Single-arm Trial of BIBW 2992 (Afatinib) in Demographically and Genotypically Selected NSCLC Patients
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: BIBW2992; BIBW2992 + paclitaxel
Intervention description: tablet BIBW high dose; tablet BIBW 2992 in combination with i.v. paclitaxel 3 weekly
Intervention MeSH terms: Paclitaxel; Afatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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