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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Non-small Cell Lung Cancer, EGFR Gene Mutation, Brain Metastases

Intervention / Treatment
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* Drug: AZD3759
* Drug: Erlotinib
* Drug: Gefitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Properly completed patient informed consent Male or female aged at least 18 years 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. No prior treatment with chemotherapy, EGFR-TKIs, or biological therapies that are considered first line treatment for advanced NSCLC. 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. Eligible patients are not candidates for definitive surgical resection or radiation of all lesions in the opinion of the treating physician. 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. Patients may have prior placement of a properly functioning CNS shunt or Ommaya reservoir. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks. 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. (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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD3759 Group<br>AZD3759 group will receive a 200 mg twice daily dose of AZD3759 | Drug: AZD3759<br>* AZD3759 200mg PO BID.<br>|
| Active Comparator: Erlotinib or Gefitinib Group<br>SoC EGFR-TKI Erlotinib or Gefitinib Group will get EGFRTKI Erlotinib 150 mg or Gefitinib 250 mg PO Q.D | Drug: Erlotinib<br>* SoC EGFRTKI Erlotinib 150 mg PO Q.D<br>* Other names: Tarceva;Drug: Gefitinib<br>* SoC EGFRTKI Gefitinib 250 mg PO Q.D<br>* Other names: Iressa;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Central Nervous System Metastases, Respiratory Tract Diseases, EGFR, Exon 19Del, L858R, Lung Neoplasm, Carcinoma, Non-Small-Cell Lung, Neoplasms