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AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02296125
Recruitment Status : Active, not recruiting
First Posted : November 20, 2014
Results First Posted : November 6, 2018
Last Update Posted : December 30, 2020
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE October 22, 2014
First Posted Date  ICMJE November 20, 2014
Results First Submitted Date  ICMJE June 13, 2018
Results First Posted Date  ICMJE November 6, 2018
Last Update Posted Date December 30, 2020
Actual Study Start Date  ICMJE December 3, 2014
Actual Primary Completion Date June 19, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 14, 2019)
  • Median Progression Free Survival (PFS) (Months) [ Time Frame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression ]
    Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS. The primary endpoint of PFS was based on Investigator assessment.
  • Percentage of Participants in Progression Free Survival at 6, 12, and 18 Months [ Time Frame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression ]
    Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS.
Original Primary Outcome Measures  ICMJE
 (submitted: November 18, 2014)
Progression Free Survival (PFS) [ Time Frame: At baseline and every 6 weeks until objective disease progression (approximately 11.5 months) ]
Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 14, 2019)
  • Objective Response Rate (ORR) [ Time Frame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression ]
    ORR was defined as the number (%) of participants with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy. ORR was based on Investigator assessment.
  • Duration of Response (DoR) [ Time Frame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression ]
    Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy.
  • Disease Control Rate (DCR) [ Time Frame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression ]
    The DCR was defined as the percentage of participants who had a best overall response (BOR) of Complete response (CR), Partial response (PR) or Stable disease (SD) ≥6 weeks prior to any Progressive disease (PD) event and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy.
  • Depth of Response [ Time Frame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression ]
    The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy
  • Overall Survival (OS)- Number of Participants With an Event [ Time Frame: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months) ]
    Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy
  • Plasma Concentrations of AZD9291 [ Time Frame: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months) ]
    To characterise the pharmacokinetics (PK) of osimertinib
  • Plasma Concentrations of Metabolites AZ5104 [ Time Frame: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months) ]
    To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ5104.
  • Plasma Concentrations of Metabolite AZ7550 [ Time Frame: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months) ]
    To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ7550.
  • Participants Reported Outcome by Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 Questionnaire) [ Time Frame: Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months) ]
    The CTSQ-16 was a 16-item questionnaire measuring 3 domains related to participant's satisfaction with cancer therapy: Expectations of therapy, Feelings about side effects, and Satisfaction with therapy. Scores ranged from 0 to 100 for each domain, with a higher score associated with the best outcome on each domain. The three domains of interest were separately analysed using an ANCOVA stratified by race (Asian versus Non-Asian) and mutation type (Ex19del versus L858R). The results of the analyses were presented in terms of mean together with standard deviation.
  • Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13) [ Time Frame: Questionnaires completed at baseline, first 9 months, and at week 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 and 36 ]
    The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.
  • Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) [ Time Frame: Questionnaires completed at baseline, first 9 months, and at week 6, 12, 18, 24, 30, and 36. ]
    The EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, combined to produce 5 functional scales, 3 symptom scales, 6 individual items, and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2014)
  • Objective Response Rate (ORR) [ Time Frame: At baseline and every 6 weeks until objective disease progression (approximately 11.5 months) ]
    Defined as the number (%) of patients with measurable disease with at least 1 visit response of CR (Complete response) or PR (Partial response).
  • Progression Free Survival (PFS) in patients with positive (or negative) T790M mutation [ Time Frame: At baseline and every 6 weeks until objective disease progression (approximately 11.5 months) ]
    PFS defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.
  • Overall survival (OS) [ Time Frame: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months) ]
    Defined as the time from randomization until death from any cause
  • Patient Reported Outcome by Therapy Satisfaction (CTSQ-16 Questionnaire) [ Time Frame: Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months) ]
    Measured by the Cancer Therapy Satisfaction Questionnaire 16 items (CTSQ-16). The questionnaire assesses the satisfaction with and preference for chemo, hormonal, and biological therapies in either oral (pill) and/or IV form.
  • Plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550; and ratio of metabolite to AZD9291 [ Time Frame: Blood samples will be collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months) ]
    The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550.
  • Patients reported disease-related symptoms and HRQoL by EORTC QLQ-C30 [ Time Frame: Questionnaires completed at baseline and every 6 weeks until the time of second progression (approximately 20 months) ]
    Questionnaire consisting of 30 items measuring subjects general cancer symptoms and functioning.
  • Duration of Response (DoR) [ Time Frame: At baseline and every 6 weeks until objective disease progression (approximately 11.5 months) ]
    Defined as the time from the date of first documented response (i.e., subsequently confirmed) until the date of documented progression or death in the absence of disease progression.
  • Disease Control Rate (DCR) [ Time Frame: At baseline and every 6 weeks until objective disease progression (approximately 11.5 months) ]
    Defined as the percentage of patients who have a best overall response of CR or PR or SD (Stable disease).
  • Depth of Response [ Time Frame: At baseline and every 6 weeks until objective disease progression (approximately 11.5 months) ]
    Defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline.
  • Patients reported disease-related symptoms and HRQoL by EORTC QLQ-LC13 [ Time Frame: Questionnaires completed at baseline, weekly and then every 3 weeks until the time of second progression (approximately 20 months) ]
    A complementary questionnaire measuring lung cancer symptoms and side effects from conventional chemo- and radiotherapy.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: November 18, 2014)
Incidence of Adverse Events (AEs) [ Time Frame: Adverse events will be collected from baseline until 28 days after the last dose of AZD9291/SoC EGFR-TKI (expected average 13 months) ]
AEs graded by CTCAE version 4.0
 
Descriptive Information
Brief Title  ICMJE AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer
Official Title  ICMJE A Phase III, Double-blind, Randomised Study to Assess the Safety and Efficacy of AZD9291 Versus a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor as First Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non Small Cell Lung Cancer.
Brief Summary To assess the efficacy and safety of AZD9291 versus a standard of care epidermal growth factor receptor tyrosine kinase inhibitor in patients with locally advanced or Metastatic Non Small Cell Lung Cancer
Detailed Description This is a Phase III, double-blind, randomised study assessing the efficacy and safety of AZD9291 (80 mg orally, once daily) versus a standard of care (SoC) Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) (either gefitinib [250 mg orally, once daily] or erlotinib [150 mg orally, once daily]) in patients with locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is known to be EGFR sensitising mutation (EGFRm) positive, treatment-naïve and eligible for first-line treatment with an EGFR-TKI.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer
Intervention  ICMJE
  • Drug: AZD9291 80 mg/40 mg + placebo

    The initial dose of AZD9291 80 mg once daily can be reduced to 40 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment.

    Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.

  • Drug: Placebo Erlotinib 150/100mg
    The initial dose of Placebo Erlotinib 150 mg once daily can be reduced to Placebo 100 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
    Other Name: Placebo Tarceva 150/100 mg
  • Drug: Placebo Gefitinib 250 mg
    The initial dose of Placebo Gefitinib 250 mg once daily cannot be reduced. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
    Other Name: Placebo Iressa 250 mg
  • Drug: Erlotinib 150/100 mg

    The initial dose of Erlotinib 150mg once daily can be reduced to 10 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment.

    Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.

    Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have the option to receive open-label AZD9291 (crossover to active AZD9291).

    Other Name: Tarceva 150/100 mg
  • Drug: Gefitinib 250 mg

    The initial dose of Gefitinib 250mg once daily cannot be reduced. A cycle of treatment is defined as 21 days of once daily treatment.

    Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.

    Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have the option to receive open-label AZD9291 (crossover to active AZD9291).

    Other Name: Iressa 250mg
  • Drug: Placebo AZD9291 80 mg/ 40 mg
    The initial dose of Placebo AZD9291 80 mg once daily can be reduced to Placebo AZD9291 40 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
Study Arms  ICMJE
  • Experimental: AZD9291+ placebo
    AZD9291 (80 mg or 40 mg orally, once daily) plus placebo Erlotinib (150mg or 100mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily), in accordance with the randomization schedule.
    Interventions:
    • Drug: AZD9291 80 mg/40 mg + placebo
    • Drug: Placebo Erlotinib 150/100mg
    • Drug: Placebo Gefitinib 250 mg
  • Active Comparator: Standard of Care + placebo AZD9291

    Erlotinib (150 mg or 100 mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily) plus placebo AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomisation schedule.

    Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have the option to receive open-label AZD9291 (crossover to active AZD9291).

    Interventions:
    • Drug: Erlotinib 150/100 mg
    • Drug: Gefitinib 250 mg
    • Drug: Placebo AZD9291 80 mg/ 40 mg
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 29, 2017)
674
Original Estimated Enrollment  ICMJE
 (submitted: November 18, 2014)
650
Estimated Study Completion Date  ICMJE December 31, 2021
Actual Primary Completion Date June 19, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female, aged at least 18 years.
  2. Pathologically confirmed adenocarcinoma of the lung.
  3. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy.
  4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R).
  5. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status.
  6. Patients must be treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with gefitinib or erlotinib as selected by the participating centre. Prior adjuvant and neo-adjuvant therapy is permitted(chemotherapy, radiotherapy, investigational agents).
  7. Provision of informed consent prior to any study specific procedures, sampling, and analysis.
  8. World Health Organization Performance Status of 0 to 1 with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks

Exclusion Criteria:

  1. Treatment with any of the following:

    • Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC.
    • Prior treatment with an EGFR-TKI.
    • Major surgery within 4 weeks of the first dose of study drug.
    • Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
    • Patients currently receiving medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4.
    • Alternative anti-cancer treatment
    • Treatment with an investigational drug within five half-lives of the compound or any of its related material.
  2. Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of study drug.
  3. Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids.
  4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
  5. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9291.
  6. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTcF value.
    • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
    • Any patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
  7. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
  8. Involvement in the planning and/or conduct of the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Brazil,   Bulgaria,   Canada,   China,   Czechia,   France,   Germany,   Hungary,   Israel,   Italy,   Japan,   Korea, Republic of,   Malaysia,   Philippines,   Poland,   Portugal,   Romania,   Russian Federation,   Spain,   Sweden,   Switzerland,   Taiwan,   Thailand,   Turkey,   Ukraine,   United Kingdom,   United States,   Vietnam
Removed Location Countries Czech Republic,   Saudi Arabia
 
Administrative Information
NCT Number  ICMJE NCT02296125
Other Study ID Numbers  ICMJE D5160C00007
2014-002694-11 ( EudraCT Number )
U1111-1160-2242 ( Other Grant/Funding Number: 112455 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Parexel
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP