Phase III Study of Nazartinib (EGF816) Versus Erlotinib/Gefitinib in First-line Locally Advanced / Metastatic NSCLC With EGFR Activating Mutations

Study Overview
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Brief Summary
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This is a phase III, open label, randomized controlled multi-center global study designed to evaluate the safety and efficacy of single agent nazartinib (EGF816) compared with investigator's choice (erlotinib or gefitinib) in patients with locally advanced or metastatic NSCLC who are treatment naïve and whose tumors harbor EGFR activating mutations (L858R or ex19del).

Official Title
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A Randomized, Open-label, Phase III Study of Single Agent Nazartinib Versus Investigator's Choice (Erlotinib or Gefitinib) as First-Line Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring EGFR Activating Mutations

Conditions
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Carcinoma, Non-small Cell Lung

Intervention / Treatment
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* Drug: EFG816
* Drug: erlotinib or gefitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained prior to any screening procedures. Histologically documented locally advanced or metastatic, stage IIIB/ IIIC or stage IV NSCLC with documented EGFR activating mutation (L858R or ex19del) Provision of a tumor tissue sample to allow for retrospective analysis of EGFR mutation status No prior treatment with any systemic antineoplastic therapy in the advanced setting Recovered from all toxicities related to prior treatment Presence of at least one measurable lesion according to RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) performance ≤1 Meet the following laboratory values at the screening visit: Absolute Neutrophil Count ≥1.5 x 109/L Platelets ≥75 x 109/L Hemoglobin (Hgb) ≥9 g/dL Creatinine Clearance ≥ 45 mL/min using Cockcroft-Gault formula Total bilirubin ≤1.5 x ULN Aspartate transaminase (AST) ≤ 3.0 x ULN, except for patients with liver metastasis, who may only be included if AST ≤5.0 x ULN Alanine transaminase (ALT) ≤ 3.0 x ULN, except for patients with liver metastasis, who may only be included if ALT ≤5.0 x ULN Exclusion Criteria: Prior treatment with EGFR-TKI. Known T790M positive mutation. Any other known EGFR activating mutations other than L858R or ex19del. Patients whose tumors harbor other EGFR mutations concurrent with L858R or ex19del EGFR mutations are eligible. Symptomatic brain metastases History of interstitial lung disease or interstitial pneumonitis Any medical condition that would, in the investigator's judgment, the patient's in the study due to safety concerns, compliance with clinical study procedures or interpretation of study results Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years.. Presence of clinically significant ophthalmologic abnormalities Bullous and exfoliative skin disorders of any grade Presence or history of microangiopathic hemolytic anemia with thrombocytopenia. Known history of testing positive for human immunodeficiency virus (HIV) infection Cardiac or cardiac repolarization abnormality Major surgery: ≤4 weeks to starting study treatment or who have not recovered from side effects of such procedure. Unable or unwilling to swallow tablets or capsules Female patients who are either pregnant or nursing Women of child bearing potential who refuse or are not able to use a highly effective method of contraception as defined in the study protocol. Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after the last dose of study treatment. Other protocol-defined inclusion/exclusion criteria may apply

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EGF816<br>Investigational treatment arm of EGF816 (nazartinib). | Drug: EFG816<br>* It will be administered orally daily.<br>* Other names: nazartinib;|
| Active Comparator: Investigator's Choice<br>Investigator's Choice (erlotinib or gefitinib). | Drug: erlotinib or gefitinib<br>* Investigator's choice between erlotinib or gefitinib. These will be locally sourced. Erlotinib will be administered orally daily. Gefitinib will be administered orally daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Blinded independent review committee (BIRC) | PFS using central BIRC assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by BIRC per RECIST 1.1) or death due to any cause, whichever occurs first. | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from date of randomization to date of death due to any cause. | Approximately 6 years | 
| PFS by investigator | PFS by Investigator assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by Investigator per RECIST 1.1) or death due to any cause, whichever occurs first. | Approximately 3 years | 
| PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1 | PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1 is defined as time from date of randomization to the first documented disease progression (clinical or radiologic) as per investigator assessment on next-line therapy or death from any cause, whichever occurs first. | Approximately 4 years | 
| Time to progression in Central Nervous System (CNS) per central neuro-radiologist BIRC | Time to progression in CNS, defined as time from date of randomization to the date of first documented progression of brain metastases as assessed by central neuro-radiologist BIRC per modified RECIST 1.1 for patients with at least one non-measurable and/or measurable lesion in the brain at baseline. | Approximately 3 years | 
| Overall response rate (ORR) by central BIRC | ORR in accordance with RECIST 1.1. ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) | Approximately 3 years | 
| Duration of response (DOR) by central BIRC | DOR is defined as the time from date of first documented response (CR and PR) to the date of the first documented progression or death due to underlying cancer, whichever occurs first. | Approximately 3 years | 
| Disease control rate (DCR) by central BIRC | DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD). | Approximately 3 years | 
| Time to response (TTR) by central BIRC | TTR is defined as the time from the date of randomization to the first documented response CR or PR. | Approximately 3 years | 
| CNS ORR per central neuro-radiologist BIRC | CNS ORR in patients with brain metastases who have measurable disease in the brain at baseline review per modified RECIST 1.1 | Approximately 3 years | 
| CNS DoR per central neuro-radiologist BIRC | CNS DoR in patients with brain metastases who have measurable disease in the brain at baseline per modified RECIST 1.1 | Approximately 3 years | 
| Charactise Plasma PK (Cmax) of EGF816 | Peak plasma concentration (Cmax) of EGF816 and its metabolite (LMI258) | Day 1 of Cycles 1 to 6 inclusive (21 day cycle) | 
| Charactise Plasma PK (AUC) of EGF816 | Area under the plasma concentration versus time curve (AUC) of EGF816 and its metabolite (LMI258) | Day 1 of Cycles 1 to 6 inclusive (21 day cycle) | 
| Charactise Plasma PK (t1/2) of EGF816 | Elimination half life (t1/2) of EGF816 and its metabolite (LMI258) | Day 1 of Cycles 1 to 6 inclusive (21 day cycle) | 
| Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-C30 Questionnaire | HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life score | Approximately 4 years | 
| Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-LC13 Questionnaire | HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 quality of life score | Approximately 4 years | 
| Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by EuroQoL-5 Dimension-5 (EQ-5D-5L) Questionnaire | Global health status/quality of life score of the EQ-5D-5L | Approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non small cell lung cancer, NSCLC, EGFR mutation, EGF816, nazartinib, erlotinib, gefitinib