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

Primary Purpose

Carcinoma, Non-small Cell Lung

Status

Withdrawn

Phase

Phase 3

Locations

Study Type

Interventional

Intervention

EFG816

erlotinib or gefitinib

About this trial

This is an interventional treatment trial for Carcinoma, Non-small Cell Lung focused on measuring Non small cell lung cancer, NSCLC, EGFR mutation, EGF816, nazartinib, erlotinib, gefitinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

EGF816

Investigator's Choice

Arm Description

Investigational treatment arm of EGF816 (nazartinib).

Investigator's Choice (erlotinib or gefitinib).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Overall Survival

Overall survival is defined as the time from date of randomization to date of death due to any cause.

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.

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.

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.

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)

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.

Disease control rate (DCR) by central BIRC

DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD).

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.

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

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

Charactise Plasma PK (Cmax) of EGF816

Peak plasma concentration (Cmax) of EGF816 and its metabolite (LMI258)

Charactise Plasma PK (AUC) of EGF816

Area under the plasma concentration versus time curve (AUC) of EGF816 and its metabolite (LMI258)

Charactise Plasma PK (t1/2) of EGF816

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

HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life score

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

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

Full Information

NCT ID

NCT03529084

First Posted

April 18, 2018

Last Updated

November 21, 2019

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03529084

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2019

Overall Recruitment Status

Withdrawn

Why Stopped

Decision by Sponsor not to continue with the trial.

Study Start Date

July 24, 2018 (Anticipated)

Primary Completion Date

August 13, 2020 (Anticipated)

Study Completion Date

June 3, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Carcinoma, Non-small Cell Lung

Keywords

Non small cell lung cancer, NSCLC, EGFR mutation, EGF816, nazartinib, erlotinib, gefitinib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Masking Description

blinded independent review committee for primary endpoint of PFS

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

EGF816

Arm Type

Experimental

Arm Description

Investigational treatment arm of EGF816 (nazartinib).

Arm Title

Investigator's Choice

Arm Type

Active Comparator

Arm Description

Investigator's Choice (erlotinib or gefitinib).

Intervention Type

Drug

Intervention Name(s)

EFG816

Other Intervention Name(s)

nazartinib

Intervention Description

It will be administered orally daily.

Intervention Type

Drug

Intervention Name(s)

erlotinib or gefitinib

Intervention Description

Investigator's choice between erlotinib or gefitinib. These will be locally sourced. Erlotinib will be administered orally daily. Gefitinib will be administered orally daily.

Primary Outcome Measure Information:

Title

Progression Free Survival (PFS) by Blinded independent review committee (BIRC)

Description

Time Frame

Approximately 3 years

Secondary Outcome Measure Information:

Title

Overall Survival

Description

Overall survival is defined as the time from date of randomization to date of death due to any cause.

Time Frame

Approximately 6 years

Title

PFS by investigator

Description

Time Frame

Approximately 3 years

Title

PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1

Description

Time Frame

Approximately 4 years

Title

Time to progression in Central Nervous System (CNS) per central neuro-radiologist BIRC

Description

Time Frame

Approximately 3 years

Title

Overall response rate (ORR) by central BIRC

Description

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)

Time Frame

Approximately 3 years

Title

Duration of response (DOR) by central BIRC

Description

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.

Time Frame

Approximately 3 years

Title

Disease control rate (DCR) by central BIRC

Description

DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD).

Time Frame

Approximately 3 years

Title

Time to response (TTR) by central BIRC

Description

TTR is defined as the time from the date of randomization to the first documented response CR or PR.

Time Frame

Approximately 3 years

Title

CNS ORR per central neuro-radiologist BIRC

Description

CNS ORR in patients with brain metastases who have measurable disease in the brain at baseline review per modified RECIST 1.1

Time Frame

Approximately 3 years

Title

CNS DoR per central neuro-radiologist BIRC

Description

CNS DoR in patients with brain metastases who have measurable disease in the brain at baseline per modified RECIST 1.1

Time Frame

Approximately 3 years

Title

Charactise Plasma PK (Cmax) of EGF816

Description

Peak plasma concentration (Cmax) of EGF816 and its metabolite (LMI258)

Time Frame

Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Title

Charactise Plasma PK (AUC) of EGF816

Description

Area under the plasma concentration versus time curve (AUC) of EGF816 and its metabolite (LMI258)

Time Frame

Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Title

Charactise Plasma PK (t1/2) of EGF816

Description

Elimination half life (t1/2) of EGF816 and its metabolite (LMI258)

Time Frame

Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Title

Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-C30 Questionnaire

Description

HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life score

Time Frame

Approximately 4 years

Title

Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-LC13 Questionnaire

Description

HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 quality of life score

Time Frame

Approximately 4 years

Title

Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by EuroQoL-5 Dimension-5 (EQ-5D-5L) Questionnaire

Description

Global health status/quality of life score of the EQ-5D-5L

Time Frame

Approximately 4 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Learn more about this trial

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

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