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

Phase 3

Withdrawn

• Conditions: Carcinoma, Non-small Cell Lung
• Interventions: Drug: EFG816; Drug: erlotinib or gefitinib

• Registration Number: NCT03529084
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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).

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study First Submitted: 2018-04-18
• Study First Submitted QC: 2018-05-07
• Study First Posted: 2018-05-18
• Study Start: 2018-07-24
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-21
• Last Update Posted: 2019-11-22
• Primary Completion: 2020-08-13
• Study Completion: 2024-06-03

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EGF816	EFG816	Investigational treatment arm of EGF816 (nazartinib).
Investigator's Choice	erlotinib or gefitinib	Investigator's Choice (erlotinib or gefitinib).

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) by Blinded independent review committee (BIRC)	Approximately 3 years	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.

Secondary Outcome Measures

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