0 12

Cited 0 times in

Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study

Authors
 Myung-Ju Ahn  ;  Dong-Wan Kim  ;  Byoung Chul Cho  ;  Sang-We Kim  ;  Jong Seok Lee  ;  Jin-Seok Ahn  ;  Tae Min Kim  ;  Chia-Chi Lin  ;  Hye Ryun Kim  ;  Thomas John  ;  Steven Kao  ;  Jonathan W Goldman  ;  Wu-Chou Su  ;  Ronald Natale  ;  Sarit Rabbie  ;  Bryony Harrop  ;  Philip Overend  ;  Zhenfan Yang  ;  James Chih-Hsin Yang 
Citation
 Lancet. Respiratory Medicine, Vol.5(11) : 891-902, 2017 
Journal Title
 Lancet. Respiratory Medicine 
Issue Date
2017
MeSH
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacokinetics ; Australia ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/secondary ; Central Nervous System Neoplasms/drug therapy ; Central Nervous System Neoplasms/genetics ; Central Nervous System Neoplasms/secondary ; Dose-Response Relationship, Drug ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Male ; Meningeal Neoplasms/drug therapy ; Meningeal Neoplasms/genetics ; Meningeal Neoplasms/secondary ; Middle Aged ; Mutation ; Piperazines/administration & dosage ; Piperazines/adverse effects ; Piperazines/pharmacokinetics ; Quinazolines/administration & dosage ; Quinazolines/adverse effects ; Quinazolines/pharmacokinetics ; Receptor, Epidermal Growth Factor/drug effects ; Receptor, Epidermal Growth Factor/genetics ; Republic of Korea ; Taiwan ; Treatment Outcome ; United States
Abstract
BACKGROUND: CNS metastases-including brain and leptomeningeal metastases-from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine kinase inhibitor with high capability to penetrate the blood-brain barrier. We aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal metastases. METHODS: This open-label, multicentre, phase 1 study was undertaken at 11 centres and hospitals in Australia, South Korea, Taiwan, and the USA. Eligible patients included those with histologically confirmed, advanced-stage, EGFR-mutant NSCLC. The study was done in two parts, with dose-escalation and dose-expansion phases. In the dose-escalation phase, patients who had progressed after treatment with an EGFR tyrosine kinase inhibitor received AZD3759 at 50 mg, 100 mg, 200 mg, 300 mg, or 500 mg twice a day. In the dose-expansion phase, AZD3759 at 200 mg or 300 mg twice a day was administered to patients with either brain or leptomeningeal metastases who had never received an EGFR tyrosine kinase inhibitor and patients with leptomeningeal metastases who had been pretreated with an EGFR tyrosine kinase inhibitor. The primary objective was safety and tolerability, with severity of adverse events assessed with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03. This trial is registered with ClinicalTrials.gov, number NCT02228369. FINDINGS: Between Nov 18, 2014, and Sept 7, 2016, 67 patients with NSCLC were enrolled into the study, 29 to the dose-escalation phase and 38 to the dose-expansion phase. At data cutoff (Dec 12, 2016), three (10%) patients in the dose-escalation phase and 20 (53%) in the dose-expansion phase were still receiving treatment. Dose-limiting toxic effects occurred in two (67%) of three patients who received 500 mg twice a day in the dose-escalation phase (grade 3 acne [n=1] and intolerable grade 2 mucosal inflammation [n=1]); hence, doses of 200 mg and 300 mg twice a day were selected for further assessment in the dose-expansion phase. Drug-related skin and gastrointestinal disorders of any grade occurred in 35 (92%) and 29 (76%) patients in the dose-expansion phase, respectively, and led to treatment discontinuation in one (4%) patient treated with 200 mg twice a day (grade 3 increase of alanine aminotransferase and aspartate aminotransferase) and two (13%) patients given 300 mg twice a day (grade 3 diarrhoea [n=1] and grade 3 skin rash [n=1]). Grade 3 skin and gastrointestinal disorders occurred in four (17%) and two (9%) patients, respectively, at a dose of 200 mg twice a day, and in six (40%) and four (27%) patients, respectively, at a dose of 300 mg twice a day. No grade 4 disorders arose. Other grade 3 disorders included hepatobiliary and renal disorders (three [13%] at 200 mg twice a day), asthenia (one [7%] at 300 mg twice a day), infections and infestations (one [7%] at 300 mg twice a day), and metabolism and nutrition disorders (one [4%] at 200 mg twice a day and one [7%] at 300 mg twice a day). INTERPRETATION: AZD3759 at a dose of 200 mg twice daily showed a tolerable safety profile in patients with NSCLC and CNS metastases who had either never received a tyrosine kinase inhibitor or who had been pretreated with a tyrosine kinase inhibitor. The good penetration of the blood-brain barrier by AZD3759, and its promising clinical activity, support further assessment of this compound in studies.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/161575
DOI
10.1016/S2213-2600(17)30378-8
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
Yonsei Authors
김혜련(Kim, Hye Ryun) ; 조병철(Cho, Byoung Chul)
사서에게 알리기
  feedback
Full Text
https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S2213260017303788
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse