Progressive symptomatic or asymptomatic ErbB2 overexpressing breast cancer brain metastases. MedDRA version: 8.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer
Conditions
Sponsors
GlaxoSmithKline R&D Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed written informed consent; 2. Age = 18 years old; 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; 4. Life expectancy of at least 12 weeks; 5. Subjects must have histologically or cytologically confirmed invasive breast cancer, with Stage IV disease; 6. ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB 2 gene amplification by FISH, or ErbB 2 gene amplification by FISH alone (in subjects whose tumor blocks were not assessed by IHC). Subjects with tumors that are 2+ by IHC but negative by FISH assay are ineligible; 7. At least one measurable lesion in the brain, defined as any lesion = 10mm in longest dimension on T1-weighted, gadolinium-enhanced MRI. Measurable brain lesions should not have been treated with prior stereotactic radio surgery (SRS); an exception being a brain lesion whose longest linear dimension increased = 50% following SRS and whose absolute longest dimension now measures = 15mm; 8. Prior treatment of brain metastases with WBRT and/or SRS; 9. Unequivocal evidence of new and / or progressive lesions in the brain on an imaging study; Note: Subjects with progressive brain lesions are not required to meet RECIST criteria for CNS progression in order to be eligible for this study. 10. Prior treatment with trastuzumab, either alone or in combination with chemotherapy is required. Trastuzumab will be discontinued at least 2 weeks prior to enrollment on study; 11. Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive; 12. At least 2 weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic therapy, or hormonal therapy for cancer, and sufficiently recovered or stabilized from side effects associated with prior therapy. Concurrent treatment with bisphosphonates is permitted; 13. At least 3 weeks since major surgical procedures; 14. Able to swallow and retain oral medications; 15. Female subjects with child bearing potential or male subjects able to father a child must be completely abstinent from intercourse or use acceptable methods for birth control during the course of the study; 16. Subjects must complete all screening assessments as outlined in the protocol; 17. Subjects must have normal organ and marrow function as defined below: SYSTEM LABORATORY VALUES Hematologic ANC (absolute neutrophil count) =1.0 x 109/L Hemoglobin = 9 g/dL (after transfusion if needed) Platelets = 50 x 109/L Hepatic Albumin = 2.5 g/dL Serum bilirubin = 1.5x ULN unless due to Gilbert’s syndrome AST and ALT = 5x ULN if documented liver metastases = 3x ULN without liver metastases Renal Serum Creatinine = 2.0 mg/dL or Calculated Creatinine Clearance* = 25 mL/min *Calculated by the Cockcroft and Gault Method Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. 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; 2. Concurrent treatment with an investigational agent or participation in another treatment clinical trial; 3. 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; 4. Subjects with leptomeningeal carcinomatosis as the only site of CNS involvement; 5. History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib; 6. Concurrent treatment with medications listed in Section 8.2, Prohibited Medications; 7. Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with active, uncontrolled ulcerative colitis are also excluded; 8. History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents, or other contraindication to gadolinium contrast; 9. Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or shrapnel; 10. 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; 11. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent; 12. Pre-existing severe cerebral vascular disease, such as stroke involving a major vessel, CNS vasculitis, or malignant hypertension; 13. 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, with the exception of asymptomatic atrial fibrillation requiring anticoagulation • 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 14. Uncontrolled infection; 15. 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; 16. Pregnant or lactating females; 17. No prior lapatinib therapy; 18. Any other investigational drugs from 30 days or five half lives, prior to the first dose of lapatinib until 30 days after the last dose of lapatinib.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the CNS objective response rate to monotherapy lapatinib in subjects with progressive brain metastases from ErbB2-overexpressing breast cancer. A CNS objective response is defined as either a Complete Response (CR) or Partial Response (PR), as assessed by volumetric analysis of brain magnetic resonance imaging (MRI), provided there is no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of tumor-related neurological signs and symptoms (NSS). ;Secondary Objective: To determine improvement in neurological signs and symptoms (NSS), measured using the Neurological Examination Worksheet • To determine the percentage of subjects who obtain a CNS objective response or improvement in baseline NSS • To determine duration of CNS objective response • To determine percentage of subjects with CNS disease control (complete response, partial response or stable disease) at 6 months of lapatinib therapy • To determine time to progression at any site • To determine overall survival (OS) • To describe and summarize site of first progression and cause of death • To determine the qualitative and quantitative toxicities associated with oral lapatinib, given at a dose of 750 mg BID. ;Primary end point(s): CNS objective response rate is the primary study endpoint, where CNS objective response is defined as either a CR or PR, assessed by volumetric analyses of magnetic resonance imaging (MRI), provided there is no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of neurological signs and symptoms (NSS). | — |
Countries
Austria, Belgium, Germany, Greece, Italy, Spain, Sweden, United Kingdom
Outcome results
None listed