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

• ClinicalTrials.gov Identifier: NCT03529084
• Recruitment Status: Withdrawn
• First Posted: May 18, 2018
• Last Update Posted: November 22, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 18, 2018
• First Posted Date: May 18, 2018
• Last Update Posted Date: November 22, 2019
• Estimated Study Start Date: July 24, 2018
• Estimated Primary Completion Date: August 13, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 7, 2018)

Progression Free Survival (PFS) by Blinded independent review committee (BIRC) [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 23, 2018)

• Overall Survival [ Time Frame: Approximately 6 years ]
  Overall survival is defined as the time from date of randomization to date of death due to any cause.
• PFS by investigator [ Time Frame: 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.
• PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1 [ Time Frame: 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.
• Time to progression in Central Nervous System (CNS) per central neuro-radiologist BIRC [ Time Frame: 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.
• Overall response rate (ORR) by central BIRC [ Time Frame: 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 [ Time Frame: 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.
• Disease control rate (DCR) by central BIRC [ Time Frame: Approximately 3 years ]
  DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD).
• Time to response (TTR) by central BIRC [ Time Frame: Approximately 3 years ]
  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 [ Time Frame: 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
• CNS DoR per central neuro-radiologist BIRC [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Approximately 4 years ]
  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 [ Time Frame: 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 [ Time Frame: Approximately 4 years ]
  Global health status/quality of life score of the EQ-5D-5L

Original Secondary Outcome Measures (submitted: May 7, 2018)

• Overall Survival [ Time Frame: Approximately 6 years ]
  Overall survival is defined as the time from date of randomization to date of death due to any cause.
• PFS by investigator [ Time Frame: 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.
• PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1 [ Time Frame: 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.
• Time to progression in Central Nervous System (CNS) per central neuro-radiologist BIRC [ Time Frame: 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.
• Overall response rate (ORR) by central BIRC [ Time Frame: 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 responce (DOR) by central BIRC [ Time Frame: 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.
• Disease control rate (DCR) by central BIRC [ Time Frame: Approximately 3 years ]
  DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD).
• Time to response (TTR) by central BIRC [ Time Frame: Approximately 3 years ]
  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 [ Time Frame: 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
• CNS DoR per central neuro-radiologist BIRC [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Approximately 4 years ]
  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 [ Time Frame: 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 [ Time Frame: Approximately 4 years ]
  Global health status/quality of life score of the EQ-5D-5L

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description:

blinded independent review committee for primary endpoint of PFS

Primary Purpose: Treatment

• Condition: Carcinoma, Non-small Cell Lung

Intervention

• Drug: EFG816
  It will be administered orally daily.
  Other Name: nazartinib
• Drug: erlotinib or gefitinib

  Investigator's choice between erlotinib or gefitinib. These will be locally sourced.

  Erlotinib will be administered orally daily. Gefitinib will be administered orally daily.

Study Arms

• Experimental: EGF816
  Investigational treatment arm of EGF816 (nazartinib).
  Intervention: Drug: EFG816
• Active Comparator: Investigator's Choice
  Investigator's Choice (erlotinib or gefitinib).
  Intervention: Drug: erlotinib or gefitinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: June 7, 2018): 0
• Original Estimated Enrollment (submitted: May 7, 2018): 410
• Estimated Study Completion Date: June 3, 2024
• Estimated Primary Completion Date: August 13, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT03529084
• Other Study ID Numbers: CEGF816A2302; 2017-003998-34 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

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.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: November 2019