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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03653546
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : May 9, 2019
Sponsor:
Information provided by (Responsible Party):
Alpha Biopharma (Jiangsu) Co., Ltd.

Tracking Information
First Submitted Date  ICMJE August 22, 2018
First Posted Date  ICMJE August 31, 2018
Last Update Posted Date May 9, 2019
Actual Study Start Date  ICMJE October 29, 2018
Estimated Primary Completion Date June 15, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
PFS assessed by Blinded Independent Central Radiological [ Time Frame: 36 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
Overall PFS assessed by Blinded Independent Central Radiological [ Time Frame: 36 months ]
To assess if first line treatment with AZD3759 results in significant overall PFS efficacy compared to Gefitinib or Erlotinib as determined by Blinded Independent Central Radiological (BICR) review using modified RECIST 1.1.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
  • PFS assess by investigator [ Time Frame: 36 months ]
    Investigator assessment of PFS using RECIST 1.1
  • Intracranial PFS (iPFS) assessed by investigator [ Time Frame: 36 months ]
    Intracranial PFS (iPFS) assessed by investigator using RECIST 1.1
  • Intracranial PFS (iPFS) assessed by BICR [ Time Frame: 36 months ]
    Intracranial PFS (iPFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1
  • Extracranial PFS (ePFS) assessed by investigator [ Time Frame: 36 months ]
    Extracranial PFS (ePFS) assessed by investigator using RECIST 1.1
  • Extracranial PFS (ePFS) assessed by BICR [ Time Frame: 36 months ]
    Extracranial PFS (ePFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1
  • Objective Response Rate (ORR) assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Objective Response Rate (ORR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1
  • Disease Control Rate (DCR) assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Disease Control Rate (DCR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1
  • Duration of Response (DoR) assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Duration of Response (DoR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1
  • Overall ORR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Overall ORR assessed by investigator using RECIST 1.1
  • Overall DCR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Overall DCR assessed by investigator using RECIST 1.1
  • Overall DoR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Overall DoR assessed by investigator using RECIST 1.1
  • ORR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
    ORR for Intracranial lesions assessed by investigator using RANO-BM
  • DCR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
    DCR for Intracranial lesions assessed by investigator using RANO-BM
  • DoR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
    DoR for Intracranial lesions assessed by investigator using RANO-BM
  • Overall Survival [ Time Frame: 36 months ]
    Overall Survival
  • Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). [ Time Frame: 36 months ]
    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.
  • Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire BN20 (EORTC QLQ-BN20). [ Time Frame: 36 months ]
    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.
  • Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE) [ Time Frame: 36 months ]
    Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)
  • Neurological function improvement rate assessed by RANO-BM criteria [ Time Frame: 36 months ]
    Neurological function improvement rate assessed by RANO-BM criteria
  • Number of participants with treatment-related Adverse Events as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
  • Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
    Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0
  • Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
    Incidence of laboratory abnormalities collected by hematology 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 [ Time Frame: 36 months ]
    Incidence of laboratory abnormalities collected by biochemistry 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 [ Time Frame: 36 months ]
    Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0
  • Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period. [ Time Frame: 36 months ]
    Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.
  • Systolic and Diastolic Blood Pressure assessed during the study period. [ Time Frame: 36 months ]
    Systolic and Diastolic Blood Pressure assessed during the study period.
  • Pulse rate assessed during the study period. [ Time Frame: 36 months ]
    Pulse rate to assessed during the study period.
  • Body temperature assessed during the study period. [ Time Frame: 36 months ]
    Body temperature assessed during the study period.
  • PFS assess by BICR [ Time Frame: 36 months ]
    Blinded Independent Central Radiological (BICR) assessment of PFS using modified RECIST 1.1.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • Overall PFS assess by investigator [ Time Frame: 36 months ]
    Investigator assessment of PFS using modified RECIST 1.1
  • Intracranial PFS (iPFS) assessed by investigator [ Time Frame: 36 months ]
    Intracranial PFS (iPFS) assessed by investigator using modified RECIST 1.1
  • Intracranial PFS (iPFS) assessed by BICR [ Time Frame: 36 months ]
    Intracranial PFS (iPFS) assessed by Blinded Independent Central Radiological (BICR) using modified RECIST 1.1
  • Extracranial PFS (ePFS) assessed by investigator [ Time Frame: 36 months ]
    Extracranial PFS (ePFS) assessed by investigator using modified RECIST 1.1
  • Extracranial PFS (ePFS) assessed by BICR [ Time Frame: 36 months ]
    Extracranial PFS (ePFS) assessed by Blinded Independent Central Radiological (BICR) using modified RECIST 1.1
  • To compare the iPFS assessed by investigator with iPFS assessed by BICR [ Time Frame: 36 months ]
    To compare the iPFS assessed by investigator with iPFS assessed by BICR using modified RECIST 1.1
  • To compare the ePFS assessed by investigator with ePFS assessed by BICR [ Time Frame: 36 months ]
    To compare the ePFS assessed by investigator with ePFS assessed by BICR using modified RECIST 1.1
  • To assess ORR between study cohorts for Intracranial lesions [ Time Frame: 36 months ]
    To assess ORR between study cohorts for Intracranial lesions using modified RECIST 1.1 per investigator assessment
  • To assess DCR between study cohorts for Intracranial lesions [ Time Frame: 36 months ]
    To assess DCR between study cohorts for Intracranial lesions using modified RECIST 1.1 per investigator assessment
  • To assess DoR between study cohorts for Intracranial lesions [ Time Frame: 36 months ]
    To assess DoR between study cohorts for Intracranial lesions using modified RECIST 1.1 per investigator assessment
  • To assess ORR between study cohorts for Extracranial lesions [ Time Frame: 36 months ]
    To assess ORR between study cohorts for Extracranial lesions using modified RECIST 1.1 per investigator assessment
  • To assess DCR between study cohorts for Extracranial lesions [ Time Frame: 36 months ]
    To assess DCR between study cohorts for Extracranial lesions using modified RECIST 1.1 per investigator assessment
  • To assess DoR between study cohorts for Extracranial lesions [ Time Frame: 36 months ]
    To assess DoR between study cohorts for Extracranial lesions using modified RECIST 1.1 per investigator assessment
  • To assess Overall ORR between the study cohorts [ Time Frame: 36 months ]
    To assess Overall ORR between the study cohorts using modified RECIST 1.1 per investigator assessment
  • To assess Overall DCR between the study cohorts [ Time Frame: 36 months ]
    To assess Overall DCR the study cohorts using modified RECIST 1.1 per investigator assessment
  • To assess Overall DoR between the study cohorts [ Time Frame: 36 months ]
    To assess Overall DoR between the study cohorts using modified RECIST 1.1 per investigator assessment
  • To assess ORR between the study cohorts for intracranial disease [ Time Frame: 36 months ]
    To assess ORR between the study cohorts for intracranial disease using modified RANO criteria per investigator assessment
  • To assess DCR between the study cohorts for intracranial disease [ Time Frame: 36 months ]
    To assess DCR between the study cohorts for intracranial disease using modified RANO criteria per investigator assessment
  • To assess DoR between the study cohorts for intracranial disease [ Time Frame: 36 months ]
    To assess DoR between the study cohorts for intracranial disease using modified RANO criteria per investigator assessment
  • Overall Survival [ Time Frame: 36 months ]
    Overall Survival
  • Change from baseline in Questionnaire QLQ-C30 [ Time Frame: 36 months ]
    Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
  • Change from baseline in Questionnaire QLQ-BN20 [ Time Frame: 36 months ]
    Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-BN20)
  • Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE) [ Time Frame: 36 months ]
    Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)
  • Neurological function improvement rate assessed by modified RANO criteria [ Time Frame: 36 months ]
    Neurological function improvement rate assessed by modified RANO criteria
  • Number of participants with treatment-related Adverse Events as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
  • Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
    Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0
  • Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
    Incidence of laboratory abnormalities collected by hematology 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 [ Time Frame: 36 months ]
    Incidence of laboratory abnormalities collected by biochemistry 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 [ Time Frame: 36 months ]
    Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0
  • Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG to be assessed during the study period. [ Time Frame: 36 months ]
    Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG to be assessed during the study period.
  • Blood pressure to be assessed during the study period. [ Time Frame: 36 months ]
    Blood pressure to be assessed during the study period.
  • Pulse rate to be assessed during the study period. [ Time Frame: 36 months ]
    Pulse rate to be assessed during the study period.
  • Body temperature to be assessed during the study period. [ Time Frame: 36 months ]
    Body temperature to be assessed during the study period.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE First Line Treatment in EGFR Mutation Positive Advanced NSCLC Patients With Central Nervous System Metastases
Official Title  ICMJE 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
Brief Summary

Primary Hypothesis 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 Non-Small Cell Lung Cancer (NSCLC) with Central Nervous System (CNS) metastasis

Secondary Hypothesis The safety profile of AZD3759 is comparable to EGFR TKI first-line treatment in patients with advanced NSCLC with 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 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.

Primary Objective:

The primary objective of this study is to determine if administration of single agent AZD3759 compared to Standard of Care (SoC) EGFR-TKI as first-line therapy results in a significant increase in Progression Free Survival (PFS) in the study patient population by Blinded Independent Central Radiological(BICR) review.

Secondary Objectives:

Key secondary objective for this study is to determine if AZD3759 vs. SoC EGFR TKI administration demonstrates additional benefit in terms of safety, Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), and overall PFS using modified RECIST 1.1 criteria by investigator assessment.

Additional secondary objectives include assessment of Health Related Quality of Life (HRQoL), neurological function, and Overall Survival (OS).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Non-small Cell Lung Cancer
  • EGFR Gene Mutation
  • Brain Metastases
Intervention  ICMJE
  • Drug: AZD3759
    Advanced Non-Small Cell Lung Cancer (NSCLC) with CNS metastases.
  • Drug: Erlotinib
    SoC EGFRTKI Erlotinib 150 mg PO Q.D
    Other Name: Tarceva
  • Drug: Gefitinib
    SoC EGFRTKI Gefitinib 250 mg PO Q.D
    Other Name: Iressa
Study Arms  ICMJE
  • Experimental: AZD3759 Group
    AZD3759 group will receive a 200 mg twice daily dose of AZD3759
    Intervention: Drug: AZD3759
  • 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
    Interventions:
    • Drug: Erlotinib
    • Drug: Gefitinib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 7, 2019)
432
Original Estimated Enrollment  ICMJE
 (submitted: August 28, 2018)
300
Estimated Study Completion Date  ICMJE October 16, 2021
Estimated Primary Completion Date June 15, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: John Ge, M.D. +86 (0)21-63862197 john.ge@alphabiopharma.com.cn
Contact: Yang Lu, M.D. +86(0)21-63862186 yang.lu@alphabiopharma.com.cn
Listed Location Countries  ICMJE China,   Korea, Republic of,   Singapore,   Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03653546
Other Study ID Numbers  ICMJE AZD3759-003
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Alpha Biopharma (Jiangsu) Co., Ltd.
Study Sponsor  ICMJE Alpha Biopharma (Jiangsu) Co., Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Alpha Biopharma (Jiangsu) Co., Ltd.
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP