Afatinib on CNS Metastases and LMD in EGFR Mutation Positive NSCLC

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Non-small Cell Lung Cancer, Leptomeningeal Disease, Central Nervous System Metastases

Intervention / Treatment
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* Drug: Afatinib
* Drug: Afatinib


Participation Criteria
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Eligibility Criteria
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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 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.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>Standard dose oral afatinib. If patients in Part A do not benefit from the regimen, they can be enrolled into Part B | Drug: Afatinib<br>* 40mg daily<br>* Other names: Gilotrif;|
| Experimental: Part B<br>Intermittent high dose oral afatinib | Drug: Afatinib<br>* 160mg for 3 days every 3 weeks<br>* Other names: Gilotrif;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Afatinib concentration in plasma using standard dosing and high intermittent dosing | To assess the difference in drug ratio from two difference dosing of afatinib | Day 1 to Day 29 of drug treatment | 
| Afatinib concentration in Cerebral Spinal Fluid (CSF) using standard dosing and high intermittent dosing | To assess the difference in drug ratio from two difference dosing of afatinib | Part A: Day 15; Part B: Day 17 and 31 | 
| Neurological Progression Free Survival |  | From time of first study drug administration until first occurrence of disease progression, or death from any cause, up to 2 years | 
| Neurological Response Rate |  | From time of first study drug administration until first occurrence of disease progression, up to 2 years | 
| Overall Survival |  | From time of first study drug administration to death from any cause, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cell-free DNA sequencing of Cerebrospinal Fluid | To detect EGFR T790M and activating mutation status | From time of first study drug administration to end of study treatment, up to 2 years | 
| European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 | To assess the physical, physiological and social functions. The scale ranges from 1=not all all to 4-very much | From time of first study drug administration through to end of study treatment or disease progression, up to 2 years | 
| EORTC Quality of Life Questionnaire Brain Cancer Module | To assess future uncertainty, visual disorder, motor dysfunction, and communication deficit. The scale ranges from 1=not all all to 4-very much | From time of first study drug administration through to end of study treatment or disease progression, up to 2 years | 
| Incidences of treatment-emergent adverse events (AE) | AEs will be graded according to CTCAE, Version 4.0 | From time of first study drug administration to 28 days after last treatment administration |