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 study has been completed.
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
First received: July 16, 2012
Last updated: December 21, 2015
Last verified: December 2015

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.

Condition Intervention Phase
Carcinoma, Non-Small-Cell Lung
Drug: Dose escalation followed by treatment with MTD
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Determination of Maximally Tolerated Dose (MTD) of intermittent high-dose afatinib [ Time Frame: up to 36 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Objective response rate for patients with EGFR T790M mutations according to RECIST v1.1 [ Time Frame: up to 36 months ] [ Designated as safety issue: No ]
  • Cmax of afatinib as determined on day 3 of course 1 for patients in Part A [ Time Frame: up to 36 months ] [ Designated as safety issue: No ]
  • Determination of dosage for expansion cohort in Part B [ Time Frame: up to 36 months ] [ Designated as safety issue: No ]

Enrollment: 35
Study Start Date: July 2012
Study Completion Date: September 2015
Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Afatinib
Establish the Maximal Tolerated Dose of a pulsatile, high-dose regimen of afatinib in patients with advanced solid tumors followed by treatment at that dose or a lower dose in patients with stage IV non-small cell lung cancer harboring EGFR T790M mutations who have progressed on therapy with a reversible tyrosine kinase inhibitor
Drug: Dose escalation followed by treatment with MTD
Fixed 3+3 dose escalation; expansion of MTD cohort


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01647711

United States, Colorado
1200.121.01001 Boehringer Ingelheim Investigational Site
Aurora, Colorado, United States
United States, Massachusetts
1200.121.01002 Boehringer Ingelheim Investigational Site
Boston, Massachusetts, United States
1200.121.01004 Boehringer Ingelheim Investigational Site
Boston, Massachusetts, United States
Sponsors and Collaborators
Boehringer Ingelheim
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01647711     History of Changes
Other Study ID Numbers: 1200.121 
Study First Received: July 16, 2012
Last Updated: December 21, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Lung Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms

ClinicalTrials.gov processed this record on May 26, 2016