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
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: BIBW 2992 MA2 40mg/day; BIBW 2992 MA2 50mg/day; BIBW 2992 MA2 20mg/day; BIBW 2992 QD
Intervention description: Phase I step: Increased dose cohorts from low dose to MTD; Phase I step: Increased dose cohorts from low dose to MTD; Phase I step: Increased dose cohorts from low dose to MTD; Phase II step: This is an open label study. Patients are treated with BIBW 2992 until disease progression or undue AEs.
Intervention MeSH terms: Afatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 74.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No

Summary:

      The objective of the Phase I step is to estimate the MTD at a dose level up to 50 mg/day
      (i.e., overseas recommended Phase II dose) in patients with advanced NSCLC and to determine
      the recommended dose for the Phase II step.

      The objective of the Phase II step is to estimate the efficacy of BIBW 2992 monotherapy in
      patients with first generation EGFR-TKI-resistant advanced NSCLC at the recommended dose
      determined in the Phase I step.
    

Eligibility criteria:

        Inclusion criteria:

        Phase II step;

          1. 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.

          2. 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

          3. Male or female patients age >=20 years at the enrolment.

          4. Life expectancy of at least three (3) months after the start of administration of the
             investigational drug.

          5. Eastern Cooperative Oncology Group (ECOG) performance Score 0 or 1.

          6. 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.

          7. Written informed consent that is consistent with ICH-GCP guidelines.

        Exclusion criteria:

        Phase II step;

          1. Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within two weeks before starting
             the study medication.

          2. 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.

          3. 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.

          4. Patients with distinct / suspected pulmonary fibrosis or interstitial lung disease by
             the chest radiographic findings, or patients with a previous history of.

          5. Brain tumor, and / or brain metastases, which are symptomatic or requiring treatment
             at the enrolment.

          6. 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).

          7. 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.

          8. Coelomic fluid retention (such as pleural effusion, ascites or pericardial effusion)
             requiring treatment.

          9. Uncontrolled concomitant diseases (e.g. diabetes mellitus, hypertension etc).

         10. History of serious drug hypersensitivity.

         11. 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

         12. 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.

         13. Pregnant or breast-feeding women, or women suspected of being pregnant.

         14. Known positive HBs antigen, HCV antibody, or HIV antibody test.

         15. Known or suspected active drug or alcohol abuse.

         16. Other patients judged ineligible for enrolment in the study by the investigator
             (sub-investigator).