Lux-Breast 3; Randomised Phase II Study of Afatinib Alone or in Combination With Vinorelbine Versus Investigator's Choice of Treatment in Patients With HER2 Positive Breast Cancer With Progressive Brain Metastases After Trastuzumab and/or Lapatinib Based Therapy

Inclusion Criteria

Inclusion criteria:

1. patients with HER2 positive breast cancer with a documented central nervous system
(CNS) recurrence/progression (by imaging) during or after a HER2 inhibitor
(Trastuzumab and/or Lapatinib) based therapy (no leptomeningeal carcinomatosis as the
only site of CNS metastases)

2. at least one measurable and progressive lesion in the brain (=10 mm on T1-weighted,
gadolinium-enhanced Magnetic Resonance Imaging). Measurable or non measurable
extracranial metastases allowed.

3. previous treatment with HER2 inhibitors to be discontinued prior to first study
treatment administration (at least 14 days for trastuzumab and other antibodies, at
least 7 days for lapatinib).

4. previous chemotherapy and hormonal therapy (adjuvant and metastatic regimens)
allowed, but chemotherapy must have been discontinued at least 14 days and hormonal
therapy at least 7 days prior to first study treatment administration.

5. Patients must have recovered to baseline condition or to Common Terminology Criteria
for Adverse Events (CTCAE) version 3.0 grade = 1 from any acute CTCAE v. 3.0 grade =2
side effects of previous treatments.

6. prior surgery, whole brain radiotherapy or stereotactic radiosurgery allowed provided
that there is unequivocal evidence of one or more new and/or progressive brain
metastases after completion of whole brain radiotherapy or stereotactic radiosurgery.

Exclusion criteria:

1. Prior treatment with HER2- tyrosine kinase inhibitor other than lapatinib

2. Any other current malignancy or malignancy diagnosed within the past five (5) years
(other than bilateral primary breast cancer, metastases to the contralateral breast,
non-melanomatous skin cancer and in situ cervical cancer).

3. Significant chronic or recent acute gastrointestinal disorders with diarrhoea as a
major symptom e.g. Crohn's disease, malabsorption or Common Terminology Criteria
(CTC) grade =2 diarrhoea of any aetiology.