Single-arm Trial of BIBW 2992 (Afatinib) in Demographically and Genotypically Selected NSCLC Patients

A Phase II Single-arm Trial of BIBW 2992 in Demographically and Genotypically Selected NSCLC

The primary objective of this open-label, single arm Phase II trial is to explore the efficacy of BIBW 2992 defined by the objective response rate (CR, PR) as determined by the RECIST criteria, in patients with advanced NSCLC Stage IIIB or IV whose tumours harbour activating mutations within exon 18 to exon 21 of the EGFR receptor, in patients with mutations in the HER2/neu receptor and in patients with EGFR FISH positive tumours with no EGFR mutations.

Inclusion criteria:

1. patients with pathologically confirmed diagnosis of NSCLC stage IIIB/IV adeno- or bronchoalveolar carcinoma (BAC)
2. non smokers patients or patients having smoked less than 15 pack years and who stopped smoking for at least one year before diagnosis (except for patients with her2-neu mutation)
3. presence of activating mutation(s) in exon 18 to exon 21 of the EGFR or HER2-neu-receptor confirmed by direct DNA sequencing of NSCLC tumor tissue or increased copy number of the EGFR gene as determined by FISH analysis
4. prior treatment up to 3 lines of chemotherapy except for HER2-neu patients (no restrictions) no prior EGFR TKI therapy for EGFR mutation negative and FISCH positive patients
5. patients with at least one tumor lesion that can accurately be measured by CTscan or MRI in at least one dimension with long diameter to be recorded as > or equal to 20 mm using conventional techniques or > or equal to 10 mm with spiral CT scan
6. male or female patient aged above or equal to 18 years
7. life expectancy of at least 3 months
8. written informed consents that is consistent with ICH-GCP guidelines
9. ECOG performance score 0, 1 or 2

Exclusion criteria:

1. more than 3 prior cytotoxic chemotherapy treatment regimen for relapsed or metastatic NSCLC, except for patients with HER2-neu mutations who may have received any prior therapy
2. Any chemo-, hormone- or immunotherapy within the past 4 weeks or within less than 4 half-lives of the previous drug prior to treatment with the trial drug and/or persistence of toxicities of prior anticancer therapies which are deemed to be clinically relevant
3. brain metastases which are symptomatic; patients with treated asymptomatic brain metastases are eligible with stable brain disease for at least 4 weeks without requirement for steroids or anti-epileptic therapy
4. significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g. Crohn's disease, malabsorption or CTCAE Grade > 2 diarrhea of any etiology at baseline
5. patients who have any other life-threatening illness or organ system dysfunction, which in the opinion of the investigator, would either compromise patient safety or interfere with the evaluation of the safety of the test drug
6. other malignancies diagnosed within the past 5 years (other than non melanomatous skin cancer and in situ cervical cancer)
7. radiotherapy within the past 2 weeks prior to treatment with the trial drug
8. patients with any serious active infection (i.e., requiring an IV antibiotic, antifungal, or antiviral agents)
9. patients with known HIV, active hepatitis B or active hepatitis C
10. known or suspected active drug or alcohol abuse
11. women of childbearing potential or men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial
12. pregnancy or breast feeding
13. patient unable to comply with the protocol
14. 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
15. Cardiac left ventricular function with resting ejection fraction of less than 50% measured by multigated blood pool imaging of the heart (MUGA scan) or Echocardiogram.
16. Absolute neutrophil count (ANC) less than 1500/mm³.
17. Platelet count less than 100 000 / mm³.
18. Bilirubin greater than 1.5 mg / dl (>26 µmol / L, SI unit equivalent).
19. Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than three times the upper limit of normal (if related to liver metastases greater than five times the upper limit of normal).
20. Serum creatinine greater than 1.5 times of the upper normal limit