Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Disease Progression

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Trastuzumab

Mitogens

Pertuzumab

Antineoplastic Agents, Immunological

Participants with CNS metastases secondary to HER2-positive MBC will receive pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Participants will receive 840 milligrams (mg) loading dose of pertuzumab, followed every 3 weeks thereafter by a dose of 420 mg via intravenous (IV) infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Participants will receive trastuzumab at a dose of 6 milligrams per kilogram (mg/kg) of body weight once weekly via IV infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Clinical Trials

This study will examine the safety and efficacy of pertuzumab in combination with high-dose trastuzumab in adult participants with HER2-positive MBC with CNS metastases and disease progression in the brain following radiotherapy.

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

An Open-Label, Single-Arm, Phase II Study of Pertuzumab With High-Dose Trastuzumab for the Treatment of Central Nervous System Progression Post-Radiotherapy in Patients With HER2-Positive Metastatic Breast Cancer (PATRICIA)

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.

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.

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.

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.

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.

Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months, confirmed by repeat assessment according to RANO-BM criteria. Among participants who achieved clinical benefit, duration of clinical benefit in the CNS was defined as the time from documentation of the first CR, PR, or SD ≥6 months to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of clinical benefit was censored on the last date the participant was known to be progression free. Duration of clinical benefit was estimated by the Kaplan-Meier method.

Progression-free survival (CNS) was defined as the time from the date of first dose to disease progression in the CNS or death from any cause. If no progressive disease in the CNS and no death occurred, progression-free survival (CNS) was censored on the date of the last CNS tumor assessment. If a post-baseline assessment was not available, progression-free survival (CNS) was censored on Day 1.

Progression-free survival (systemic) was defined as the time from the date of first dose to systemic disease progression or death from any cause. If no systemic disease progression and no death occurred, progression-free survival (systemic) was censored on the date of the last systemic tumor assessment. If a post-baseline assessment was not available, progression-free survival (systemic) was censored on Day 1.

Progression-free survival (CNS or systemic) was defined as the time from the date of first dose to CNS or systemic disease progression or death from any cause. If no CNS or systemic disease progression and no death occurred, data was censored on the date of the last CNS or systemic tumor assessment, whichever occurred first. If a post-baseline assessment was not available, data was censored on Day 1.

Overall survival 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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

Genentech, Inc.

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.

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.

Pertuzumab + Trastuzumab

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Women of Childbearing Potential Status

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.

Left Ventricular Ejection Fraction (LVEF) Value at Baseline

Intent-to-Treat (ITT) population: all enrolled patients in the study, regardless of whether they were exposed to study treatment.

Medical Communications

With Objective Response (Confirmed CR or PR)

Confirmed Complete Response (CR)

Confirmed Partial Response (PR)

Without Objective Response

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.

Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria

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.

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

With Clinical Benefit (Confirmed CR,PR,or SD≥4mos)

Confirmed Stable Disease (SD) ≥4 Months

Without Clinical Benefit

Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria

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.

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

With Clinical Benefit (Confirmed CR,PR,or SD≥6mos)

Confirmed Stable Disease (SD) ≥6 Months

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

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.

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

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

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

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

Overall Survival

All Deaths

Deaths ≤30 Days From Last Dose of Study Drug

Deaths >30 Days From Last Dose of Study Drug

Primary Cause of Death: Progressive Disease

Primary Cause of Death: Other Cause (and Cancer)

Primary Cause of Death: Unknown

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

Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death

Any TEAE - Any Grade

Any TEAE - Grade 1

Any TEAE - Grade 2

Any TEAE - Grade 3

Any TEAE - Grade 4

Any TEAE - Grade 5

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 SAE - Any Grade

Any SAE - Grade 1

Any SAE - Grade 2

Any SAE - Grade 3

Any SAE - Grade 4

Any SAE - Grade 5

Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0

Withdrawal of Any Study Drug - Any Grade TEAE

Withdrawal of Any Study Drug - Grade 3 TEAE

Withdrawal of Pertuzumab Only - Any Grade TEAE

Withdrawal of Both Study Drugs - Any Grade TEAE

Withdrawal of Both Study Drugs - Grade 3 TEAE

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

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

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 of Special Interest - Any Grade

Asymptomatic Decline in LVEF - Grade 3

Percentage of Participants With at Least One TEAE of Special Interest by Highest Grade of Severity, According to NCI-CTCAE v4.0

Baseline

Week 6

Week 12

Week 24

Week 36

Week 48

Week 60

Week 72

Week 84

Week 96

Week 108

Week 120

Week 132

Survival Follow-Up 1

Survival Follow-Up 2

Survival Follow-Up 3

Survival Follow-Up 4

Survival Follow-Up 5

Survival Follow-Up 6

Survival Follow-Up 7

Survival Follow-Up 8

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.

Median Left Ventricular Ejection Fraction (LVEF) Values Over Time

Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time

Overall: Lymphocytes (10^9/L), Low - Grade 3

Overall: Lymphocytes (10^9/L), High - Grade 3

Overall: Lymphocytes (10^9/L), Low - Grade 4

Overall: Lymphocytes (10^9/L), High - Grade 4

Baseline: Lymphocytes (10^9/L), Low - Grade 3

Baseline: Lymphocytes (10^9/L), Low - Grade 4

Week 18: Lymphocytes (10^9/L), Low - Grade 3

Week 18: Lymphocytes (10^9/L), Low - Grade 4

Week 36: Lymphocytes (10^9/L), Low - Grade 3

Week 36: Lymphocytes (10^9/L), Low - Grade 4

Week 60: Lymphocytes (10^9/L), Low - Grade 3

Week 60: Lymphocytes (10^9/L), Low - Grade 4

Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time

Overall: Glucose (mmol/L), Low - Grade 3

Overall: Glucose (mmol/L), High - Grade 3

Overall: Glucose (mmol/L), Low - Grade 4

Overall: Glucose (mmol/L), High - Grade 4

Week 6: Glucose (mmol/L), High - Grade 3

Week 12: Glucose (mmol/L), High - Grade 3

Week 18: Glucose (mmol/L), High - Grade 3

Overall: Potassium (mmol/L), Low - Grade 3

Overall: Potassium (mmol/L), High - Grade 3

Overall: Potassium (mmol/L), Low - Grade 4

Overall: Potassium (mmol/L), High - Grade 4

Unscheduled Visit: Potassium (mmol/L),Low -Grade 4

Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time

Week 1 Day 1

Week 4 Day 1

Week 10 Day 1

Week 16 Day 1

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.

Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints

Maximum Serum Concentrations (Cmax) of Pertuzumab at Specified Timepoints

Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints

Maximum Serum Concentrations (Cmax) of Trastuzumab at Specified Timepoints

Week 20

Week 28

Week 40

Week 52

Week 64

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

Spots Global Cancer Trial Database 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

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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