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  • Status : Approved
    • First Submitted Date : 2018/06/15
    • Registered Date : 2018/09/14
    • Last Updated Date : 2018/09/04
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1. Background

Background Information
CRIS
Registration Number
KCT0003183 
Unique Protocol ID 2016-09-058 
Public/Brief Title An Open label, Multicenter, Phase II study of AZD9291 in non-small cell lung cancer (NSCLC) patients harboring T790M mutation who failed EGFR TKIs and with brain and/or leptomeningeal metastasis 
Scientific Title An Open label, Multicenter, Phase II study of AZD9291 in non-small cell lung cancer (NSCLC) patients harboring T790M mutation who failed EGFR TKIs and with brain and/or leptomeningeal metastasis  
Acronym AZD9291_BM/LM 
MFDS Regulated Study Yes
IND/IDE Protocol Yes
Registered
at Other Registry
Yes
Name of Registry/
Registration Number
ClinicalTrials.gov-NCT03257124 
Healthcare Benefit
Approval Status
Submitted pending

2. Institutional Review Board/Ethics Committee

Institutional Review Board Information
Board Approval Status Submitted approval 
Board Approval Number SMC 2016-09-058-004 
Approval Date 2017-03-14 
Institutional Review Board  
Name Samsung Medical Center Institutional Review Board 
Address 81, Irwon-ro, Gangnam-gu, Seoul 
Telephone 02-3410-2973 
Data Monitoring Committee No  

3. Contact Details

Contact Details Information
Contact Person for Principal Investigator / Scientific Queries  
Name MyungJu An 
Title Professor 
Telephone +82-2-3410-3438 
Affiliation Samsung Medical Center 
Address 81, Irwon-ro, Gangnam-gu, Seoul, Republic of Korea 
Contact Person for Public Queries
Name MyungJu An 
Title Professor 
Telephone +82-2-3410-3438 
Affiliation Samsung Medical Center 
Address 81, Irwon-ro, Gangnam-gu, Seoul, Republic of Korea 
Contact Person for Updating Information
Name MyungJu An 
Title Professor 
Telephone +82-2-3410-3438 
Affiliation Samsung Medical Center 
Address 81, Irwon-ro, Gangnam-gu, Seoul, Republic of Korea 

4. Status

Status Information
Study Site Multi-center (Number of center : 7)
Overall Recruitment Status Recruiting  
Date of First Enrollment 2017-05-16 , Actual
Target Number of Participant 80
Primary Completion Date 2019-12-31 , Anticipated
Study Completion Date 2019-12-31 , Anticipated
Recruitment Status by Participating Study Site 1
Name of Study Site Samsung Medical Center 
Recruitment Status Recruiting  
Date of First Enrollment 2017-05-16 , Actual
Recruitment Status by Participating Study Site 2
Name of Study Site Gachon University Gil Medical Center 
Recruitment Status Recruiting  
Date of First Enrollment 2017-09-21 , Actual
Recruitment Status by Participating Study Site 3
Name of Study Site The Catholic University of Korea, Seoul St. Mary's Hospital 
Recruitment Status Recruiting  
Date of First Enrollment 2018-01-08 , Actual
Recruitment Status by Participating Study Site 4
Name of Study Site Yonsei University Health System, Severance Hospital 
Recruitment Status Recruiting  
Date of First Enrollment 2017-10-31 , Actual
Recruitment Status by Participating Study Site 5
Name of Study Site Ulsan Univeristy Hospital 
Recruitment Status Recruiting  
Date of First Enrollment 2018-12-01 , Anticipated
Recruitment Status by Participating Study Site 6
Name of Study Site VHS Medical Center 
Recruitment Status Recruiting  
Date of First Enrollment 2018-12-01 , Anticipated
Recruitment Status by Participating Study Site 7
Name of Study Site Chungbuk National University Hospital 
Recruitment Status Recruiting  
Date of First Enrollment 2017-12-22 , Actual

5. Source of Monetary / Material Support

Source of Monetary / Material Support Information
Source of Monetary/Material Support 1   
Organization Name AstraZeneca Korea 
Organization Type Pharmaceutical Company  
Project ID ESR -16-11752 

6. Sponsor Organization

Sponsor Organization Information
Sponsor Organization 1   
Organization Name Samsung Medical Center 
Organization Type Medical Institute  

7. Study Summary

Study Summary Information
Lay Summary Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. The identification of epidermal growth factor receptor (EGFR) mutation and its targeting agents, such as gefitinib, erlotinib, or afatinib have improved clinical outcomes in patients with EGFR mutant NSCLC, leading to the standard treatment as first line therapy.
However, the incidence of central nervous system (CNS) metastasis is increasing during the disease course, including brain metastasis (BM) and/or leptomeningeal metastasis (LM), especially in patients with EGFR mutation, which accounts for ~40%. The hypothesis behind this phenomenon can be explained that due to limited blood brain barrier (BBB) penetration of current EGFR tyrosine kinase inhibitors (TKIs), leading to ineffective treatment or prevention of CNS disease. For patients with symptomatic BM, radiotherapy is the only considered standard of care and there is no proven molecular targeted therapy for the treatment/prevention of CNS metastasis. The median survival for CNS disease is poor, thus there is an emerging unmet medical need to discover and develop a new agent, which could effectively cross the BBB. Furthermore, patients treated with EGFR TKIs develop acquired resistance and T790M accounts for 50-60% of resistance mechanism.
AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that AZD9291 has significant exposure in the brain and activity against EGFR mutant brain metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11 evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291, other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case series or undetermined for T790M mutation status, indicating more systematic study is warranted.
Based on these data, we are going to conduct phase II study of AZD9291 in NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal metastasis.  

8. Study Design

Study Design Information
Study Type Interventional Study 
Study Purpose Treatment    
Phase Phase2 
Intervention Model Single Group  
Blinding/Masking Open 
Allocation Non-RCT 
Intervention Type Drug  
Intervention Description Patients will be treated 160 mg/day of AZD9291 orally (1 cycle for 28 days). Subjects (with the exception of subjects with insulin dependent diabetes) must fast for ≥ 1 hours prior to taking a dose to ≥ 2 hour post dose. Water is permitted during this fasting period. Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation. If the efficacy will be proven, the patient could receive the treatment continuously.  
Number of Arms
Arm 1 Arm Label BM cohort & LM ± BM cohort 
Target Number of Participant 80 
Arm Type Experimental 
Arm Description Patients will be treated 160 mg/day of AZD9291 orally (1 cycle for 28 days). Subjects (with the exception of subjects with insulin dependent diabetes) must fast for ≥ 1 hours prior to taking a dose to ≥ 2 hour post dose. Water is permitted during this fasting period. Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation. If the efficacy will be proven, the patient could receive the treatment continuously. 

9. Subject Eligibility

Subject Eligibility Information
Condition(s) / Problem(s) * Neoplasms
Rare Disease No
Inclusion
Criteria
Gender Both 
Age 19 Year ~ No Limit
Description ① EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or plasma. For patients with intracranial progression, prior radiation therapy is not mandatory. Extracranial progression is allowed.
② Patients who failed to 3rd generation EGFR TKIs (AZD9291 (80mg), Rociletinib, HM61713, or others) and develop CNS progression but stable extracranial disease
③ Age ≥18 years
④ ECOG performance status of 0 to 2
⑤ For BM, at least one measurable intracranial lesion as ≥ 10mm in the longest diameter by magnetic resonance imaging (MRI)
⑥ For LM, at least one site of CNS leptomeningeal disease that can be assessed by MRI
⑦ Adequate organ function as evidenced by the following;
Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL, CCr ≥ 50mL/min
⑧ Female subjects must either be of non-reproductive potential
⑨ Subject is willing and able to comply with the protocol
⑩ Signed written informed consent  
Exclusion Criteria ① Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week
② Any unresolved toxicities from prior therapy, greater than CTCAE grade 1
③ Mean QT interval corrected for heart rate (QTc) ≥ 470 ms
④ Uncontrolled systemic illness including uncontrolled hypertension, active bleeding, or active infection.
⑤ Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment
⑥ History of hypersensitivity to AZD9291
⑦ Known intracranial haemorrahge which is unrelated to tumor
⑧ Refractory nausea and vomiting  
Healthy Volunteers  

10. Outcome Measure(s)

Outcome Measure(s) Information
Type of Primary Outcome Efficacy 
Primary Outcome(s) 1 
Outcome Overall response rate (ORR) in CNS –brain metastasis cohort, - Overall survival – Leptomeningeal with or without brain metastasis cohort 
Timepoint The primary endpoint is objective response rate (ORR) for BM cohort defined as the number (%) of subjects with measurable disease with at least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria. Overall survival (OS) for LM cohort is measured from the date of start of study to the date of death from any cause. 
Secondary Outcome(s) 1 
Outcome Whole body disease control rate (DCR), Time to brain progression, Progression free survival (PFS) in BM cohort, Overall survival (OS), Adverse events (AEs), Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF) 
Timepoint • Disease control rate (DCR) defined as the number (%) of subjects with measurable disease with at least one visit response of CR (complete response), PR (partial response) or SD (stable disease) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria. • Time to brain progression: Time to brain progression is measured from the date of start of study to the date of progression of BM or LM . • Progression-free survival (PFS) is measured from the date of start of study to the date of disease progression or death from any cause. • Overall survival (OS): OS is measured from the date of start of study to the date of death from any cause. • Adverse events (AEs): Adverse events will be measured by the CTCAE scale, version 4. • Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF): EGFR mutation and T790M mutation tests will be performed in primary tumor tissue and cell free DNA of plasma or CSF. 

11. Study Results and Publication

Study Results and Publication Information
Result Registerd No

12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

Sharing of Study Data Information
Sharing Statement No 
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