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

Genentech, Inc.40 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic Breast Cancer

Interventions

PertuzumabDRUG

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.

TrastuzumabDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (16)

Arizona Cancer Center

Tucson, Arizona, United States

City of Hope National Medical Center

Duarte, California, United States

Outcomes

Primary Outcomes

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.

Time frame: From Baseline until disease progression (assessed every 6 weeks for first 2 scans, followed by every 8 weeks for 2 scans, then every 12 weeks until disease progression; up to approximately 3.5 years)

Secondary Outcomes

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.

Time frame: From documentation of first complete response (CR) or partial response (PR) to the time of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 3.5 years)

Data from ClinicalTrials.gov

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Stanford Cancer Institute

Stanford, California, United States

University of Miami Hospital & Clinics

Miami, Florida, United States

H. Lee Moffitt Cancer Center and Research Inst.

Tampa, Florida, United States

Northwestern University

Chicago, Illinois, United States

University of Maryland Medical Center; Department of Neurology

Baltimore, Maryland, United States

Associates in Oncology-Hematology, PC

Bethesda, Maryland, United States

Dana Farber Cancer Inst.

Boston, Massachusetts, United States

Allina Health System

Saint Paul, Minnesota, United States

...and 6 more locations

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.

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.

Time frame: From documentation of first complete response (CR), partial response (PR), or stable disease (SD) ≥4 months to the date of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 5 years)

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.

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.

Time frame: From documentation of first complete response (CR), partial response (PR), or stable disease (SD) ≥6 months to the date of disease progression, relapse, or death from any cause, whichever occurred first (up to approximately 5 years)

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.

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

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.

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

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.

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

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.

Time frame: 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

Time frame: 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.