First Line Treatment in EGFR Mutation Positive Advanced NSCLC Patients With Central Nervous System (CNS) Metastases (BM)

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

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

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer; Brain Metastases; EGFR Gene Mutation
• Intervention / Treatment: Drug: AZD3759; Drug: Erlotinib; Drug: Gefitinib

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.

• Study Type: Interventional
• Enrollment (Actual): 492
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100021
    • China site
  • Beijing, China, 100071
    • China site
  • Beijing, China, 100142
    • China site
  • Beijing, China, 100730
    • China site
  • Chongqing, China, 400030
    • China site
  • Chongqing, China, 400037
    • China site
  • Chongqing, China, 400042
    • China site
  • Shanghai, China, 200030
    • China site
  • Shanghai, China, 200032
    • China site
  • Tianjin, China, 300052
    • China site
  • Anhui
    • Hefei, Anhui, China, 230001
      • China site
  • Fujian
    • Fuzhou, Fujian, China, 350014
      • China site
    • Xiamen, Fujian, China, 361003
      • China site
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • China site
    • Guangzhou, Guangdong, China, 510180
      • China site
  • Heilongjiang
    • Haerbin, Heilongjiang, China, 150081
      • China site
  • Henan
    • Zhengzhou, Henan, China, 450008
      • China site
    • Zhengzhou, Henan, China, 450052
      • China site
  • Hubei
    • Wuhan, Hubei, China, 430022
      • China site
    • Wuhan, Hubei, China, 430030
      • China site
    • Wuhan, Hubei, China, 430079
      • China site
    • Yichang, Hubei, China, 443003
      • China site
  • Hunan
    • Changsha, Hunan, China, 410013
      • China site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210002
      • China site
    • Nanjing, Jiangsu, China, 210009
      • China site
    • Suzhou, Jiangsu, China, 215004
      • China site
    • Wuxi, Jiangsu, China, 214062
      • China site
    • Xuzhou, Jiangsu, China, 221002
      • China site
    • Yangzhou, Jiangsu, China, 225001
      • China site
  • Jilin
    • Changchun, Jilin, China, 130012
      • China site
    • Changchun, Jilin, China, 130021
      • China site
  • Shaanxi
    • Xi'an, Shaanxi, China, 710061
      • China site
  • Shandong
    • Jinan, Shandong, China, 250117
      • China site 0123
    • Linyi, Shandong, China, 276000
      • China site
    • Weifang, Shandong, China, 261000
      • China site
    • Yantai, Shandong, China, 264000
      • China site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • China site
  • Yunnan
    • Kunming, Yunnan, China, 650118
      • China site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • China site
    • Hangzhou, Zhejiang, China, 310022
      • China site
    • Hangzhou, Zhejiang, China, 311100
      • China site
• Korea, Republic of
  • Chungbuk, Korea, Republic of, 28644
    • Korea site
  • Daegu, Korea, Republic of, 42415
    • Korea site
  • Gyeonggi-do, Korea, Republic of, 16247
    • Korea site
  • Gyeongsang, Korea, Republic of, 52727
    • Korea site
  • Incheon, Korea, Republic of, 21565
    • Korea site
  • Seoul, Korea, Republic of, 03080
    • Korea site
  • Seoul, Korea, Republic of, 05368
    • Korea site
  • Seoul, Korea, Republic of, 06351
    • Korea site
  • Seoul, Korea, Republic of, 06591
    • Korea site
  • Seoul, Korea, Republic of, 07061
    • Korea site
  • Suwon, Korea, Republic of, 16499
    • Korea site
  • Ulsan, Korea, Republic of, 44033
    • Korea site
• Singapore
  • Singapore, Singapore, 308433
    • Singapore site
• Taiwan
  • Taichung, Taiwan, 407
    • Taiwan site
  • Tainan, Taiwan, 704
    • Taiwan site
  • Taipei, Taiwan, 100
    • Taiwan site
  • Taoyuan, Taiwan, 333
    • Taiwan site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AZD3759 Group; AZD3759 group will receive a 200 mg twice daily dose of AZD3759	Drug: AZD3759; AZD3759 200mg PO BID.
ACTIVE_COMPARATOR: Erlotinib or Gefitinib Group; SoC EGFR-TKI Erlotinib or Gefitinib Group will get EGFRTKI Erlotinib 150 mg or Gefitinib 250 mg PO Q.D	Drug: Erlotinib; SoC EGFRTKI Erlotinib 150 mg PO Q.D; Other Names: Tarceva; Drug: Gefitinib; SoC EGFRTKI Gefitinib 250 mg PO Q.D; Other Names: Iressa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS assessed by Blinded Independent Central Radiological	To assess if first line treatment with AZD3759 results in significant PFS efficacy compared to Gefitinib or Erlotinib as determined by Blinded Independent Central Radiological (BICR) review using RECIST 1.1.	48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS assess by investigator	Investigator assessment of PFS using RECIST 1.1	48 months
Intracranial PFS (iPFS) assessed by investigator	Intracranial PFS (iPFS) assessed by investigator using RECIST 1.1	48 months
Intracranial PFS (iPFS) assessed by BICR	Intracranial PFS (iPFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1	48 months
Extracranial PFS (ePFS) assessed by investigator	Extracranial PFS (ePFS) assessed by investigator using RECIST 1.1	48 months
Extracranial PFS (ePFS) assessed by BICR	Extracranial PFS (ePFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1	48 months
Objective Response Rate (ORR） assessed by investigator using RECIST 1.1	Objective Response Rate (ORR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1	48 months
Disease Control Rate (DCR) assessed by investigator using RECIST 1.1	Disease Control Rate (DCR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1	48 months
Duration of Response (DoR) assessed by investigator using RECIST 1.1	Duration of Response (DoR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1	48 months
Overall ORR assessed by investigator using RECIST 1.1	Overall ORR assessed by investigator using RECIST 1.1	48 months
Overall DCR assessed by investigator using RECIST 1.1	Overall DCR assessed by investigator using RECIST 1.1	48 months
Overall DoR assessed by investigator using RECIST 1.1	Overall DoR assessed by investigator using RECIST 1.1	48 months
ORR for Intracranial lesions assessed by investigator using RANO-BM	ORR for Intracranial lesions assessed by investigator using RANO-BM	48 months
DCR for Intracranial lesions assessed by investigator using RANO-BM	DCR for Intracranial lesions assessed by investigator using RANO-BM	48 months
DoR for Intracranial lesions assessed by investigator using RANO-BM	DoR for Intracranial lesions assessed by investigator using RANO-BM	48 months
Overall Survival	Overall Survival	48 months
Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).	The 30-items questionnaire measures cancer patients' functioning and symptoms. The scale range of EORTC QLQ-C30 is 30-126. Lower values represent a better outcome.	48 months
Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire BN20 (EORTC QLQ-BN20).	The 20-items questionnaire was used among brain cancer patients. The scale range of EORTC BN20 is 20-80. Lower values represent a better outcome.	48 months
Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)	Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)	48 months
Neurological function improvement rate assessed by RANO-BM criteria	Neurological function improvement rate assessed by RANO-BM criteria	48 months
Number of participants with treatment-related Adverse Events as assessed by CTCAE v5.0	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	48 months
Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0	Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0	48 months
Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0	Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0	48 months
Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0	Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0	48 months
Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0	Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0	48 months
Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.	Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.	48 months
Systolic and Diastolic Blood Pressure assessed during the study period.	Systolic and Diastolic Blood Pressure assessed during the study period.	48 months
Pulse rate assessed during the study period.	Pulse rate to assessed during the study period.	48 months
Body temperature assessed during the study period.	Body temperature assessed during the study period.	48 months
PFS assess by BICR	Blinded Independent Central Radiological (BICR) assessment of PFS using modified RECIST 1.1.	48 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pop-PK analysis	Population pharmacokinetic analysis	48 months
Exposure-Response analysis	explore the correlation in exposure and efficacy, exposure and safety in the Study	48 months

Collaborators and Investigators

• Sponsor: Alpha Biopharma (Jiangsu) Co., Ltd.
• Investigators: Study Chair: Yilong Wu, M.D., Guangdong Provincial People's Hospital; Principal Investigator: Myung-Ju Ahn, M.D., Samsung Medical Center, Sungkyunkwan University School of Medicine; Principal Investigator: Jie Wang, M.D., Cancer Institute and Hospital, Chinese Academy of Medical Sciences; Principal Investigator: Qing Zhou, M.D., Guangdong Provincial People's Hospital

Publications and helpful links

General Publications

• Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. doi: 10.1093/jnci/85.5.365.
• Barajas RF Jr, Cha S. Imaging diagnosis of brain metastasis. Prog Neurol Surg. 2012;25:55-73. doi: 10.1159/000331174. Epub 2012 Jan 6.
• Deeken JF, Loscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007 Mar 15;13(6):1663-74. doi: 10.1158/1078-0432.CCR-06-2854.
• Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008 Jan 1;14(1):162-8. doi: 10.1158/1078-0432.CCR-07-1468.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 29, 2018
• Primary Completion (ACTUAL): July 12, 2022
• Study Completion (ACTUAL): July 12, 2022

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: August 28, 2018
• First Posted (ACTUAL): August 31, 2018

Study Record Updates

• Last Update Posted (ACTUAL): November 21, 2022
• Last Update Submitted That Met QC Criteria: November 18, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Respiratory Tract Diseases; Neoplasms; EGFR; Carcinoma, Non-Small-Cell Lung; Lung Neoplasm; L858R; Central Nervous System Metastases; Exon 19Del
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Gefitinib
• Other Study ID Numbers: AZD3759-003

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