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

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ClinicalTrials.gov Identifier: NCT03653546
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
Alpha Biopharma (Jiangsu) Co., Ltd.

Study Description
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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.


Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer EGFR Gene Mutation Brain Metastases Drug: AZD3759 Drug: Erlotinib Drug: Gefitinib Phase 2 Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 432 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 29, 2018
Estimated Primary Completion Date : June 15, 2021
Estimated Study Completion Date : October 16, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: AZD3759 Group
AZD3759 group will receive a 200 mg twice daily dose of AZD3759
 Drug: AZD3759
Advanced Non-Small Cell Lung Cancer (NSCLC) with CNS metastases.
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 Name: Tarceva

Drug: Gefitinib
SoC EGFRTKI Gefitinib 250 mg PO Q.D
Other Name: Iressa


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. PFS assess by investigator [ Time Frame: 36 months ]
    Investigator assessment of PFS using RECIST 1.1

  2. Intracranial PFS (iPFS) assessed by investigator [ Time Frame: 36 months ]
    Intracranial PFS (iPFS) assessed by investigator using RECIST 1.1

  3. Intracranial PFS (iPFS) assessed by BICR [ Time Frame: 36 months ]
    Intracranial PFS (iPFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1

  4. Extracranial PFS (ePFS) assessed by investigator [ Time Frame: 36 months ]
    Extracranial PFS (ePFS) assessed by investigator using RECIST 1.1

  5. Extracranial PFS (ePFS) assessed by BICR [ Time Frame: 36 months ]
    Extracranial PFS (ePFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1

  6. 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

  7. 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

  8. 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

  9. Overall ORR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Overall ORR assessed by investigator using RECIST 1.1

  10. Overall DCR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Overall DCR assessed by investigator using RECIST 1.1

  11. Overall DoR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
    Overall DoR assessed by investigator using RECIST 1.1

  12. ORR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
    ORR for Intracranial lesions assessed by investigator using RANO-BM

  13. DCR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
    DCR for Intracranial lesions assessed by investigator using RANO-BM

  14. DoR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
    DoR for Intracranial lesions assessed by investigator using RANO-BM

  15. Overall Survival [ Time Frame: 36 months ]
    Overall Survival

  16. 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.

  17. 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.

  18. 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)

  19. Neurological function improvement rate assessed by RANO-BM criteria [ Time Frame: 36 months ]
    Neurological function improvement rate assessed by RANO-BM criteria

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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.

  26. Systolic and Diastolic Blood Pressure assessed during the study period. [ Time Frame: 36 months ]
    Systolic and Diastolic Blood Pressure assessed during the study period.

  27. Pulse rate assessed during the study period. [ Time Frame: 36 months ]
    Pulse rate to assessed during the study period.

  28. Body temperature assessed during the study period. [ Time Frame: 36 months ]
    Body temperature assessed during the study period.

  29. PFS assess by BICR [ Time Frame: 36 months ]
    Blinded Independent Central Radiological (BICR) assessment of PFS using modified RECIST 1.1.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03653546


Contacts
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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

Locations
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Sponsors and Collaborators
Alpha Biopharma (Jiangsu) Co., Ltd.
Investigators
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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
  Study Documents (Full-Text)

Documents provided by Alpha Biopharma (Jiangsu) Co., Ltd.:
Study Protocol  [PDF] February 12, 2019

More Information
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Publications:

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Responsible Party: Alpha Biopharma (Jiangsu) Co., Ltd.
ClinicalTrials.gov Identifier: NCT03653546    
Other Study ID Numbers: AZD3759-003
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alpha Biopharma (Jiangsu) Co., Ltd.:
Central Nervous System Metastases
Respiratory Tract Diseases
EGFR
Exon 19Del
 L858R
Lung Neoplasm
Carcinoma, Non-Small-Cell Lung
Neoplasms
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms, Second Primary
Neoplasms
Neoplastic Processes
Pathologic Processes
Erlotinib Hydrochloride
 Gefitinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action