A Study of Pertuzumab With High-Dose Trastuzumab for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (MBC) With Central Nervous System (CNS) Progression Post-Radiotherapy

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Pertuzumab
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed HER2-positive MBC Progression of or new brain metastases after completion of whole-brain radiotherapy or stereotactic radiosurgery Completion of whole-brain radiotherapy or stereotactic radiosurgery more than 60 days prior to enrollment Stable systemic disease Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 LVEF at least 50% Adequate hematologic, renal, and hepatic function Life expectancy more than 12 weeks Exclusion Criteria: Progression of systemic disease at Screening Leptomeningeal disease History of intolerance or hypersensitivity to study drug Use of certain investigational therapies within 21 days prior to enrollment Current anthracycline use Unwillingness to discontinue ado-trastuzumab emtansine or lapatinib use Active infection Pregnant or lactating women Significant history or risk of cardiac disease Symptomatic intrinsic lung disease or lung involvement History of other malignancy within the last 5 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pertuzumab + Trastuzumab<br>Participants with CNS metastases secondary to HER2-positive MBC will receive pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. | Drug: Pertuzumab<br>* 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.<br>* Other names: RO4368451;Drug: Trastuzumab<br>* 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.<br>* Other names: RO0452317;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response in the CNS, Assessed Using Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria | 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Duration of Response in the CNS, Assessed Using RANO-BM Criteria | 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. | 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) | 
| Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or Stable Disease [SD] ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria | 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. | 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) | 
| Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥4 Months) in the CNS, Assessed Using RANO-BM Criteria | 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. | 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) | 
| Percentage of Participants With Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria | 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. | 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) | 
| Median Duration of Clinical Benefit (Confirmed CR, PR, or SD ≥6 Months) in the CNS, Assessed Using RANO-BM Criteria | 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. | 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) | 
| Progression-Free Survival (CNS), Assessed Using RANO-BM Criteria | 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. | From the date of first dose to disease progression in the CNS or death from any cause, whichever occurred first (up to approximately 5 years) | 
| Progression-Free Survival (Systemic), Assessed Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) | 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. | From the date of first dose to systemic disease progression or death from any cause, whichever occurred first (up to approximately 5 years) | 
| Progression-Free Survival (CNS or Systemic), Assessed Using RANO-BM Criteria and RECIST v1.1 | 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. | 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) | 
| Overall Survival | 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. | From the date of first dose until death due to any cause (up to approximately 5 years) | 
| Number of Deaths by Time (≤30 or >30 Days) From Last Study Drug Administration and by Primary Cause of Death |  | From date of first dose until death due to any cause (up to approximately 5 years) | 
| Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) by Highest Grade of Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) | 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. | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) | 
| Number of Participants With at Least One Treatment-Emergent Serious Adverse Event (SAE) by Highest Grade of Severity, According to NCI-CTCAE v4.0 | 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. | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) | 
| 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 | 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. | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) | 
| 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 | 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. | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) | 
| Number of Participants With at Least One TEAE Leading to Trastuzumab Dose Modification by Highest Grade of Severity According to NCI-CTCAE v4.0 | 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. | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) | 
| Percentage of Participants With at Least One TEAE of Special Interest by Highest Grade of Severity, According to NCI-CTCAE v4.0 | 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. | From the first dose until 30 days after the last dose of study treatment (up to approximately 5 years) | 
| Median Left Ventricular Ejection Fraction (LVEF) Values Over Time | 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. | 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) | 
| Number of Participants by Investigator Interpretation of Left Ventricular Ejection Fraction (LVEF) Assessments Over Time | 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. | 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) | 
| Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Hematology Tests Over Time | 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. | Baseline, Weeks 18, 36, and 60 (up to approximately 5 years) | 
| Number of Participants With NCI-CTCAE v4.0 Grades 3 and 4 Clinical Laboratory Abnormalities in Blood Chemistry Tests Over Time | 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. | Weeks 6, 12, and 18, and Unscheduled Visits (up to approximately 5 years) | 
| Observed Trough Serum Concentrations (Cmin) of Pertuzumab at Specified Timepoints | Per protocol eligibility criteria, participants were not required to be pertuzumab naïve; therefore pertuzumab was detectable in some participants pre-dose at Week 1. | Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16 | 
| Maximum Serum Concentrations (Cmax) of Pertuzumab at Specified Timepoints |  | Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16 | 
| Observed Trough Serum Concentrations (Cmin) of Trastuzumab at Specified Timepoints | Per protocol eligibility criteria, participants were not required to be trastuzumab naïve; therefore trastuzumab was detectable in some participants pre-dose at Week 1. | Pre-dose (0-4 hours) on Day 1 of Weeks 1, 4, 10, and 16 | 
| Maximum Serum Concentrations (Cmax) of Trastuzumab at Specified Timepoints |  | Post-infusion (0-30 minutes, infused over 60 minutes) on Day 1 of Week 1 and 16 | 
| Symptom Severity Scale Score Over Time, Assessed by Participant Reporting on the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Questionnaire | 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. | Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64 | 
| Symptom Interference Scale Score Over Time, Assessed by Participant Reporting on the MDASI-BT Questionnaire | 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. | Baseline, Weeks 6, 12, 20, 28, 40, 52, and 64 |