Afatinib (BIBW 2992) QTcF Trial in Patients With Relapsed or Refractory Solid Tumours

Inclusion criteria:

1. Male or female patients aged at least 18 years old.
2. Histologically or cytologically confirmed diagnosis of a solid malignant tumour, known to express EGFR/HER2 that is either refractory to standard therapies, or for which no standard treatment is available (including patients with brain metastases).
3. At least one tumor lesion that can accurately be measured by computed tomography (CT) or magnetic resonance imaging (MRI) in at least one dimension with longest diameter to be recorded as greater than or equal to 20 mm using conventional techniques or greater than or equal to 10 mm with spiral CT scan.
4. Life expectancy of at least 3 months.
5. Written informed consent that is consistent with ICH-GCP guidelines.
6. Eastern Cooperative Oncology Group (ECOG) performance score 0,1 or 2.
7. Patients must have recovered from any previous surgery.
8. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment. Breast feeding mothers will be excluded since these agents may be toxic to infants.

For patients with Glioma and brain metastases the following additional inclusion criteria should apply:

1. Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemo-radiotherapy. Patients with prior low-grade glioma are eligible if histological assessment demonstrates transformation to WHO Grade IV malignant glioma.
2. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on Gd MRI performed within 14 days prior to first treatment (Day 1).

Exclusion criteria:

Major exclusion criteria; 9. Radiotherapy within the past 2 weeks prior to treatment with the trial drug. 10. Chemo-, hormone- (other than megestrol acetate or steroids required for maintenance non-cancer therapy) or immunotherapy within the past 4 weeks before first drug administration.

11\. Patients not completely recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapies to CTC \< Grade 1. Prior chemotherapy is allowed if completed at least 4 weeks prior to first trial treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from the acute toxicities of that therapy.

12\. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2 inhibiting drugs within the past four weeks before start of therapy or concomitantly with this trial.

15\. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, including New York Heart Association (NYHA) functional classification of 3.

16\. Cardiac left ventricular function with resting ejection fraction \< 50% measured by multigated blood pool imaging of the heart (MUGA scan) or Echocardiogram.

17\. QTcF- interval \> 470 ms at screening. 18. PR-interval \> 230 ms at screening. 19. QRS-interval \>120 ms at screening. 20. ST-segment and T/U-wave abnormalities at screening, as will be assessed by a cardiology specialist of a central lab.

21\. Absolute neutrophil count (ANC) \< 1,500/mm3. 22. Platelet count \< 100,000 / mm3. 23. Bilirubin \> 1.5 mg / dl (\>26 micro mol / L, SI unit equivalent). Aspartate amino transferase (AST) or alanine amino transferase (ALT) \> or equal to three times the upper limit of normal (if related to liver metastases \> five times the upper limit of normal).

24\. Serum creatinine \> 1.5 times of the upper normal limit or calculated/measured creatinine clearance \> or equal to 45 ml / min.

25\. Patients with known Interstitial Lung Disease (ILD) For Patients with glioma and brain metastases additional exclusion criteria apply;

1. Patients with untreated or symptomatic brain metastases. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least four (4) weeks, no history of cerebral oedema or bleeding in the past four (4) weeks. Steroids will be allowed. Anti-epileptic therapy will be allowed if no changes are anticipated within the initial 14 days of treatment (QTC-evaluation).
2. Less than 4 weeks between radiotherapy and start of study treatment, unless new enhancing lesion outside of radiation field or radiologically progressive on two consecutive MRI scans at least four weeks apart or biopsy-proven recurrence.
3. Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure.
4. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas).
5. Less than four weeks from prior treatment with bevacizumab.
6. Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study.