- - Patients progressing locally in the CNS after prior systemic treatment and Whole brain
radiotherapy (WBRT)/ Stereotactic radiosurgery (SRS) (or declines radiotherapy), for
which no standard therapy options are available
- Performance status of Eastern Cooperative Oncology Group (ECOG) 0-3
- Adequate organ function
- Absolute neutrophil count (ANC) ≥1500 / mm3 .
(ANC >1000/mm3 may be considered in
special circumstances such as benign cyclical neutropenia as judged by the
investigator and in discussion with the sponsor).
- - Platelet count ≥75,000 / mm3 .
- - Estimated creatinine clearance > 45ml/min
- Left ventricular function with resting ejection fraction ≥ 50% or above the
institutional Lower Limit of Normal (LLN).
- - Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal
(Patients with Gilbert's syndrome total bilirubin must be ≤4 times institutional
upper limit of normal)
- Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ three
times the upper limit of (institutional/central) normal (ULN) (if related to
liver metastases ≤ five times ULN).
- - Written informed consent that is consistent with ICH-GCP guidelines
- Symptomatic brain metastases requiring high dose steroids.
Patients are excluded from
Part A if they develop cerebral manifestation under afatinib. (Those progressing on
afatinib will proceed to part B with HDI afatinib)
- - Hormonal treatment within 2 weeks prior to start of study treatment (continued use of
anti-androgens and/or gonadorelin analogues for treatment of prostate cancer
permitted) Radiotherapy within 4 weeks prior to randomization, except as follows:
- Palliative radiation to target organs other than chest may be allowed up to 2
weeks prior to randomisation, and
- Single dose palliative treatment for symptomatic metastasis outside above
allowance to be discussed with sponsor prior to enrolling.
- - Major surgery within 4 weeks before starting study treatment or scheduled for surgery
during the projected course of the study
- Known hypersensitivity to afatinib or the excipients of any of the trial drugs
- History or presence of clinically relevant cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA)
classification of ≥ 3, unstable angina or poorly controlled arrhythmia as determined
by the investigator.
Myocardial infarction within 6 months prior to randomisation.
- - Women of child-bearing potential (WOCBP) and men who are able to father a child,
unwilling to be abstinent or use highly effective methods of birth control that result
in a low failure rate of less than 1% per year when used consistently and correctly
prior to study entry, for the duration of study participation and for at least after treatment has ended.
- - Women who are pregnant, nursing, or who plan to become pregnant while in the trial
- Any history of or concomitant condition that, in the opinion of the Investigator,
would compromise the patient's ability to comply with the study or interfere with the
evaluation of the efficacy and safety of the test drug
- Previous or concomitant malignancies at other sites, except effectively treated
nonmelanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or
effectively treated malignancy that has been in remission for more than 3 years and is
considered to be cured.
- - Requiring treatment with any of the prohibited concomitant medications listed in
2.1 that cannot be stopped for the duration of trial participation
- - Known pre-existing interstitial lung disease
- Any history or presence of poorly controlled gastrointestinal disorders that could
affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis,
chronic diarrhoea, malabsorption)
- Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA),
active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV