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.
Name: Dose escalation followed by treatment with MTD
Description: Fixed 3+3 dose escalation; expansion of MTD cohortType: DrugAfatinib
Description: Percentage of participants with Dose Limiting Toxicities (DLTs), based on investigator assessment, for determination of Maximum Tolerated Dose (MTD). MTD was defined as the dose in which less than 2 of up to 6 patients developed a DLT.
Measure: Percentage of Participants With Dose Limiting Toxicities Time: 28 daysDescription: Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).
Measure: Maximum Tolerated Dose Time: 28 daysDescription: Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. Objective response was defined as Complete Response (CR): Disappearance of all target lesion or Partial Response and (PR): >=30% decrease in the sum of the longest diameter of target lesions, according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. This endpoint was originally planned to be analysed in part B of the study, however as no participants were treated in part B the analysis was performed on the part A participants.
Measure: Objective Response Rate for Patients With EGFR T790M Mutations Time: From first drug administration until last drug administration, up to 420 daysDescription: Maximum measured concentration (Cmax) of afatinib as determined on day 3 of course 1 for patients in Part A
Measure: Cmax of Afatinib on Day 3 of Course 1 Time: 47 hours (h) 55 minutes (min), 49h, 50h, 51h, 52h, 53h, 54h, 55h after first dose administration (on day 3 of course 1)Description: Determination of dosage for expansion cohort in Part B. Dosage was the MTD or less depending on tolerability.
Measure: Determination of Dosage for Expansion Cohort in Part B Time: 28 daysSingle Group Assignment
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A Phase 1b Study of Intermittent Administration of High Doses of the Irreversible EGFR Inhibitor Afatinib as a Means of Achieving Plasma Levels Active Against Non-small Cell Lung Cancer With Known T790M Mutations. --- T790M ---
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 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. --- T790M ---
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. --- T790M ---
Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).. Objective Response Rate for Patients With EGFR T790M Mutations. --- T790M ---
Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. --- T790M ---
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. --- T790M ---