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AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3)

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ClinicalTrials.gov Identifier: NCT02151981
Recruitment Status : Active, not recruiting
First Posted : June 2, 2014
Results First Posted : July 21, 2017
Last Update Posted : May 3, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE May 15, 2014
First Posted Date  ICMJE June 2, 2014
Results First Submitted Date  ICMJE April 12, 2017
Results First Posted Date  ICMJE July 21, 2017
Last Update Posted Date May 3, 2021
Actual Study Start Date  ICMJE August 4, 2014
Actual Primary Completion Date April 15, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 19, 2021)
Progression Free Survival (PFS) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (by investigator assessment) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
Original Primary Outcome Measures  ICMJE
 (submitted: May 30, 2014)
Progression-Free Survival (PFS) [ Time Frame: At baseline and every 6 weeks from randomization until progression (up to approximately 12 months) ]
To assess the efficacy of AZD9291 compared with platinum-based doublet chemotherapy by assessment of Progression Free Survival using investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 19, 2021)
  • Objective Response Rate (ORR) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy.
  • Duration of Response (DoR) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.
  • Disease Control Rate (DCR) by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD at >=6 weeks, prior to any progressive disease (PD).
  • Tumour Shrinkage by Investigator Assessment [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). ]
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Tumour size was calculated as the sum of the longest diameters (SLD) of the Target Lesions. Tumour shrinkage is percentage change in tumour size from baseline using RECIST v1.1 tumour response.
  • Secondary: Overall Survival (OS) [ Time Frame: From date of randomization until time of final OS analysis, a median follow-up of 43 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2014)
  • Objective Response Rate (ORR) [ Time Frame: At baseline and every 6 weeks from randomization until progression (up to approximately 12 months) ]
    To assess the efficacy of AZD9291 compared with platinum-based doublet chemotherapy by assessment of Objective Response Rate (ORR) using investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
  • Duration of Response (DoR) [ Time Frame: At baseline and every 6 weeks from randomization until progression (up to approximately 12 months) ]
    To assess the efficacy of AZD9291 compared with platinum-based doublet chemotherapy by assessment of Duration of Response (DoR) using investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
  • Disease Control Rate (DCR) [ Time Frame: At baseline and every 6 weeks from randomization until progression (up to approximately 12 months) ]
    To assess the efficacy of AZD9291 compared with platinum-based doublet chemotherapy by assessment of Disease Control Rate (DCR) using investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
  • Overall Survival (OS) [ Time Frame: From randomization to end of study (Last subject last visit (LSLV)) (up to approximately 24 months) ]
    To assess the efficacy of AZD9291 compared with platinum-based doublet chemotherapy by assessment of Overall Survival (OS).
  • Tumour shrinkage according to RECIST 1.1 [ Time Frame: At baseline and every 6 weeks from randomization until progression (up to approximately 12 months) ]
    To assess the efficacy of AZD9291 compared with platinum-based doublet chemotherapy by assessment of Tumour shrinkage using investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
  • Patient Reported Outcomes by EORTC QLQ-C30 questionnaire [ Time Frame: Questionnaires completed at baseline and every 6 weeks from randomization until end of study (up to approximately 24 months) ]
    To assess the impact of AZD9291 compared with platinum-based doublet chemotherapy on patients' disease-related symptoms and health related quality of life (HRQoL)
  • Patient Reported Outcomes by EORTC QLQ-LC13 questionnaire [ Time Frame: Questionnaires completed at baseline and every 3 weeks from randomization until end of study (up to approximately 24 months) ]
    To assess the impact of AZD9291 compared with platinum-based doublet chemotherapy on patients' disease-related symptoms and health related quality of life (HRQoL)
  • Patient Reported Outcomes by EQ-5D-5L questionnaire [ Time Frame: Questionnaires completed at baseline and every 6 weeks from randomization until end of study (up to approximately 24 months) ]
    To assess the impact of AZD9291 compared with platinum-based doublet chemotherapy on patients' disease-related symptoms and health related quality of life (HRQoL)
Current Other Pre-specified Outcome Measures
 (submitted: January 19, 2021)
  • Time to First Subsequent Therapy (TFST) [ Time Frame: From date of randomisation until time of final OS analysis, a median follow-up of 43 months ]
    Time from randomisation to first subsequent anti-cancer therapy (FST) following randomised treatment discontinuation, or death if no FST administered. Any patient not known to have died nor received any subsequent anti-cancer therapy (ST) was censored at the last time known not to have received ST, ie, the last follow-up visit this was confirmed.
  • Time to Second Subsequent Therapy (TSST) [ Time Frame: From date of randomisation until time of final OS analysis, a median follow-up of 43 months ]
    Time from randomisation to second subsequent anti-cancer therapy (SST) following randomised treatment discontinuation, or death if no SST administered. Any patient not known to have died nor received any SST was censored at the last time known not to have received SST, ie, the last follow-up visit this was confirmed.
Original Other Pre-specified Outcome Measures
 (submitted: May 30, 2014)
Safety and Tolerability as assessed by number and severity of adverse events, clinical chemistry, haematology, urinalysis, vital signs, physical examination, wieght, ECG and WHO Performance status [ Time Frame: Adverse events will be collected from baseline until 28 days after the last dose, expected average 13 months ]
To assess the safety and tolerability profile of AZD9291 compared with platinum-based doublet chemotherapy.
 
Descriptive Information
Brief Title  ICMJE AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Official Title  ICMJE A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).
Brief Summary A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene
Detailed Description This is a phase III, open label, randomized study assessing Osimertinib (80 mg, orally, once daily) versus platinum-based doublet chemotherapy (standard of care) in subjects with confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent and whose tumours harbour a T790M mutation within the EGFR Gene. Subjects must be chemotherapy naive and must agree to provide a biopsy for central confirmation of T790 mutation status following confirmed disease progression on their first line EGFR-TKI treatment (e.g. erlotinib, gefitinib or afatinib). Suitable subjects will then be randomized to receive either Osimertinib (80mg orally, once daily) or platinum-based doublet chemotherapy (pemetrexed 500 mg/m2 + carboplatin area under the plasma concentration-time curve AUC 5 or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2) on Day 1 of every 21-day cycle in a 2:1 (Osimertinib: platinum-based doublet chemotherapy) ratio. Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator. The primary objective of the study is to assess the efficacy of Osimertinib compared with platinum-based doublet chemotherapy by assessment of Progression Free Survival (PFS), using investigator assessments according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1), as well as asensitivity analysis of Progression Free Survival using Blinded Independent Central Review (BICR).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Anticancer Treatment
Intervention  ICMJE
  • Drug: Chemotherapy
    Randomization to either Osimertinib or platinum-based doublet-chemotherapy on Day 1 of every 21d cycle in a 2:1 (Osimertinib:platinum-based doublet-chemotherapy) ratio
    Other Names:
    • Osimertinib
    • Platinum-based Doublet-Chemotherapy
  • Drug: Cross-over to Osimertinib

    Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator.

    Subjects who stop platinum-based doublet chemotherapy for reasons other than objective disease progression according to RECIST 1.1 will not be eligible to cross-over to Osimertinib.

Study Arms  ICMJE
  • Experimental: Osimertinib
    Osimertinib 80 mg, orally, once daily
    Interventions:
    • Drug: Chemotherapy
    • Drug: Cross-over to Osimertinib
  • Active Comparator: Platinum-based doublet chemotherapy
    pemetrexed 500mg/m2 + carboplatin AUC5 or pemetrexed 500mg/m2 + cisplatin 75mg/m2
    Intervention: Drug: Chemotherapy
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 23, 2017)
419
Original Estimated Enrollment  ICMJE
 (submitted: May 30, 2014)
1540
Estimated Study Completion Date  ICMJE December 31, 2021
Actual Primary Completion Date April 15, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects with histologically or cytologically documented NSCLC.
  • Locally advanced or metastatic NSCLC
  • Radiological documentation of disease progression following 1st line EGFR TKI Treatment without any further treatment
  • Eligible to receive treatment with the selected doublet-chemotherapy
  • Central confirmation of T790M+ mutation status
  • World Health Organization (WHO) performance status 0-1
  • At least one lesion, not previously irradiated.

Exclusion Criteria:

  • • Prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months prior of starting 1st EGFR TKI treatment
  • Treatment with more than one prior line of treatment for advanced NSCLC
  • Treatment with an approved EGFR-TKI (e.g.,erlotinib, gefitinib, afatinib) within 8 days or approximately 5x half-life of the first dose of study treatment
  • Any investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment
  • Previous treatment with Osimertinib, or a 3rd generation EGFR TKI

For subjects who cross-over to Osimertinib:

  • Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review.
  • At least 14 days since last dose of platinum-based doublet chemotherapy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 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,   Canada,   China,   France,   Germany,   Hong Kong,   Hungary,   Italy,   Japan,   Korea, Republic of,   Mexico,   Netherlands,   Russian Federation,   Spain,   Sweden,   Taiwan,   United Kingdom,   United States
Removed Location Countries Norway
 
Administrative Information
NCT Number  ICMJE NCT02151981
Other Study ID Numbers  ICMJE D5160C00003
Has Data Monitoring Committee No
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 Not Provided
Investigators  ICMJE
Principal Investigator: Yilong Wu, MD Guangdong General Hospital, Guangdong, 510030, China
Principal Investigator: Vassiliki A Papadimitrakopoulou, MD The University of Texas/M.D. Anderson Cancer Center, Houston, Tx, USA
PRS Account AstraZeneca
Verification Date April 2021

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