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Trial record 1 of 1 for:    NCT03711422
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Afatinib on CNS Metastases and LMD in EGFR Mutation Positive NSCLC

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03711422
Recruitment Status : Recruiting
First Posted : October 18, 2018
Last Update Posted : April 28, 2021
Information provided by (Responsible Party):
National Cancer Centre, Singapore

Brief Summary:
Brain metastases occurs in up to 50% of patients with EGFR mutant NSCLC. Leptomeningeal disease is a subset of patients with brain metastases for which there remains an unmet need. This trial aims to evaluate the role of two dosing schedules of afatinib in management of leptomeningeal disease in EGFR mutant NSCLC, specifically to determine Central Nervous System (CNS) penetration of afatinib, as well as clinical activity. Patients will start on daily dosing initially followed by pulsed intermittent dosing should we observe no clinical activity. A secondary objective is to identify the resistance spectrum in leptomeningeal disease. It is anticipated that optimal dosing schedule of afatinib e.g. pulsed dosing may improve CNS disease control.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Leptomeningeal Disease Central Nervous System Metastases Drug: Afatinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Dose Finding Study of Continuous and Intermittent High-dose (HDI) Afatinib (EGFR TKI) on CNS Metastases and Leptomeningeal Disease (LMD) in Patients With Advanced Refractory EGFR Mutation Positive Non-small Cell Lung Cancer
Actual Study Start Date : November 16, 2018
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2021

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Part A
Standard dose oral afatinib. If patients in Part A do not benefit from the regimen, they can be enrolled into Part B
Drug: Afatinib
40mg daily
Other Name: Gilotrif

Experimental: Part B
Intermittent high dose oral afatinib
Drug: Afatinib
160mg for 3 days every 3 weeks
Other Name: Gilotrif

Primary Outcome Measures :
  1. Afatinib concentration in plasma using standard dosing and high intermittent dosing [ Time Frame: Day 1 to Day 29 of drug treatment ]
    To assess the difference in drug ratio from two difference dosing of afatinib

  2. Afatinib concentration in Cerebral Spinal Fluid (CSF) using standard dosing and high intermittent dosing [ Time Frame: Part A: Day 15; Part B: Day 17 and 31 ]
    To assess the difference in drug ratio from two difference dosing of afatinib

  3. Neurological Progression Free Survival [ Time Frame: From time of first study drug administration until first occurrence of disease progression, or death from any cause, up to 2 years ]
  4. Neurological Response Rate [ Time Frame: From time of first study drug administration until first occurrence of disease progression, up to 2 years ]
  5. Overall Survival [ Time Frame: From time of first study drug administration to death from any cause, up to 2 years ]

Secondary Outcome Measures :
  1. Cell-free DNA sequencing of Cerebrospinal Fluid [ Time Frame: From time of first study drug administration to end of study treatment, up to 2 years ]
    To detect EGFR T790M and activating mutation status

  2. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 [ Time Frame: From time of first study drug administration through to end of study treatment or disease progression, up to 2 years ]
    To assess the physical, physiological and social functions. The scale ranges from 1="not all all" to 4-"very much"

  3. EORTC Quality of Life Questionnaire Brain Cancer Module [ Time Frame: From time of first study drug administration through to end of study treatment or disease progression, up to 2 years ]
    To assess future uncertainty, visual disorder, motor dysfunction, and communication deficit. The scale ranges from 1="not all all" to 4-"very much"

  4. Incidences of treatment-emergent adverse events (AE) [ Time Frame: From time of first study drug administration to 28 days after last treatment administration ]
    AEs will be graded according to CTCAE, Version 4.0

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients progressing locally in the CNS after prior systemic treatment and Whole brain radiotherapy (WBRT)/ Stereotactic radiosurgery (SRS) (or declines radiotherapy), for which no standard therapy options are available
  • Performance status of Eastern Cooperative Oncology Group (ECOG) 0-3
  • Adequate organ function

    • Absolute neutrophil count (ANC) ≥1500 / mm3 . (ANC >1000/mm3 may be considered in special circumstances such as benign cyclical neutropenia as judged by the investigator and in discussion with the sponsor).
    • Platelet count ≥75,000 / mm3 .
    • Estimated creatinine clearance > 45ml/min
    • Left ventricular function with resting ejection fraction ≥ 50% or above the institutional Lower Limit of Normal (LLN).
    • Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal (Patients with Gilbert's syndrome total bilirubin must be ≤4 times institutional upper limit of normal)
    • Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ three times the upper limit of (institutional/central) normal (ULN) (if related to liver metastases ≤ five times ULN).
  • Written informed consent that is consistent with ICH-GCP guidelines

Exclusion Criteria:

  • Symptomatic brain metastases requiring high dose steroids. Patients are excluded from Part A if they develop cerebral manifestation under afatinib. (Those progressing on afatinib will proceed to part B with HDI afatinib)
  • Hormonal treatment within 2 weeks prior to start of study treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted) Radiotherapy within 4 weeks prior to randomization, except as follows:

    • Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to randomisation, and
    • Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling.
  • Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study
  • Known hypersensitivity to afatinib or the excipients of any of the trial drugs
  • History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of ≥ 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to randomisation.
  • Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly prior to study entry, for the duration of study participation and for at least <XX weeks; 2 weeks for afatinib, XX weeks for comparator,> after treatment has ended.
  • Women who are pregnant, nursing, or who plan to become pregnant while in the trial
  • 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
  • Previous or concomitant malignancies at other sites, except effectively treated nonmelanoma 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.
  • Requiring treatment with any of the prohibited concomitant medications listed in Section that cannot be stopped for the duration of trial participation
  • Known pre-existing interstitial lung disease
  • Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis, chronic diarrhoea, malabsorption)
  • Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03711422

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Contact: Daniel SW Tan, MD +65 6436 8000
Contact: Xiao Wen Lee +65 6436 8000

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National Cancer Center Singapore Recruiting
Singapore, Singapore, 169690
Contact: Daniel SW Tan, BSc, MBBS, MRCP   
Principal Investigator: Daniel Tan Shao Weng         
Sponsors and Collaborators
National Cancer Centre, Singapore
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Principal Investigator: Daniel SW Tan, MD National Cancer Centre, Singapore
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Responsible Party: National Cancer Centre, Singapore Identifier: NCT03711422    
Other Study ID Numbers: 1200.275
First Posted: October 18, 2018    Key Record Dates
Last Update Posted: April 28, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasm Metastasis
Meningeal Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action