Neoplasms, Breast
Conditions
Keywords
breast cancer, brain metastases, ErbB2 positive, HER2 positive, neoplasms, cancer, lapatinib, LAP016A2202, LAP016A, CLAP016A2202, GW572016
Brief summary
Determine how safe and effective lapatinib is when used to treat patients with ErbB2 overexpressing breast cancer that has spread to the brain and is still progressing there even after radiation treatment using WBRT (whole brain radiotherapy) or SRS (stereotactic radiosurgery) to the brain. Lapatinib is an oral drug that will be taken every day. Tests for safety and efficacy will be performed every 4 weeks or 8 weeks (depending on the test) during the course of the study.
Interventions
DRUGlapatinib
tyrosine kinase inhibitor
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed Informed Consent * ErbB2(HER2)overexpressing breast cancer. * Brain lesion(s) which are progressing. * Prior treatment of brain metastases with Whole Brain Radiotherapy (WBR)and/or Stereotactic Radiosurgery (SRS). * Prior treatment with trastuzumab (Herceptin), either alone or in combination with chemotherapy. * Cardiac ejection fraction(LVEF)within the institutional range of normal as measured by Echocardiogram. * Able to swallow an oral medication. * Adequate kidney and liver function. * Adequate bone marrow function.
Exclusion criteria
* Pregnant or lactating females. * Conditions that would effect the absorption of an oral drug. * History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents. * Pre-existing severe cerebral vascular disease, such as stroke involving a major vessel. * Serious medical or psychiatric disorder that would interfere with the patient's safety or informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Central Nervous System (CNS) Best Overall Response | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | Summary of CNS Objective Response (Lapatinib Monotherapy - MITT Population) Response to lapatinib in patients with progressive brain metastases from ErbB2-overexpressing breast cancer. The primary indicator of drug efficacy was CNS objective response rate. A CNS objective response was defined as either a Complete response (CR) or Partial response (PR), as assessed by volumetric analysis of brain Magnetic resonance imaging (MRI), provided there was no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of Neurological signs and symptoms (NSS) A CNS objective response rate was defined as a 50% volumetric reduction in sum of CNS target lesions, with no new or progressive CNS or non-CNS lesions, no increases in tumor-related steroid requirements and no worsening of neurological signs or symptoms |
| The Percentage of Participants With Central Nervous System (CNS) Objective Response Rate - Response Rate (CR + PR) | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | Summary of CNS Objective Response (the Complete Response + Partial Response) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Central Nervous System (CNS) Objective Response | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | The duration of CNS objective response, defined as the time from first CNS Objective response until tumor progression at any site or death due to any cause. A CNS objective response was defined as either a Complete Response (CR) or Partial Response (PR), as assessed by volumetric analysis of magnetic resonance imaging (MRI), provided there was no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of tumor-related neurological signs or symptoms. |
| Percentage of Patients With CNS Disease Control (Complete Response, Partial Response or Stable Disease) at 6 Months of Lapatinib Therapy | from Start of lapatinib to 6 months | The CNS disease control rate, defined as the percentage of subjects with CR, PR or stable disease at Week 24 |
| Time to Progression (TTP) at Any Site | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | Summary of Kaplan-Meier Estimates for Progression Free Survival at Any Site |
| Percentage of Participants With Improvement in Neurological Signs and Symptoms (NSS) Measured Using the Neurological Examination Worksheet | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | Physician-reported NSS worksheet is derived from 13 AEs and measured by NCI CTCAE v3.0 grouped into 7 categories: level of consciousness, neurological symptoms, cranial nerves, language, strength, sensation, & ataxia. Improvement of NSS required: Decrease by 1 or more grades from baseline of any tumor-related NSS, with confirmation at least 4 wks later, No development or worsening in any tumor-related NSS during interval, No radiographic evidence of CNS progression (assessed by volumetric MRI) or systemic (non-CNS) progression (assessed by RECIST) during interval, Stable or decreasing steroids during interval as defined by GSK equivalent doses of an alternative corticosteroid or a dose increase for non-tumor related reasons didn't constitute a steroid increase. Improvement in any non-tumor associated NSS didn't constitute improvement in NSS. Neurological exam, using Neurological Examination Worksheet was assessed at baseline & each 4 wks. Categories below are not mutually exclusive. |
| Summary of Site of First Progression | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | baseline to time of disease progression or death |
| Primary Cause of Death | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | Summary of Overall All-cause mortality (Main Study and Extension) |
| Overall Survival (OS) | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | Overall survival (OS) defined as the time from initiation of investigational product to death due to any cause. |
| Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | baseline and weeks 8, 16, 24, 32, 40, 48 | Summary of Proportion of Subjects with a CNS Objective Response or Improvement in Baseline NSS |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Greece, India, Italy, Japan, Poland, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The Intent-to-Treat (ITT) Population: all subjects who received at least one dose of study medication Modified ITT (MITT) Population: all subjects who received at least four doses (750 mg lapatinib twice daily for two days) of study medication and who had measurable brain metastases (≥1 cm in diameter) at baseline assessment
Pre-assignment details
Main phase: ITT 95 in Cohort A, 147 in Cohort B. MITT, 94 in Cohort A, and 143 subjects in Cohort B Optional open-label extension phase: 51 subjects. Long-term follow up (LTFU) Protocol amendment added on 15-Apr-2013
Participants by arm
| Arm | Count |
|---|---|
| Cohorts A Overall - Main Study and Extension Phase - 750 mg lapatinib administered orally twice daily Cohort A subjects had Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and one or two prior trastuzumab-containing regimens, in total, for treatment of breast cancer in adjuvant and/or metastatic settings. | 95 |
| Cohort B 750mg lapatinib administered orally twice daily. Cohort B subjects had ECOG performance status 2 and/or more than 2 prior trastuzumab-containing regimens for treatment of breast cancer in the adjuvant and/or metastatic settings. | 147 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 54 | 90 |
| Overall Study | disease progression, coma, 1 unknown | 10 | 11 |
| Overall Study | Investigator decision | 7 | 15 |
| Overall Study | Lost to Follow-up | 7 | 10 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Sponsor terminated study | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Cohorts A | Cohort B | Total |
|---|---|---|---|
| Age, Continuous | 50.3 years STANDARD_DEVIATION 10.33 | 49.3 years STANDARD_DEVIATION 10.73 | 49.8 years STANDARD_DEVIATION 10.53 |
| Age, Customized 18-64 years 242 | 85 Participants | 135 Participants | 220 Participants |
| Age, Customized <18 years 242 | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 65-84 years 242 | 10 Participants | 11 Participants | 21 Participants |
| Age, Customized >85 years 242 | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized African American/African | 3 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asia - East | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian - Central/South | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian - Japanese | 6 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian - South-East Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Mixed race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White - Arabic/North African | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White - White/ Caucasian/European | 83 Participants | 129 Participants | 212 Participants |
| Sex: Female, Male Female | 94 Participants | 147 Participants | 241 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 78 / 95 | 128 / 147 |
| other Total, other adverse events | 90 / 95 | 131 / 147 |
| serious Total, serious adverse events | 36 / 95 | 52 / 147 |
Outcome results
Primary
The Number of Participants With Central Nervous System (CNS) Best Overall Response
Summary of CNS Objective Response (Lapatinib Monotherapy - MITT Population) Response to lapatinib in patients with progressive brain metastases from ErbB2-overexpressing breast cancer. The primary indicator of drug efficacy was CNS objective response rate. A CNS objective response was defined as either a Complete response (CR) or Partial response (PR), as assessed by volumetric analysis of brain Magnetic resonance imaging (MRI), provided there was no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of Neurological signs and symptoms (NSS) A CNS objective response rate was defined as a 50% volumetric reduction in sum of CNS target lesions, with no new or progressive CNS or non-CNS lesions, no increases in tumor-related steroid requirements and no worsening of neurological signs or symptoms
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: Modified ITT (MITT) Population is defined as all subjects who received at least four doses (750 mg lapatinib 2x daily for 2 days) of study medication and who had measurable brain metastases (greater than or equal to 1cm in diameter) at baseline assessment. MITT was the primary population for analysis of efficacy data in lapatinib monotherapy arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Partial response (PR) | 6 Participants |
| Cohort A | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Progressive disease (PD) | 40 Participants |
| Cohort A | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Stable disease (SD) | 40 Participants |
| Cohort A | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Unknown | 8 Participants |
| Cohort A | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Complete response (CR) | 0 Participants |
| Cohort B | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Unknown | 18 Participants |
| Cohort B | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Complete response (CR) | 0 Participants |
| Cohort B | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Partial response (PR) | 9 Participants |
| Cohort B | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Stable disease (SD) | 46 Participants |
| Cohort B | The Number of Participants With Central Nervous System (CNS) Best Overall Response | Progressive disease (PD) | 70 Participants |
Primary
The Percentage of Participants With Central Nervous System (CNS) Objective Response Rate - Response Rate (CR + PR)
Summary of CNS Objective Response (the Complete Response + Partial Response)
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: Modified ITT (MITT) Population is defined as all subjects who received at least four doses (750 mg lapatinib 2x daily for 2 days) of study medication and who had measurable brain metastases (greater than or equal to 1cm in diameter) at baseline assessment. MITT was the primary population for analysis of efficacy data in lapatinib monotherapy arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | The Percentage of Participants With Central Nervous System (CNS) Objective Response Rate - Response Rate (CR + PR) | 6 percentage of participants |
| Cohort B | The Percentage of Participants With Central Nervous System (CNS) Objective Response Rate - Response Rate (CR + PR) | 6 percentage of participants |
Secondary
Duration of Central Nervous System (CNS) Objective Response
The duration of CNS objective response, defined as the time from first CNS Objective response until tumor progression at any site or death due to any cause. A CNS objective response was defined as either a Complete Response (CR) or Partial Response (PR), as assessed by volumetric analysis of magnetic resonance imaging (MRI), provided there was no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of tumor-related neurological signs or symptoms.
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: Lapatinib monotherapy MITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Duration of Central Nervous System (CNS) Objective Response | 2.43 months |
| Cohort B | Duration of Central Nervous System (CNS) Objective Response | 1.58 months |
Secondary
Overall Survival (OS)
Overall survival (OS) defined as the time from initiation of investigational product to death due to any cause.
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: Lapatinib Monotherapy MITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Overall Survival (OS) | 10.78 months |
| Cohort B | Overall Survival (OS) | 5.82 months |
Secondary
Percentage of Participants With Improvement in Neurological Signs and Symptoms (NSS) Measured Using the Neurological Examination Worksheet
Physician-reported NSS worksheet is derived from 13 AEs and measured by NCI CTCAE v3.0 grouped into 7 categories: level of consciousness, neurological symptoms, cranial nerves, language, strength, sensation, & ataxia. Improvement of NSS required: Decrease by 1 or more grades from baseline of any tumor-related NSS, with confirmation at least 4 wks later, No development or worsening in any tumor-related NSS during interval, No radiographic evidence of CNS progression (assessed by volumetric MRI) or systemic (non-CNS) progression (assessed by RECIST) during interval, Stable or decreasing steroids during interval as defined by GSK equivalent doses of an alternative corticosteroid or a dose increase for non-tumor related reasons didn't constitute a steroid increase. Improvement in any non-tumor associated NSS didn't constitute improvement in NSS. Neurological exam, using Neurological Examination Worksheet was assessed at baseline & each 4 wks. Categories below are not mutually exclusive.
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: MITT population~Analysis was performed on combined cohorts in order to have a sufficient sample size to analyze association of CNS Volumetric Change from Baseline and NSS Improvement
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Percentage of Participants With Improvement in Neurological Signs and Symptoms (NSS) Measured Using the Neurological Examination Worksheet | Subjects with NSS improvement | 24 Participants |
| Cohort A | Percentage of Participants With Improvement in Neurological Signs and Symptoms (NSS) Measured Using the Neurological Examination Worksheet | >=20% volumetric reduction of lesion | 8 Participants |
| Cohort A | Percentage of Participants With Improvement in Neurological Signs and Symptoms (NSS) Measured Using the Neurological Examination Worksheet | any volumetric reduction of lesion | 14 Participants |
| Cohort A | Percentage of Participants With Improvement in Neurological Signs and Symptoms (NSS) Measured Using the Neurological Examination Worksheet | volumetric increase or withdrew | 9 Participants |
Secondary
Percentage of Patients With CNS Disease Control (Complete Response, Partial Response or Stable Disease) at 6 Months of Lapatinib Therapy
The CNS disease control rate, defined as the percentage of subjects with CR, PR or stable disease at Week 24
Time frame: from Start of lapatinib to 6 months
Population: MITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Percentage of Patients With CNS Disease Control (Complete Response, Partial Response or Stable Disease) at 6 Months of Lapatinib Therapy | 9 percentage of participants |
| Cohort B | Percentage of Patients With CNS Disease Control (Complete Response, Partial Response or Stable Disease) at 6 Months of Lapatinib Therapy | 2 percentage of participants |
Secondary
Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS)
Summary of Proportion of Subjects with a CNS Objective Response or Improvement in Baseline NSS
Time frame: baseline and weeks 8, 16, 24, 32, 40, 48
Population: MITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 8 | 23 percentage of participants |
| Cohort A | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 16 | 2 percentage of participants |
| Cohort A | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 24 | 8 percentage of participants |
| Cohort A | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 32 | 17 percentage of participants |
| Cohort A | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 40 | 0.0 percentage of participants |
| Cohort A | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 48 | 0.0 percentage of participants |
| Cohort B | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 40 | 0.0 percentage of participants |
| Cohort B | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 8 | 14 percentage of participants |
| Cohort B | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 32 | 0.0 percentage of participants |
| Cohort B | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 16 | 8 percentage of participants |
| Cohort B | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 48 | 0.0 percentage of participants |
| Cohort B | Percentage of Subjects With a CNS Objective Response or Improvement in Baseline Neurological Signs and Symptoms (NSS) | week 24 | 11 percentage of participants |
Secondary
Primary Cause of Death
Summary of Overall All-cause mortality (Main Study and Extension)
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Primary Cause of Death | Other | 4 Participants |
| Cohort A | Primary Cause of Death | Disease under study | 74 Participants |
| Cohort B | Primary Cause of Death | Disease under study | 124 Participants |
| Cohort B | Primary Cause of Death | Other | 4 Participants |
Secondary
Summary of Site of First Progression
baseline to time of disease progression or death
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: MITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Summary of Site of First Progression | CNS progression | 69 Participants |
| Cohort A | Summary of Site of First Progression | Non-CNS prgression | 1 Participants |
| Cohort A | Summary of Site of First Progression | CNS and Non-CNS progression | 12 Participants |
| Cohort B | Summary of Site of First Progression | CNS progression | 72 Participants |
| Cohort B | Summary of Site of First Progression | Non-CNS prgression | 10 Participants |
| Cohort B | Summary of Site of First Progression | CNS and Non-CNS progression | 36 Participants |
Secondary
Time to Progression (TTP) at Any Site
Summary of Kaplan-Meier Estimates for Progression Free Survival at Any Site
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Population: Lapatinib Monotherapy MITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Time to Progression (TTP) at Any Site | 2.60 months |
| Cohort B | Time to Progression (TTP) at Any Site | 1.87 months |