Patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells MedDRA version: 21.1 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.1 Level: PT Classification code 10055113 Term: Breast cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Tyverb (Studienware)
Product Name: Lapatinib
Product Code: GW572016
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Lapatinib
CAS Number: 388082-78-8
Current Sponsor code: GW5
Sponsors
Universitätsklinikum Ulm
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. Questions about eligibility criteria should be addressed PRIOR to requesting randomization. The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards used to ensure that patients who enter this study are medically appropriate candidates for this therapy. For the safety of the patients, as well as to ensure that the results of this study can be useful for making treatment decisions regarding other patients with similar diseases, it is important that no exceptions are made to these criteria for admission to the study. Patients must fulfill all of the following criteria to be eligible for admission to the study: 1. Written informed consent in study participation. 2. Metastatic breast cancer which cannot be treated by surgery or radiotherapy only. The primary tumor and/or biopsies from metastatic sites or locoregional recurrences must have been con-firmed as cancer by histopathology. Estrogen Receptor (ER) and Progesterone Receptor (PgR) status must have been documented. 3. All primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences that were investigated for HER2 status showed HER2-negativity (i.e.: immunohistochemistry (IHC) score 0-1+ or 2+ and fluorescent in situ hybridization (FISH) negative or just FISH neg-ative, whichever was performed). In patients for which standard HER2-testing was not available at time of primary diagnosis and for which a biopsy of metastatic sites or locoregional recurrences were not performed are regarded as having a HER-2 negative tumor. 4. Evidence of HER2-positive CTCs. Evidence is assumed if the following holds: • At least one CTC could be extracted from 7.5 ml patient blood by means of the Cell-Search® Circulating Tumor Cell Kit (Veridex LLC, Raritan, USA) and • At least one of all extracted CTCs was found to be HER2-positive. HER2 status must be assessed by means of IHC or FISH. 5. Indication for a standard chemo- or endocrine therapy whose combination with lapatinib is either approved (see SPC of Tyverb® 250 mg tablets) or has been investigated in prior clinical trials (see tables of section 8.2.1.). 6. Tumor evaluation has been performed within 6 weeks before randomization and results are available. 7. Patients must have at least one lesion that can be evaluated according to RECIST guideline version 1.1. Patients with measurable and/or non-measurable disease are eligible. [Eisenhauer 2009]. 8. Age = 18 years. 9. ECOG Score < 2 (see APPENDIX III – PERFORMANCE STATUS SCALES/SCORES). 10. Adequate organ function within 7 days before randomization, evidenced by the following labo-ratory results below: • absolute neutrophil count = 1500/µL, • platelet count = 100000/µL, • hemoglobin = 9g/dL, • ALT (SGPT) = 3.0 × ULN, • AST (SGOT) = 3.0 × ULN, • Bilirubin = 2 × ULN and = 35% direct, • creatinine = 2.0 mg/dl or 177µmol/L Please note: These laboratory criteria only refer to lapatinib therapy; with respect to the stan-dard anticancer therapy the relevant summaries of product characteristics (SmPCs) have to be observed additionally. 11. Left ventricular cardiac ejection fraction (LVEF) = 50%, within normal institutional limits as measured by echocardiogram. 12. In case of patients of child bearing potential: • Negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to
Exclusion criteria
Exclusion criteria: Patients who fulfill any of the following criteria are not eligible for randomization: 1.History of hypersensitivity reactions attributed to compounds of similar chemical or biological composition to lapatinib. 2. History of > 3 chemotherapy lines for metastatic disease (a chemotherapy line being defined as any new chemotherapy and any modification of an existing chemotherapy regimen regardless of the reason for change). 3. Treatment with investigational agents of any type or anticancer therapy during the trial or with-in 2 weeks prior to randomization and 6 weeks in case of nitrosoureas or mitomycin C. 4. Adverse events due to prior anticancer therapy which are > Grade 1 (NCI CTCAE) and therapeutically relevant at time of randomization. 5. Anti-retroviral therapy due to HIV infection. 6. Current active hepatic or biliary disease (with exception of patients with Gilbert’s syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator as-sessment) 7. Concurrent disease or condition that might interfere with adequate assessment or evaluation of study data, or any medical disorder that would make the patient’s participation unreasonably hazardous. 8. Other malignant diseases within the last 3 years apart from CIN of the uterine cervix and skin basalioma. 9. Disease or condition which might restrain the ability to take or resorb oral medication. This includes malabsorption syndrome, requirement for intravenous (IV) alimentation, prior surgi-cal procedures affecting absorption (for example resection of small bowel or stomach), uncon-trolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis) and any other dis-eases significantly affecting gastrointestinal function as well as inability to swallow and retain oral medication for any other reason. 10. Active cardiac disease, defined as: • History of uncontrolled, • history of arrhythmias requiring medications, or clinically significant, with the exception of asymptomatic atrial fibrillation requiring anticoagulation, • myocardial infarction less than 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. 11. Dementia, altered mental status, or any psychiatric or social condition which would prohibit the understanding or rendering of informed consent or which might interfere with the patient’s adherence to the protocol. 12. Life expectancy < 3 months. 13. Male patients. 14. Pregnancy or nursing. 15. Primary tumor or biopsies from metastatic sites or locoregional recurrences showing HER2-positivity. 16. Any prior treatment with anti-HER2 directed therapy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the trial is to prove the clinical efficacy of lapatinib (as assessed by the CTC clearance rate) in patients with metastasizing breast cancer who exhibit HER2-positive circulating tumor cells (CTC) although the primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences that were investigated for HER2 status showed HER2-negativity.;Secondary Objective: The secondary objective of the trial is to assess the level of compliance to study procedures.;Primary end point(s): Primary endpoint: CTC clearance rate: Proportion of patients with at least one CTC detected in 7.5 ml of peripheral blood drawn before treatment that show no evidence of CTCs in the blood after treatment (CTC prevalence as assessed using the CellSearch® System; Veridex LLC, Raritan, USA) ;Timepoint(s) of evaluation of this end point: Statistical analysis of experimental data will be done at the end of the study. The analysis of ef-ficacy will be based on the patients in the ITT set and the PP set. The safety analysis will be conducted on all patients who received at least one dose of the study treatment. The confirma-tory analysis of the primary endpoint will be conducted on the ITT set. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints: ? Progression free survival (PFS): Time interval from randomization until progressive disease (PD) or death from any cause, whichever comes first (as defined by RECIST guideline version 1.1 [Eisenhauer 2009]) – Overall survival: Time from randomization until death of any cause – Dynamic of CTC: Descriptive statistics of regular CTC counts (CR, PR, SD and PD are defined according to the RECIST Version 1.1 criteria [Eisenhauer 2009].) Assessment of the patients’ quality of life (QoL) in both treatment groups with regard to the total score and subscores calculated from data obtained by means of the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires. Assessment of the safety and tolerability of lapatinib based on adverse event (AE) reports. Assessment of the safety and tolerability of denosumab in patients with bone metastases based on adverse events (AE) reports. Assessment of pain intensity measured by use of a numeric rating scale (NRS) Assessment of compliance to the study protocol. ;Timepoint(s) of evaluation of this end point: Statistical analysis of experimental data will be done at the end of the study. | — |
Countries
Germany
Contacts
Public ContactFrauenklinik-Studienzentrale
Universitätsklinikum Ulm
Outcome results
None listed