Brain Metastases In ErbB2-Positive Breast Cancer

Phase 2

Terminated

Conditions: Neoplasms, Breast

Interventions: Drug: capecitabine
Drug: topotecan
Drug: lapatinib

Registration Number: NCT00437073

Lead Sponsor: GlaxoSmithKline

Brief Summary: This study is for 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. The study will determine how safe and effective lapatinib is when given in combination with capecitabine to treat patients with ErbB2 overexpressing breast cancer that has spread to the brain. Lapatinib is an oral drug that will be taken every day. Tests for safety and efficacy will be performed regularly during the course of the study.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Not provided

Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled in the study:

Subjects who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or who have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;
Concurrent treatment with an investigational agent or participation in another treatment clinical trial;
Prior therapy with a topoisomerase 1 inhibitor;
Prior lapatinib therapy;
Prior therapy with capecitabine;
Known dihydropyrimidine dehydrogenase (DPD) deficiency;
ECOG Performance Status 2 or greater;
Subjects receiving concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of their cancer. Hormone therapy for ovarian suppression which has been used for > 6 months, during which time there has been disease progression in the brain, is allowed. Concurrent treatment with bisphosphonates is allowed;
Subjects with evidence of leptomeningeal carcinomatosis at screening;
History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib;
History of allergic reactions attributed to compounds chemically related to capecitabine, fluorouracil or any excipients;
Concurrent treatment with medications listed as Prohibited Medications;
Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with active, uncontrolled ulcerative colitis are also excluded;
History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents, or other contraindication to gadolinium contrast;
Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or shrapnel;
Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the subject's safety;
Anticoagulant therapy (other than coumadin or aspirin as catheter prophylaxis) at study entry;
Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent, unless a legally acceptable representative could provide informed consent (if in accord with the policies of the local Ethics Committee);
Pre-existing severe cerebral vascular disease, such as stroke involving a major vessel, CNS vasculitis, or malignant hypertension;
Active cardiac disease, defined as one or more of the following:
History of uncontrolled or symptomatic angina
History of arrhythmias requiring medications, or clinically significant
Myocardial infarction < 6 months from study entry
Uncontrolled or symptomatic congestive heart failure
Ejection fraction below the institutional normal limit
Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient;
Uncontrolled infection;
Pregnant or lactating females;
History of other malignancy, except for curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Subjects with other malignancies who have been disease-free for at least 5 years are eligible.
Have current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
lapatinib plus capecitabine	capecitabine	A total of 55 isubjects will be enrolled into this arm. Subjects with progression of CNS and/or non-CNS disease will be considered progressors. At the time of radiographically-documented CNS and/or non-CNS disease progression, a subject randomized to this arm will be allowed to cross over to the alternative arm.
lapatinib plus capecitabine	lapatinib	A total of 55 isubjects will be enrolled into this arm. Subjects with progression of CNS and/or non-CNS disease will be considered progressors. At the time of radiographically-documented CNS and/or non-CNS disease progression, a subject randomized to this arm will be allowed to cross over to the alternative arm.
lapatinib + topotecan	lapatinib	A total of 55 isubjects will be enrolled into this arm. Subjects with progression of CNS and/or non-CNS disease will be considered progressors. At the time of radiographically-documented CNS and/or non-CNS disease progression, a subject randomized to this arm will be allowed to cross over to the alternative arm.
lapatinib + topotecan	topotecan	A total of 55 isubjects will be enrolled into this arm. Subjects with progression of CNS and/or non-CNS disease will be considered progressors. At the time of radiographically-documented CNS and/or non-CNS disease progression, a subject randomized to this arm will be allowed to cross over to the alternative arm.

Primary Outcome Measures

Name	Time	Method
Number of Participants With the Indicated Central Nervous System (CNS) Objective Response (OR)	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	CNS OR is defined as the number of participants with either a complete response (CR) or partial response (PR) as assessed by volumetric analysis of brain magnetic resonance imaging (MRI) and Response Evaluation Criteria In Solid Tumors (RECIST). CR: complete resolution of all evaluable and non-evaluable brain metastases; PR: =\>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline.
Number of Participants With the Indicated CNS Responses	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	CNS responses were assessed by volumetric (V) analysis of brain MRI and RECIST. CR: complete resolution of all evaluable and non-evaluable brain metastases (BMs). PR: =\>50% reduction in the V sum of all evaluable BMs compared to baseline. A response of "Other" was used for participants who discontinued the study prior to the first efficacy assessment. Stable Disease (SD): disease that does not meet CR, PR, or CNS progression criteria. Progressive disease (PD): a requirement for a new steroid or an increasing steroid dose for the treatment of worsening neurological signs/symptoms due to BMs.

Secondary Outcome Measures

Name	Time	Method
Duration of CNS Objective Response (Defined as the Time From the First Documented Evidence of CNS PR or CR Until the First Documented Sign of Disease Progression or Death, if Sooner)	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	CNS OR is defined as the number of participants with either a CR or PR as assessed by volumetric analysis of brain MRI and RECIST. CR: complete resolution of all evaluable and non-evaluable brain metastases; PR: =\>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Percentage of Participants With Clinical Benefit	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	Clinical benefit is defined as CR (complete resolution of all evaluable and non-evaluable brain metastases), PR (=\>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline), or stable disease (disease that does not meet CR, PR, or CNS progression criteria) for at least 6 months. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Percentage of Participants (Par.) With Objective Response by RECIST in Non-CNS Disease	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	Non-CNS disease (for par. with measurable baseline non-CNS disease) OR is defined as the number of par. with either a CR or PR as assessed by computed tomography (CT) or MRI scan and RECIST. CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough par. enrolled in the study to provide statistically valid analyses.
Time to CNS Objective Response (Defined as the Time From the Start of Treatment Until the First Documented Evidence of Partial or Complete Tumor Response [Whichever Status is Recorded First])	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	CNS OR is defined as the number of participants with either a CR or PR as assessed by volumetric analysis of brain MRI and RECIST. CR: complete resolution of all evaluable and non-evaluable brain metastases; PR: =\>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Number of Participants With the Indicated Site of Initial Disease Progression	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	The site of initial disease will be determined by taking the earliest date of known progression and assigning the appropriate category (CNS or non-CNS) based on the source of the earliest date. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Progression-free Survival	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	Progression-free survival is defined as the time from the start of treatment until the first documented sign of disease progression at any site or death due to any cause, if sooner. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Overall Survival	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	Overall survival is defined as the time from the start of treatment until death due to any cause. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Percentage of Participants With Disease Stabilization for 6 Months or More	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	The percentage participants with disease stabiliztion for 6 months or more were defined as those treated participants with a best CNS objective response of SD whose disease stabilization lasted 6 months or more from the start of treatment. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Percentage of Participants With a >=20% Volumetric Reduction in CNS Lesions	Baseline; from the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	The percentage of participants with a \>=20% volumetric reduction in CNS lesions was defined as the percentage of treated participants achieving at least a 20% volumetric reduction in CNS lesions relative to baseline. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.
Percentage of Participants With Baseline Tumor-related (TR) Neurological Signs and Symptoms (NSS), Who Experienced Improvement in NSS as Measured by the Neurological Examination Worksheet (NEW)	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	TR NSS was to be recorded by the Investigator on the NEW, using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE V3.0). Improvement was to be defined as a decrease of 1 or more CTCAE grades from baseline of any TR NSS. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.