LUX-Lung 4: BIBW 2992 (Afatinib) Phase I Trial in Advanced Non Small Cell Lung Cancer Patients & Phase II Trial in Non Small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib

Inclusion criteria

Phase II step;

• Patients with pathologic confirmation of NSCLC with tissue diagnosis or cytologic diagnosis, whose NSCLCs are locally advanced or metastatic Stage III-B / IV adenocarcinoma, and are inoperable and incurable with radiotherapy.
• Patients who have received the following pretreatments for the treatment of relapsed or metastatic NSCLC.

• Patients who have received at least one but not more than two lines of chemotherapy. ("Chemotherapy" means only the first line (doublet chemotherapies including a platinum) and/or the second line (single chemotherapy except for a platinum) of cytotoxic chemotherapy according to the standard chemotherapies, and erlotinib (Tarceva®) and gefitinib (Iressa®) should be excluded. One of the chemotherapy regimens must have been platinum-based. In addition, only one prior cytotoxic chemotherapy treatment regimen is allowed after adjuvant chemotherapy containing a platinum. More than two prior cytotoxic chemotherapy treatment regimens are not allowed.)
• After the above chemotherapies, patients who once got clinical benefits (i.e. complete response, partial response or stable disease) but progressed following at least 12 weeks of treatment with erlotinib (Tarceva®) or gefitinib (Iressa®) as the most recent treatment. ("Clinical benefit" and "progression" should be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI). In addition, "at least 12 weeks of treatment" should be 9 weeks or more as the actual "treatment period except for treatment pause due to adverse events and other reasons.) As long as the treatment is erlotinib or gefitinib monotherapy, patients can receive multiple regimens of either or both treatments, but one of the regimens should be for at least 12 weeks
• Male or female patients age >=20 years at the enrolment.
• Life expectancy of at least three (3) months after the start of administration of the investigational drug.
• Eastern Cooperative Oncology Group (ECOG) performance Score 0 or 1.
• Patients with at least one tumor lesion that can accurately be measured by CT or MRI in at least one dimension with longest diameter to be recorded as no less than double the slice thickness and >=10 mm.
• Written informed consent that is consistent with ICH-GCP guidelines.

Exclusion criteria

Phase II step;

• Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within two weeks before starting the study medication.
• Patients who have received definitive thoracic radiotherapy with curative intent. Patients who have received radiotherapy or other investigational drugs (non-oncological) within four weeks before enrolment.
• Significant gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE Grade >2 diarrhea of any etiology at the enrolment.
• Patients with distinct / suspected pulmonary fibrosis or interstitial lung disease by the chest radiographic findings, or patients with a previous history of.
• Brain tumor, and / or brain metastases, which are symptomatic or requiring treatment at the enrolment.
• Other malignancies diagnosed within the past five years (other than carcinoma in situ of gastric cancer, colon cancer and cervical cancer, and non melanomatous skin cancer).
• History of uncontrolled cardiac disease such as angina or myocardial infarction within the past 6 months at the enrolment, congestive heart failure including New York Heart Association (NYHA) functional classification of 3, or arrhythmia requiring treatment.
• Coelomic fluid retention (such as pleural effusion, ascites or pericardial effusion) requiring treatment.
• Uncontrolled concomitant diseases (e.g. diabetes mellitus, hypertension etc).
• History of serious drug hypersensitivity.
• Patients who do not have sufficient baseline organ function and whose laboratory data do not meet the following criteria at the enrolment.11

• Haemoglobin count >=9.0 g/dL
• Absolute neutrophil count (ANC) >=1500 / mm3
• Platelet count >=100 000 / mm3
• Serum creatinine <=1.5 mg/dL
• Total bilirubin <=1.5 mg/dL
• Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) <=2.5x upper limit of normal range (if related to liver metastases <=2.5x upper limit of normal also)
• PaO2 >=60torr or SpO2 >=92%
• LVEF as measured by echocardiography or multigated blood pool imaging of the heart (MUGA scan) >=50%
• QTc interval <0.47 second
• Patients who disagree with using a medically acceptable method of contraception during the administration of the investigational drug and for at least 6 months after the end of administration.
• Pregnant or breast-feeding women, or women suspected of being pregnant.
• Known positive HBs antigen, HCV antibody, or HIV antibody test.
• Known or suspected active drug or alcohol abuse.
• Other patients judged ineligible for enrolment in the study by the investigator (sub-investigator).