DETECT III - A Multicenter, Phase III Study to Compare Standard Therapy +/- Lapatinib in HER2-ve MBC-Patients With HER2+ve CTCs

Inclusion Criteria:

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 confirmed as cancer by histopathology. Estrogen Receptor (EG) and Progesterone Receptor (PgR) status must have been documented.
3. Primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences were investigated for HER2 status and all of the investigations showed HER2-negativity (i.e.: immunohistochemistry (IHC) score 0-1+ or 2+ and fluorescent in situ hybridization (FISH) negative or just FISH negative, whichever was performed).
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 CellSearch® Circulating Tumor Cell Kit (Veridex LLC) 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 accurately measured according to RECIST guideline version 1.1 \[Eisenhauer 2009\].
8. Age ≥ 18 years.
9. ECOG Score \< 2
10. Adequate organ function within 7 days before randomization, evidenced by the following laboratory results below:

    * absolute neutrophil count ≥ 1500/µL,
    * platelet count ≥ 100000/µL,
    * hemoglobin ≥ 9 g/dL,
    * ALT (SGPT) ≤ 2.5 × ULN,
    * AST (SGOT) ≤ 2.5 × ULN,
    * serum alkaline phosphatase ≤ 2.5 × ULN, (Serum alkaline phosphatase may be \> 2.5 × ULN only if bone metastases are present and AST (SGOT) and ALT (SGPT) \< 1.5× ULN)
    * creatinine ≤ 2.0 mg/dl or 177µmol/L
    * International normalized ratio (INR) and activated partial thromboplastin time or partial thromboplastin time (aPTT or PTT) ≤ 1.5 × ULN Please note: These laboratory criteria only refer to lapatinib therapy; with respect to the standard anticancer therapy the relevant summaries of product characteristics (SPCs) have to be observed additionally.
11. Left ventricular cardiac ejection fraction (LVEF) ≥ 50%, in case of planned standard chemotherapy with anthracyclines ≥ 55%, and in any case 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 randomization,
    * Contraception by means of a reliable method (i.e. non-hormonal contraception, IUD, a double barrier method, vasectomy of the sexual partner, complete sexual abstinence). Patient must consent in maintaining such contraception until 28 days after completion of study treatment.

Exclusion Criteria:

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 within 4 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) 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 assessment).
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 absorb oral medication. This includes malabsorption syndrome, requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption (for example resection of small bowel or stomach), uncontrolled inflammatory GI disease (e.g., Crohn's disease) and any other diseases 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 or symptomatic angina,
    * 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.

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