Lymphocytes (10^9/L), Low - Grade 3	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time Week 60: Lymphocytes (10^9/L), Low - Grade 4	1 Participants

SECONDARY outcome

Timeframe: Weeks 6, 12, and 18, and Unscheduled Visits (up to approximately 5 years)

Population: 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.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Glucose (mmol/L), High - Grade 3	2 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Glucose (mmol/L), Low - Grade 4	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Week 6: Glucose (mmol/L), High - Grade 3	1 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Glucose (mmol/L), Low - Grade 3	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Glucose (mmol/L), High - Grade 4	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Week 12: Glucose (mmol/L), High - Grade 3	1 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Week 18: Glucose (mmol/L), High - Grade 3	1 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Potassium (mmol/L), Low - Grade 3	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Potassium (mmol/L), High - Grade 3	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Potassium (mmol/L), Low - Grade 4	1 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Overall: Potassium (mmol/L), High - Grade 4	0 Participants
Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time Unscheduled Visit: Potassium (mmol/L),Low -Grade 4	1 Participants

SECONDARY outcome

Timeframe: Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16

Population: 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.

Per protocol eligibility criteria, participants were not required to be pertuzumab naïve; therefore pertuzumab was detectable in some participants pre-dose at Week 1.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints Week 1 Day 1	43.12 micrograms per millilitre (ug/mL) Standard Deviation 101.45
Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints Week 4 Day 1	88.03 micrograms per millilitre (ug/mL) Standard Deviation 29.91
Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints Week 10 Day 1	94.46 micrograms per millilitre (ug/mL) Standard Deviation 38.47
Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints Week 16 Day 1	101.99 micrograms per millilitre (ug/mL) Standard Deviation 41.59

SECONDARY outcome

Timeframe: Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16

Population: 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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Maximum Serum Concentrations (Cmax) of Pertuzumab at Specified Timepoints Week 1 Day 1	275.94 micrograms per millilitre (ug/mL) Standard Deviation 88.80
Maximum Serum Concentrations (Cmax) of Pertuzumab at Specified Timepoints Week 16 Day 1	225.55 micrograms per millilitre (ug/mL) Standard Deviation 56.22

SECONDARY outcome

Timeframe: Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16

Population: 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.

Per protocol eligibility criteria, participants were not required to be trastuzumab naïve; therefore trastuzumab was detectable in some participants pre-dose at Week 1.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints Week 1 Day 1	57.00 micrograms per millilitre (ug/mL) Standard Deviation 52.73
Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints Week 4 Day 1	190.82 micrograms per millilitre (ug/mL) Standard Deviation 52.22
Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints Week 10 Day 1	294.50 micrograms per millilitre (ug/mL) Standard Deviation 70.33
Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints Week 16 Day 1	306.14 micrograms per millilitre (ug/mL) Standard Deviation 90.22

SECONDARY outcome

Timeframe: Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16

Population: 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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=39 Participants 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.
Maximum Serum Concentrations (Cmax) of Trastuzumab at Specified Timepoints Week 1 Day 1	181.43 micrograms per millilitre (ug/mL) Standard Deviation 72.49
Maximum Serum Concentrations (Cmax) of Trastuzumab at Specified Timepoints Week 16 Day 1	394.14 micrograms per millilitre (ug/mL) Standard Deviation 94.09

SECONDARY outcome

Timeframe: Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64

Population: Patient-Reported Outcome (PRO)-Evaluable Population: all treated participants who had both a nonmissing baseline and at least one post-baseline PRO assessment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=36 Participants 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.
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Baseline	1.65 Score on a scale Standard Deviation 1.618
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Week 6	1.97 Score on a scale Standard Deviation 1.822
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Week 12	2.24 Score on a scale Standard Deviation 2.141
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Week 20	2.09 Score on a scale Standard Deviation 2.111
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Week 28	1.94 Score on a scale Standard Deviation 2.547
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Week 40	2.78 Score on a scale Standard Deviation 2.856
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Week 52	3.53 Score on a scale Standard Deviation 3.018
Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire Week 64	3.12 Score on a scale Standard Deviation 2.500

SECONDARY outcome

Timeframe: Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64

Population: Patient-Reported Outcome (PRO)-Evaluable Population: all treated participants who had both a nonmissing baseline and at least one post-baseline PRO assessment.

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.

Outcome measures

Measure	Pertuzumab + Trastuzumab n=36 Participants 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.
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Baseline	2.51 Score on a scale Standard Deviation 2.629
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Week 6	2.23 Score on a scale Standard Deviation 2.787
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Week 12	2.81 Score on a scale Standard Deviation 3.391
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Week 20	2.11 Score on a scale Standard Deviation 2.858
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Week 28	1.76 Score on a scale Standard Deviation 2.427
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Week 40	3.24 Score on a scale Standard Deviation 3.548
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Week 52	4.25 Score on a scale Standard Deviation 3.522
Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire Week 64	3.93 Score on a scale Standard Deviation 3.570

Adverse Events

Pertuzumab + Trastuzumab

Serious events: 7 serious events

Other events: 38 other events

Deaths: 20 deaths

Serious adverse events

Measure	Pertuzumab + Trastuzumab n=39 participants at risk 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.
Infections and infestations Gastroenteritis viral	2.6% 1/39 • Number of events 1 • 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) 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.
Infections and infestations Parainfluenzae virus infection	2.6% 1/39 • Number of events 1 • 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) 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.
Nervous system disorders Seizure	10.3% 4/39 • Number of events 4 • 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) 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.
Nervous system disorders Headache	2.6% 1/39 • Number of events 1 • 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) 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.
Nervous system disorders Hydrocephalus	2.6% 1/39 • Number of events 1 • 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) 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.
Vascular disorders Hypertension	2.6% 1/39 • Number of events 1 • 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) 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.

Other adverse events

Measure	Pertuzumab + Trastuzumab n=39 participants at risk 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.
Blood and lymphatic system disorders Anaemia	7.7% 3/39 • Number of events 3 • 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) 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.
Eye disorders Vision blurred	10.3% 4/39 • Number of events 6 • 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) 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.
Gastrointestinal disorders Diarrhoea	59.0% 23/39 • Number of events 30 • 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) 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.
Gastrointestinal disorders Nausea	30.8% 12/39 • Number of events 21 • 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) 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.
Gastrointestinal disorders Vomiting	30.8% 12/39 • Number of events 16 • 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) 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.
Gastrointestinal disorders Constipation	17.9% 7/39 • Number of events 9 • 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) 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.
Gastrointestinal disorders Dry mouth	7.7% 3/39 • Number of events 4 • 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) 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.
Gastrointestinal disorders Dysphagia	10.3% 4/39 • Number of events 4 • 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) 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.
Gastrointestinal disorders Abdominal distension	5.1% 2/39 • Number of events 6 • 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) 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.
Gastrointestinal disorders Abdominal pain	5.1% 2/39 • Number of events 5 • 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) 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.
Gastrointestinal disorders Dyspepsia	7.7% 3/39 • Number of events 5 • 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) 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.
Gastrointestinal disorders Stomatitis	5.1% 2/39 • Number of events 2 • 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) 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.
General disorders Fatigue	43.6% 17/39 • Number of events 21 • 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) 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.
General disorders Asthenia	15.4% 6/39 • Number of events 6 • 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) 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.
General disorders Gait disturbance	12.8% 5/39 • Number of events 5 • 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) 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.
General disorders Pain	10.3% 4/39 • Number of events 4 • 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) 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.
General disorders Mucosal inflammation	7.7% 3/39 • Number of events 3 • 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) 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.
General disorders Oedema peripheral	5.1% 2/39 • Number of events 5 • 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) 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.
Infections and infestations Upper respiratory tract infection	15.4% 6/39 • Number of events 10 • 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) 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.
Infections and infestations Urinary tract infection	12.8% 5/39 • Number of events 11 • 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) 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.
Infections and infestations Gastroenteritis viral	5.1% 2/39 • Number of events 2 • 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) 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.
Infections and infestations Nasopharyngitis	5.1% 2/39 • Number of events 2 • 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) 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.
Infections and infestations Sinusitis	5.1% 2/39 • Number of events 2 • 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) 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.
Injury, poisoning and procedural complications Fall	10.3% 4/39 • Number of events 7 • 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) 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.
Injury, poisoning and procedural complications Contusion	7.7% 3/39 • Number of events 3 • 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) 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.
Injury, poisoning and procedural complications Infusion related reaction	7.7% 3/39 • Number of events 3 • 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) 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.
Investigations Alanine aminotransferase increased	7.7% 3/39 • Number of events 3 • 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) 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.
Investigations Aspartate aminotransferase increased	7.7% 3/39 • Number of events 3 • 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) 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.
Investigations Blood alkaline phosphatase increased	5.1% 2/39 • Number of events 2 • 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) 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.
Investigations Neutrophil count decreased	5.1% 2/39 • Number of events 5 • 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) 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.
Investigations Platelet count decreased	5.1% 2/39 • Number of events 2 • 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) 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.
Investigations Weight increased	5.1% 2/39 • Number of events 3 • 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) 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.
Investigations White blood cell count decreased	5.1% 2/39 • Number of events 4 • 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) 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.
Metabolism and nutrition disorders Decreased appetite	15.4% 6/39 • Number of events 6 • 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) 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.
Metabolism and nutrition disorders Hypokalaemia	15.4% 6/39 • Number of events 7 • 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) 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.
Musculoskeletal and connective tissue disorders Back pain	10.3% 4/39 • Number of events 7 • 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) 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.
Musculoskeletal and connective tissue disorders Arthralgia	10.3% 4/39 • Number of events 8 • 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) 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.
Musculoskeletal and connective tissue disorders Muscle spasms	10.3% 4/39 • Number of events 5 • 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) 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.
Musculoskeletal and connective tissue disorders Muscular weakness	7.7% 3/39 • Number of events 4 • 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) 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.
Musculoskeletal and connective tissue disorders Pain in extremity	10.3% 4/39 • Number of events 5 • 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) 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.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.1% 2/39 • Number of events 2 • 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) 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.
Musculoskeletal and connective tissue disorders Myalgia	7.7% 3/39 • Number of events 3 • 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) 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.
Nervous system disorders Dizziness	17.9% 7/39 • Number of events 10 • 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) 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.
Nervous system disorders Headache	15.4% 6/39 • Number of events 15 • 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) 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.
Nervous system disorders Paraesthesia	10.3% 4/39 • Number of events 7 • 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) 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.
Nervous system disorders Dysarthria	7.7% 3/39 • Number of events 3 • 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) 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.
Nervous system disorders Neuropathy peripheral	7.7% 3/39 • Number of events 3 • 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) 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.
Nervous system disorders Syncope	5.1% 2/39 • Number of events 2 • 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) 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.
Psychiatric disorders Insomnia	17.9% 7/39 • Number of events 7 • 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) 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.
Psychiatric disorders Anxiety	12.8% 5/39 • Number of events 5 • 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) 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.
Psychiatric disorders Depression	5.1% 2/39 • Number of events 4 • 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) 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.
Respiratory, thoracic and mediastinal disorders Cough	12.8% 5/39 • Number of events 6 • 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) 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.
Respiratory, thoracic and mediastinal disorders Nasal congestion	12.8% 5/39 • Number of events 5 • 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) 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.1% 2/39 • Number of events 5 • 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) 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.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.1% 2/39 • Number of events 5 • 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) 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.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	7.7% 3/39 • Number of events 4 • 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) 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.
Skin and subcutaneous tissue disorders Rash	15.4% 6/39 • Number of events 7 • 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) 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.
Skin and subcutaneous tissue disorders Pruritus	12.8% 5/39 • Number of events 7 • 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) 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.
Skin and subcutaneous tissue disorders Dry skin	5.1% 2/39 • Number of events 2 • 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) 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.
Skin and subcutaneous tissue disorders Rash maculo-papular	5.1% 2/39 • Number of events 2 • 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) 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.
Skin and subcutaneous tissue disorders Rash papular	5.1% 2/39 • Number of events 2 • 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) 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.
Vascular disorders Hypertension	7.7% 3/39 • Number of events 4 • 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) 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.
Vascular disorders Hot flush	5.1% 2/39 • Number of events 2 • 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) 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.
Ear and labyrinth disorders Ear pain	5.1% 2/39 • Number of events 2 • 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) 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.
Eye disorders Dry eye	5.1% 2/39 • Number of events 2 • 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) 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.
Gastrointestinal disorders Abdominal pain upper	5.1% 2/39 • Number of events 2 • 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) 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.
Gastrointestinal disorders Rectal haemorrhage	5.1% 2/39 • Number of events 2 • 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) 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.
General disorders Pyrexia	5.1% 2/39 • Number of events 2 • 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) 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.
General disorders Swelling face	5.1% 2/39 • Number of events 2 • 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) 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.
Musculoskeletal and connective tissue disorders Bone pain	5.1% 2/39 • Number of events 2 • 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) 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.
Musculoskeletal and connective tissue disorders Neck pain	5.1% 2/39 • Number of events 2 • 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) 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.
Nervous system disorders Memory impairment	5.1% 2/39 • Number of events 3 • 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) 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.
Nervous system disorders Peripheral sensory neuropathy	5.1% 2/39 • Number of events 2 • 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) 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.
Nervous system disorders Taste disorder	5.1% 2/39 • Number of events 4 • 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) 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.
Nervous system disorders Seizure	5.1% 2/39 • Number of events 2 • 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) 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.
Reproductive system and breast disorders Vaginal haemorrhage	5.1% 2/39 • Number of events 2 • 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) 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.
Skin and subcutaneous tissue disorders Onychoclasis	5.1% 2/39 • Number of events 2 • 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) 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.

Additional Information

Medical Communications

Genentech, Inc.

Phone: 800-821-8590

Email: genentech@druginfo.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER