Breast cancer, developing brain metastasis/es Cancer Breast cancer
Conditions
Interventions
1. Participants will be randomised on an equal basis to either:
1.1. Lapatinib (1250 mg daily) on days 1 - 14 plus capecitabine (1000 mg/m^2 twice daily) on days 1 - 14 of 21 day cycle
Sponsors
Leeds Teaching Hospitals NHS Trust (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female aged greater than or equal to 18 years 2. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2 3. Given written informed consent prior to any trial specific procedures 4. Expected survival greater than or equal to 12 weeks 5. Histologically or cytologically confirmed invasive breast cancer, with stage IV disease including newly diagnosed central nervous system (CNS) metastasis/es 6. ErbB2 overexpression in the invasive component of the primary or metastatic lesion as locally defined by: 7.1. 3+ staining by immunohistochemistry (IHC) 7.2. 2+ staining by IHC in conjunction with ErbB2 gene amplification by FISH 7.3. ErbB2 gene amplification by FISH 8. Participants with a negative or equivocal overall result are not eligible for inclusion in the trial 9. Evidence of metastatic brain disease. To be considered evaluable for the primary endpoint and the CNS response rates endpoints, participants must have at least one measurable brain lesion that can be accurately measured in at least one dimension (shortest dimension to be recorded) as greater than 20 mm with conventional techniques or as greater than 10 mm with spiral computed tomography (CT) scan. Participants with leptomeningeal disease are not eligible for participation in the trial due to the lack of measurable disease. 10. Treated previously with taxanes or anthracyclines in the adjuvant or metastatic setting. All treatment related adverse events must be less than or equal to grade 1 at the time of randomisation. 11. Prior treatment with trastuzumab is required and all treatment related adverse events must be less than or equal to Grade 1 at the time of randomisation 12. Completed local cranial therapy (stereotactic radio surgery or whole brain radiotherapy) 13. Able to swallow and retain oral medication 14. Normal organ and bone marrow function as defined below: 15.1. Leukocytes greater than 3,000/µL 15.2. Absolute neutrophil count greater than 1,500/µL 15.3. Platelets greater than 100,000/µL 15.4. Total bilirubin within normal institutional limits 15.5. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) less than or equal to 2.5 x institutional upper limits of normal 15.6. Creatinine within normal institutional limits or creatinine clearance greater than or equal to 60 ml/min/1.73 m^2 for participants with creatinine levels above institutional normal 16. Cardiac ejection fraction greater than or equal to 50% or within the institutional limit as measured by echocardiogram scan. Note that the baseline and on treatment scan should be performed using the same modality and preferably the same institution.
Exclusion criteria
Exclusion criteria: 1. Prior therapy with lapatinib or an ErbB2 inhibitor other than trastuzumab 2. Prior treatment with capecitabine 3. Concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of cancer 4. Known dihydropyrimidine dehydrogenase (DPD) deficiency 5. Current active hepatic or biliary disease (with exception of participants with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) 6. Pregnant or lactating females. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to trial entry and for the duration of the trial participation. 7. History of significant non-breast malignancy (aside from non-melanomatous skin cancer, carcinoma in situ of the uterine cervix, superficial bladder cancer treated with curative intent) 8. History of allergic reactions attributed to compounds of a similar chemical or biological composition as to lapatinib 9. Uncontrolled inter-current illness including, but not limited to: 9.1. Ongoing or active infection 9.2. Symptomatic congestive heart failure 9.3. Unstable angina pectoris 9.4. Cardiac arrhythmia 9.5. Psychiatric illness/social situations that would limit compliance with trial requirements 10. Gastrointestinal (GI) tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis) 11. Renal function as measured by creatinine clearance less than 30 ml/min (ratio to norm less than 0.1) 12. Not recovered from adverse events due to agents administered more than 4 weeks earlier with the exception of adverse events less than or equal to grade 1 after previous chemotherapy 13. Prior treatment with epidermal growth factor receptor (EGFR) targeting therapies 14. Active cardiac disease, defined as: 14.1. History of uncontrolled angina 14.2. History of arrhythmias requiring medications, or clinically significant, with the exception of asymptomatic atrial fibrillation requiring anticoagulation 14.3. Myocardial infarction less than 6 months from trial entry 14.4. Uncontrolled or symptomatic congestive heart failure 14.5. Ejection fraction below 50% or the institutional lower normal limit 14.6. Any other cardiac condition, which in the opinion of the treating investigator, would make this protocol unreasonably hazardous for the participant 15. Any concomitant medications or substances forming part of the part of normal ongoing care locally known to affect, or have the potential to affect, the activity or pharmacokinetics of lapatinib
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time to progression of central nervous system (CNS) metastases defined as time from randomisation to the date of diagnosis of CNS disease progression as measured by Response Evaluation Criteria in Solid Tumours (RECIST) on reviewed magnetic resonance imaging (MRI) scans | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Progression-free survival (CNS or non-CNS): time from randomisation to first documented evidence of disease progression or death from any cause - 1.1. CNS progression will be assessed by RECIST of MRI-scans 1.2. Non-CNS disease progression will be measured and reported as per local standard clinical practice (i.e. clinical or radiological evidence of disease progression) 2. Overall survival defined as time from randomisation to date of death from any cause 3. CNS overall response rate (CR or PR) is defined as complete or partial response (CR or PR) as measured by RECIST and based on reviewed MRI scans 4. CNS clinical benefit response rate (confirmed CR or PR at any time or SD at the 24-week time-point) as measured by RECIST and based on reviewed MRI scans 5. Total days of steroid use for palliation of CNS symptoms will be measured every 3 weeks by research nurse-elicitation from the participants regarding their steroid use 6. General and neurological quality of life as measured by the patient self-reported EORTC QLQ-C30 and BN20 questionnaires and patient self-reported symptoms and side-effects assessments at baseline and at 12 and 24 weeks 7. Patient self-reported symptoms and side-effects assessments will also be completed every 3 weeks post-randomisation to correspond with clinically-assessed toxicity reporting according to NCI CTC-AE grading criteria 8. Delay/stabilisation of CNS symptoms will be measured using the patient self-reported EORTC QLQ-C30 and BN20 questionnaires at baseline and at 12 and 24 weeks. Patient self-reported symptoms and side-effects assessments will also be completed every 3 weeks post-randomisation to correspond with clinically-assessed toxicity reporting according to NCI CTC-AE grading criteria 9. Qualitative and quantitative toxicities: Patient self-reported symptoms and side | — |
Countries
England, United Kingdom
Outcome results
None listed