LUX-Lung 5: Afatinib Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following Afatinib Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Investigator´s choice of chemotherapy; BIBW 2992
Intervention description: BIBW 2992 in a medium dose in combination with Paclitaxel to explore safety and efficacy versus investigator´s choice of chemotherapy; BIBW 2992 will be given in a medium dose in combination with Paclitaxel to explore safety and efficacy versus investigator´s choice of chemotherapy
Intervention MeSH terms: Afatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1154.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The primary objective of this randomized, open-label, active-controlled, multi-center trial
      is to determine the efficacy of BIBW 2992 given as an add-on to chemotherapy in patients with
      NSCLC Stage IIIb or IV progressing after BIBW 2992 monotherapy compared to chemotherapy alone
      in this patient population. Patients on both treatment arms will receive best supportive care
      in addition to study treatment. Patients enrolled into the trial will be treated and followed
      until death or lost to follow-up. Additional information on the health-related quality of
      life (HRQOL) will be collected.
    

Eligibility criteria:

        Inclusion criteria:

        Part A

          1. Patients with pathologically confirmed diagnosis of NSCLC Stage IIIB (with
             cytologically proven pleural effusion or pericardial effusion) or Stage IV who have
             failed treatment with erlotinib (Tarceva) or gefitinib (Iressa).

          2. Patients should have received and failed at least one line of cytotoxic chemotherapy
             including a platinum-based regimen in patients eligible for platinum-based therapy and
             pemetrexed in pemetrexed eligible patients (unless pemetrexed is not considered a
             regulatory or clinical standard of care e.g. no label indication, no availability or
             no coverage by 3rd party payer(s)) for advanced or metastatic disease and have
             progressive disease following at least 12 weeks of treatment with erlotinib or
             gefitinib

          3. Patients pretreated with taxane-based chemotherapy for advanced or metastatic disease
             must have experienced stable disease, partial or complete response as best response

          4. Eastern Cooperative Oncology Group performance Score 0 or 1.

          5. Patients with at least one tumor lesion that can accurately be measured by magnetic
             resonance imaging (MRI), or computed tomography (CT) in at least one dimension with
             longest diameter to be recorded as 10 mm but no less than double the slice thickness
             according to RESIST 1.1.

          6. Male and female patients no less than 18 years of age.

          7. Life expectancy of at least three (3) months.

          8. Written informed consent that is consistent with ICH-GCP guidelines. Part B 1)
             Clinical benefit (disease stabilization or antitumor response) of 12 weeks duration in
             Part A of the trial determined on the second tumour assessment.

        2.) Patients should have progressed in Part A according to RECIST 1.1 3.) New informed
        consent, including consent to biomarker sampling, must be signed before patients enter Part
        B of the trial

        Exclusion criteria:

          1. Previous treatment with BIBW 2992

          2. Chemo-, hormone- (other than megestrol acetate, steroids required for maintenance
             non-cancer therapy or as premedication before chemotherapy) or immunotherapy within
             the past 4 weeks; except for TKI pretreatment (2 weeks only)

          3. Active/symptomatic brain metastases including leptomeningeal disease. Patients with a
             history of treated brain metastasis must have a stable or normal brain MRT/CT scan at
             screening and be at least 4 weeks post-radiation or surgery for brain metastasis.
             Dexamethasone therapy will be allowed if administered as a stable dose for at least
             one month before randomization.

          4. Significant or recent acute gastrointestinal disorders with diarrhea as a major
             symptom e.g., Crohn's disease, mal-absorption, 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 five (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. History or presence of clinically relevant cardiovascular abnormalities such as
             uncontrolled hypertension, congestive heart failure New york Heart Association (NYHA)
             functional classification of 3, unstable angina, or poorly controlled arrhythmia.
             Myocardial infarction within 6 months prior to entering the trial.

          9. 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 .

         10. Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or
             equivalent) at or greater than 400 mg/m2

         11. Absolute neutrophil count (ANC) at or less than 1500 / mm3

         12. Platelet count at or less than 100,000 / mm3

         13. Bilirubin at or greater than 1.5 mg / dL (>26 mol / L, SI unit equivalent)

         14. Aspartate amino transferase (AST) or alanine amino transferase (ALT) at or greater
             than three times the upper limit of normal (if related to liver metastases at or
             greater than five times the upper limit of normal)

         15. Serum creatinine at or greater 1.5 times the upper normal limit or calculated/measured
             creatinine clearance at or less than 45 mL/min

         16. Women of child-bearing potential or men who are able to father a child unwilling to
             use a medically acceptable method of contraception during the trial

         17. Pregnancy or breast feeding

         18. Patients unable to comply with the protocol

         19. Patients with any serious active infection including known human immunodeficiency
             virus (HIV), active hepatitis B or active hepatitis C

         20. Known or suspected active drug or alcohol abuse

         21. Pre-existing or current Interstitial lung disease (ILD) 22.)

         22. Peripheral polyneuropathy of > Grade 2

         23. Requirement for treatment with any of the pohibited concomitant medication listed in
             section 4.2.2.1.