Afatinib on CNS Metastases and LMD in EGFR Mutation Positive NSCLC

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 21 Years and Over
Gender All
More Inclusion & Exclusion Criteria

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 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 4.2.
2.1 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT03711422
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

National Cancer Centre, Singapore
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Daniel SW Tan, MD
Principal Investigator Affiliation National Cancer Centre, Singapore
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Not yet recruiting
Countries
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Non-small Cell Lung Cancer, Leptomeningeal Disease, Central Nervous System Metastases
Arms & Interventions

Arms

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

Experimental: Part B

Intermittent high dose oral afatinib

Interventions

Drug: - Afatinib

40mg daily

Drug: - Afatinib

160mg for 3 days every 3 weeks

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

Daniel SW Tan, MD

daniel.tan.s.w@singhealth.com.sg

+65 6436 8000

For additional contact information, you can also visit the trial on clinicaltrials.gov.

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