A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Dose escalation followed by treatment with MTD
Intervention description: Fixed 3+3 dose escalation; expansion of MTD cohort
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This trial is divided into Part A and Part B. The primary objective of Part A is to establish
      the Maximal Tolerated Dose of intermittent high dose afatinib. The primary objective of Part
      B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M
      mutations to a dose of intermittent afatinib established in Part A.

      The secondary objective is to explore tumor response and tumor-derived biological markers of
      response to afatinib, as well as pharmacokinetic parameters of afatinib.
    

Eligibility criteria:

        Inclusion criteria:

        Part A only:

          1. Patients with histologically confirmed advanced solid tumours that are metastatic or
             unresectable and for which standard curative or palliative measures do not exist or
             are no longer effective. Patients who refuse standard therapy are also eligible.

             Part B only:

          2. Pathologically confirmed diagnosis of Stage IV (M1a or b) non-small cell lung cancer

          3. Documented Epidermal Growth Factor Receptor (EGFR) T790M mutation

          4. Progression of disease on a reversible tyrosine kinase inhibitor within 30 days of
             starting study drug. Loss of exposure to prior EGFR TKI should not be >30 days; any
             procedural delay in confirmation of progression is to be discussed with the BI
             Clinical Monitor.

             Parts A and B:

          5. Evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

          6. Age >/= to 18 years

          7. Eastern Cooperative Group (ECOG) performance status 0-1

          8. Adequate organ function

          9. Recovered from any previous therapy-related toxicity to </= to Grade 1 at study entry
             (except for stable sensory neuropathy </= Grade 2 and alopecia)

         10. Written informed consent

         11. Ability to take oral medication

        Exclusion criteria:

        Parts A and B:

          1. Chemotherapy, biological therapy, or investigational agents (except erlotinib or
             gefitinib) within 4 weeks prior to the start of study treatment

          2. Hormonal treatment within 2 weeks prior to the start of study treatment (continued use
             of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer is
             permitted)

          3. Radiotherapy within two weeks prior to the start of study treatment (except palliative
             radiotherapy given for symptom control)

          4. Less than 3 days from prior treatment with gefitinib or erlotinib. Patients with
             adverse events related to gefitinib or erlotinib must recover to Grade 1 or less to be
             eligible.

          5. Major surgery within 4 weeks before starting study treatment or scheduled for surgery
             during the projected course of the study

          6. Known hypersensitivity to afatinib or the excipients of any of the trial drugs

          7. History or presence of clinically relevant cardiovascular abnormalities such as
             uncontrolled hypertension, congestive heart failure New York Heart Association
             classification of 3, unstable angina or poorly controlled arrhythmia as determined by
             the investigator. Myocardial infarction within 6 months prior to starting study
             treatment

          8. Women of childbearing potential and men who are able to father a child, unwilling to
             be abstinent or use adequate contraception prior to study entry, for the duration of
             study participation and for at least 2 months after treatment has ended.

          9. Female patients of childbearing potential who are nursing; are pregnant; are not using
             an acceptable method of birth control, or do not plan to continue using this method
             throughout the study; and do not agree to submit to pregnancy testing required by this
             protocol

         10. Any history of or concomitant condition that, in the opinion of the investigator,
             would compromise the patient's ability to comply with the study or interfere with the
             evaluation of the efficacy and safety of the test drug

         11. Previous or concomitant malignancies at other sites, except effectively treated
             non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ
             or effectively treated malignancy that has been in remission for more than 3 years and
             is considered to be cured

         12. Required treatment with any of the prohibited medications listed in this protocol that
             cannot be stopped for the duration of trial participation

         13. Known pre-existing Interstitial Lung Disease

         14. Any history or presence of poorly controlled gastrointestinal disorders that could
             affect the absorption of the study drug (for example, Crohn's disease, ulcerative
             colitis, chronic diarrhea, malabsorption) in the opinion of the investigator

         15. Active hepatitis B infection (defined as the presence of Hepatitis B DNA), active
             hepatitis C infection (defined as the presence of Hepatitis C RNA) and/or known Human
             Immunodeficiency Virus carrier

         16. Prior participation in a blinded afatinib clinical study, unless permission to unblind
             was granted in consultation with the Clinical Monitor of the blinded study

         17. Meningeal carcinomatosis

         18. Patients with brain or subdural metastases are not eligible, unless they have
             completed local therapy and have discontinued use of corticosteroids or have been on
             stable doses of corticosteroids for at least 4 weeks before starting study treatment.
             Any symptoms attributed to brain metastases must be stable for at least 4 weeks before
             starting study treatment

         19. QTc interval > 0.47 seconds as measured during screening procedures