Clinical trial NCT03653546: First Line Treatment in EGFR Mutation Positive Advanced NSCLC Patients with Central Nervous System (CNS) Metastases
Official title: A Randomized, Open-label, Controlled, Multi-Center Phase II/III Study to Assess the Efficacy and Safety of AZD3759 Vs. a Standard of Care EGFR TKI, As First Line Treatment to EGFR Mutation Positive Advanced NSCLC with CNS Metastases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Non-small Cell Lung Cancer
EGFR Gene Mutation
Brain Metastases
Keywords: Central Nervous System Metastases
Respiratory Tract Diseases
EGFR
Exon 19Del
L858R
Lung Neoplasm
Carcinoma, Non-Small-Cell Lung
Neoplasms
Lead sponsor: Alpha Biopharma (Jiangsu) Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2018-08-31
Enrollment: 492
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The first-line treatment with single agent AZD3759 results in superior Progression Free Survival (PFS) compared to Standard of Care (SoC) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI), in patients with advanced EGFR mutation positive non-small cell lung cancer (NSCLC) with Central Nervous System (CNS) metastasis

Detailed description: This is a Phase II/III randomized, open-label, multicenter study to compare the efficacy and safety of first line single-agent AZD3759 vs. Erlotinib or Gefitinib treatment in patients with advanced EGFR mutation positive NSCLC with CNS metastases.

Eligible patients with documented EGFR mutation+ (L858R and/or Exon 19Del) TKI-naïve advanced NSCLC and documented intracranial disease will be enrolled.

Eligibility criteria: Inclusion Criteria:

1. Properly completed patient informed consent
2. Male or female aged at least 18 years
3. Histologically or cytologically confirmed diagnosis of NSCLC with activating EGFR mutations including L858R and/or Exon19Del. EGFR mutation status will be determined by local or central laboratory testing on tumour tissue or plasma utilizing a validated methodology which has been approved by the regulatory authority.
4. No prior treatment with chemotherapy, EGFR-TKIs, or biological therapies that are considered first line treatment for advanced NSCLC.
5. All patients must have a documented diagnosis of advanced (Stage IV) NSCLC with Magnetic Resonance Imaging (MRI) documented CNS metastases that include brain metastases (BM). BM + patients with co- existent leptomeningeal involvement are eligible for the study.
6. Eligible patients are not candidates for definitive surgical resection or radiation of all lesions in the opinion of the treating physician.
7. All patients must be stable without any systemic (oral or parenteral) corticosteroid or anticonvulsant therapy for at least 2 weeks prior to study treatment. Inhaled non-absorbable and topical corticosteroid use are permitted as indicated.
8. Patients may have prior placement of a properly functioning CNS shunt or Ommaya reservoir.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks.
10. Women of child-bearing potential and male subjects shall agree to take medically acceptable contraception measures while on study treatment and for 3 months following completion of study treatment. All women of child-bearing potential must have a negative blood pregnancy test at screening.
11. (a) For Patients with measurable CNS lesions must have AT LEAST ONE site of CNS lesion, which was not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter by MRI and which is suitable for accurate repeated measurements. Measurable extracranial disease is not required. (b) For Patients with non-measurable CNS lesions must have AT LEAST ONE extracranial lesion, which has not been previously irradiated, within the screening period that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) by CT/MRI and are suitable for accurate repeated measurement.

Primary outcomes:
measure: PFS assessed by Blinded Independent Central Radiological
timeFrame: 48 months
Secondary outcomes:
measure: PFS assess by investigator
timeFrame: 48 months
measure: Intracranial PFS (iPFS) assessed by investigator
timeFrame: 48 months
measure: Intracranial PFS (iPFS) assessed by BICR
timeFrame: 48 months
measure: Extracranial PFS (ePFS) assessed by investigator
timeFrame: 48 months
measure: Extracranial PFS (ePFS) assessed by BICR
timeFrame: 48 months
measure: Objective Response Rate (ORR） assessed by investigator using RECIST 1.1
timeFrame: 48 months
measure: Disease Control Rate (DCR) assessed by investigator using RECIST 1.1
timeFrame: 48 months
measure: Duration of Response (DoR) assessed by investigator using RECIST 1.1
timeFrame: 48 months
measure: Overall ORR assessed by investigator using RECIST 1.1
timeFrame: 48 months
measure: Overall DCR assessed by investigator using RECIST 1.1
timeFrame: 48 months
measure: Overall DoR assessed by investigator using RECIST 1.1
timeFrame: 48 months
measure: ORR for Intracranial lesions assessed by investigator using RANO-BM
timeFrame: 48 months
measure: DCR for Intracranial lesions assessed by investigator using RANO-BM
timeFrame: 48 months
measure: DoR for Intracranial lesions assessed by investigator using RANO-BM
timeFrame: 48 months
measure: Overall Survival
timeFrame: 48 months
measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).
timeFrame: 48 months
measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire BN20 (EORTC QLQ-BN20).
timeFrame: 48 months
measure: Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)
timeFrame: 48 months
measure: Neurological function improvement rate assessed by RANO-BM criteria
timeFrame: 48 months
measure: Number of participants with treatment-related Adverse Events as assessed by CTCAE v5.0
timeFrame: 48 months
measure: Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0
timeFrame: 48 months
measure: Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0
timeFrame: 48 months
measure: Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0
timeFrame: 48 months
measure: Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0
timeFrame: 48 months
measure: Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.
timeFrame: 48 months
measure: Systolic and Diastolic Blood Pressure assessed during the study period.
timeFrame: 48 months
measure: Pulse rate assessed during the study period.
timeFrame: 48 months
measure: Body temperature assessed during the study period.
timeFrame: 48 months
measure: PFS assess by BICR
timeFrame: 48 months
Other outcomes:
measure: Pop-PK analysis
timeFrame: 48 months
measure: Exposure-Response analysis
timeFrame: 48 months
Locations:
city: Hefei
country: China
facility: China site
state: Anhui
city: Fuzhou
country: China
facility: China site
state: Fujian
city: Xiamen
country: China
facility: China site
state: Fujian
city: Guangzhou
country: China
facility: China site
state: Guangdong
city: Guangzhou
country: China
facility: China site
state: Guangdong
city: Haerbin
country: China
facility: China site
state: Heilongjiang
city: Zhengzhou
country: China
facility: China site
state: Henan
city: Zhengzhou
country: China
facility: China site
state: Henan
city: Wuhan
country: China
facility: China site
state: Hubei
city: Wuhan
country: China
facility: China site
state: Hubei
city: Wuhan
country: China
facility: China site
state: Hubei
city: Yichang
country: China
facility: China site
state: Hubei
city: Changsha
country: China
facility: China site
state: Hunan
city: Nanjing
country: China
facility: China site
state: Jiangsu
city: Nanjing
country: China
facility: China site
state: Jiangsu
city: Suzhou
country: China
facility: China site
state: Jiangsu
city: Wuxi
country: China
facility: China site
state: Jiangsu
city: Xuzhou
country: China
facility: China site
state: Jiangsu
city: Yangzhou
country: China
facility: China site
state: Jiangsu
city: Changchun
country: China
facility: China site
state: Jilin
city: Changchun
country: China
facility: China site
state: Jilin
city: Xi'an
country: China
facility: China site
state: Shaanxi
city: Jinan
country: China
facility: China site 0123
state: Shandong
city: Linyi
country: China
facility: China site
state: Shandong
city: Weifang
country: China
facility: China site
state: Shandong
city: Yantai
country: China
facility: China site
state: Shandong
city: Chengdu
country: China
facility: China site
state: Sichuan
city: Kunming
country: China
facility: China site
state: Yunnan
city: Hangzhou
country: China
facility: China site
state: Zhejiang
city: Hangzhou
country: China
facility: China site
state: Zhejiang
city: Hangzhou
country: China
facility: China site
state: Zhejiang
city: Beijing
country: China
facility: China site
city: Beijing
country: China
facility: China site
city: Beijing
country: China
facility: China site
city: Beijing
country: China
facility: China site
city: Chongqing
country: China
facility: China site
city: Chongqing
country: China
facility: China site
city: Chongqing
country: China
facility: China site
city: Shanghai
country: China
facility: China site
city: Shanghai
country: China
facility: China site
city: Tianjin
country: China
facility: China site
city: Chungbuk
country: Korea, Republic of
facility: Korea Site
city: Daegu
country: Korea, Republic of
facility: Korea site
city: Gyeonggi-do
country: Korea, Republic of
facility: Korea site
city: Gyeongsang
country: Korea, Republic of
facility: Korea site
city: Incheon
country: Korea, Republic of
facility: Korea site
city: Seoul
country: Korea, Republic of
facility: Korea Site
city: Seoul
country: Korea, Republic of
facility: Korea site
city: Seoul
country: Korea, Republic of
facility: Korea Site
city: Seoul
country: Korea, Republic of
facility: Korea site
city: Seoul
country: Korea, Republic of
facility: Korea site
city: Suwon
country: Korea, Republic of
facility: Korea site
city: Ulsan
country: Korea, Republic of
facility: Korea site
city: Singapore
country: Singapore
facility: Singapore site
city: Taichung
country: Taiwan
facility: Taiwan site
city: Tainan
country: Taiwan
facility: Taiwan site
city: Taipei
country: Taiwan
facility: Taiwan site
city: Taoyuan
country: Taiwan
facility: Taiwan site
Study officials:
affiliation: Guangdong Provincial People's Hospital
name: Yilong Wu, M.D.
role: STUDY_CHAIR
affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine
name: Myung-Ju Ahn, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
name: Jie Wang, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Guangdong Provincial People's Hospital
name: Qing Zhou, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhou Q, Yu Y, Xing L, Cheng Y, Wang Y, Pan Y, Fan Y, Shi J, Zhang G, Cui J, Zhou J, Song Y, Zhuang W, Ma Z, Hu Y, Li G, Dong X, Feng J, Lu S, Wu J, Li J, Zhang L, Wang D, Xu X, Yang TY, Yang N, Guo Y, Zhao J, Yao Y, Zhong D, Xia B, Yang CT, Zhu B, Sun P, Shim BY, Chen Y, Wang Z, Ahn MJ, Wang J, Wu YL. First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial. Med. 2025 Jan 10;6(1):100513. doi: 10.1016/j.medj.2024.09.002. Epub 2024 Oct 9.