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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02296125
First received: October 22, 2014
Last updated: March 20, 2017
Last verified: March 2017
  Purpose
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

Condition Intervention Phase
Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer Drug: AZD9291 80 mg/40 mg + placebo Drug: Placebo Erlotinib 150/100mg Drug: Placebo Gefitinib 250 mg Drug: Erlotinib 150/100 mg Drug: Gefitinib 250 mg Drug: Placebo AZD9291 80 mg/ 40 mg Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until 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.


Secondary Outcome Measures:
  • 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 (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 for the first 18 months and then every 12 weeks relative to randomisation until 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 for the first 18 months and then every 12 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 for the first 18 months and then every 12 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 for the first 18 months and then every 12 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.


Other Outcome Measures:
  • 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


Estimated Enrollment: 530
Actual Study Start Date: December 3, 2014
Estimated Study Completion Date: October 15, 2018
Estimated Primary Completion Date: May 22, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AZD9291 + placebo Standard of Care
AZD9291 (80 mg or 40 mg orally, once daily) plus placebo Erlotinib (150 mg or 100 mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily), in accordance with the randomisation schedule.
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
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).

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.

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.
  Eligibility

Ages Eligible for Study:   18 Years to 100 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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).

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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02296125

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Sponsors and Collaborators
AstraZeneca
Parexel
  More Information

Additional Information:
Cancer  This link exits the ClinicalTrials.gov site

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02296125     History of Changes
Other Study ID Numbers: D5160C00007
2014-002694-11 ( EudraCT Number )
U1111-1160-2242 ( Other Grant/Funding Number: 112455 )
Study First Received: October 22, 2014
Last Updated: March 20, 2017

Keywords provided by AstraZeneca:
Advanced Non-Small Cell Lung Cancer; EGFRm+; AZD9291; TKI; Phase III

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Gefitinib
Osimertinib
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 22, 2017