Lapatinib for Brain Metastases In ErbB2-Positive Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Phase II Study of Lapatinib for Brain Metastases in Subjects With ErbB2-Positive Breast Cancer Following Trastuzumab-based Systemic Therapy and Cranial Radiotherapy

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: lapatinib


Participation Criteria
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Eligibility Criteria
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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.

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
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm<br>750 mg lapatinib administered orally twice daily | Drug: lapatinib<br>* tyrosine kinase inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 from baseline to data cutoff (25 Sept 2007); approximately 2 years | 
| 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 from baseline to data cutoff (25 Sept 2007); approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 from baseline to data cutoff (25 Sept 2007); approximately 2 years | 
| 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 | baseline and weeks 8, 16, 24, 32, 40, 48 | 
| 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 from baseline to data cutoff (25 Sept 2007); approximately 2 years | 
| 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 | from Start of lapatinib to 6 months | 
| Time to Progression (TTP) at Any Site | Summary of Kaplan-Meier Estimates for Progression Free Survival at Any Site | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | 
| Overall Survival (OS) | Overall survival (OS) defined as the time from initiation of investigational product to death due to any cause. | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | 
| Summary of Site of First Progression | baseline to time of disease progression or death | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | 
| Primary Cause of Death | Summary of Overall All-cause mortality (Main Study and Extension) | time from baseline to data cutoff (25 Sept 2007); approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, brain metastases, ErbB2 positive, HER2 positive, neoplasms, cancer, lapatinib, LAP016A2202, LAP016A, CLAP016A2202, GW572016