Afatinib on CNS Metastases and LMD in EGFR Mutation Positive NSCLC

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

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.

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer; Leptomeningeal Disease; Central Nervous System Metastases
• Intervention / Treatment: Drug: Afatinib; Drug: Afatinib

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169690
    • National Cancer Center Singapore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Gilotrif; Drug: Afatinib; 160mg for 3 days every 3 weeks; Other Names: Gilotrif
Experimental: Part B; Intermittent high dose oral afatinib	Drug: Afatinib; 40mg daily; Other Names: Gilotrif; Drug: Afatinib; 160mg for 3 days every 3 weeks; Other Names: Gilotrif

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Centre, Singapore
• Investigators: Principal Investigator: Daniel SW Tan, MD, National Cancer Centre, Singapore

Publications and helpful links

General Publications

• Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M, Serke M, Stohlmacher-Williams J, Marten A, Maria Huber R, Dickgreber NJ; Afatinib Compassionate Use Consortium (ACUC). Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015 Jan;10(1):156-63. doi: 10.1097/JTO.0000000000000380.
• Awada AH, Dumez H, Hendlisz A, Wolter P, Besse-Hammer T, Uttenreuther-Fischer M, Stopfer P, Fleischer F, Piccart M, Schoffski P. Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors. Invest New Drugs. 2013 Jun;31(3):734-41. doi: 10.1007/s10637-012-9880-0. Epub 2012 Nov 17.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2018
• Primary Completion (Actual): December 20, 2019
• Study Completion (Actual): December 20, 2019

Study Registration Dates

• First Submitted: October 10, 2018
• First Submitted That Met QC Criteria: October 16, 2018
• First Posted (Actual): October 18, 2018

Study Record Updates

• Last Update Posted (Actual): June 14, 2022
• Last Update Submitted That Met QC Criteria: June 10, 2022
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Meningeal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: 1200.275

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No