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AZD9291 First Time In Patients Ascending Dose Study (AURA)

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: NCT01802632
Recruitment Status : Completed
First Posted : March 1, 2013
Results First Posted : October 6, 2016
Last Update Posted : January 18, 2024
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE February 25, 2013
First Posted Date  ICMJE March 1, 2013
Results First Submitted Date  ICMJE April 29, 2016
Results First Posted Date  ICMJE October 6, 2016
Last Update Posted Date January 18, 2024
Actual Study Start Date  ICMJE March 4, 2013
Actual Primary Completion Date May 1, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2016)
  • Objective Response Rate (ORR) for Dose Expansion Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of 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 (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
  • Best Objective Response (BOR) for Dose Escalation Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of 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. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.
  • Objective Response Rate (ORR) for Extension Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of 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 (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Original Primary Outcome Measures  ICMJE
 (submitted: February 28, 2013)		 Safety and tolerability of AZD9291, as assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electocardiogram and opthalmic examinations [ Time Frame: Adverse events will be collected from baseline until 28 days after the last dose, expected average 6 months ]
Adverse events will be collected from consent until 28 days after the last dose. Physical examination will be conducted at screening, on the first dosing day, the first day of multiple dosing (for Part A dose escalation), then Day 1 of every 3-week cycle and at treatment discontinuation. In addition to these timepoints, ECG profile and vital signs will be assessed at the day after first dose, steady state (Day 8, and Day 9, cycle 1) and upon occurrence of any cardiac adverse event. Laboratory variables will be assessed at screening, on first dosing day, first day of multiple dosing, weekly for first cycle, Day 1 of every subsequent 3-week cycle and treatment discontinuation. Eye examination will be conducted at baseline and upon occurrence of any visual adverse event.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2016)
  • Duration of Response (DoR) for Dose Expansion Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of 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 was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).
  • Progression-Free Survival (PFS) for Dose Expansion Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of 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 first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 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.
  • Best Objective Response (BOR) for 80mg AZD9291 Extension Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of 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. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2013)
  • Plasma concentrations of AZD9291 and 2 active metabolites (AZ5104 and AZ7550) and pharmacokinetic parameters following single dose (Cmax, tmax, AUC, terminal rate constant, clearance, half life, volume of distribution and mean resistance time) [ Time Frame: Blood samples will be collected from each subject at pre-specified times after the first dose of the study (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours), On Day 8 (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours) ]
  • Plasma concentrations of AZD9291 and 2 active metabolites (AZ5104 and AZ7550) and pharmacokinetic parameters following single dose (Cmax, tmax, AUC, terminal rate constant, clearance, half life, volume of distribution and mean resistance time) [ Time Frame: Blood samples will be collected on day 9 (24 hours) of dosing in Cycle 1. An additional two samples will be taken on the day of the optional tumour biopsy (pre-dose and at the time of the tumour biopsy) for each analyte ]
  • Plasma concentrations of AZD9291 and 2 active metabolites (AZ5104 and AZ7550) and pharmacokinetic parameters following multiple doses (steady state Cmax, tmax, Cmin AUC, clearance, accumulation ratio and time dependency) [ Time Frame: Blood samples will be collected from each subject at pre-specified times after the first dose of the study (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours), On Day 8 (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours) ]
  • Plasma concentrations of AZD9291 and 2 active metabolites (AZ5104 and AZ7550) and pharmacokinetic parameters following multiple doses (steady state Cmax, tmax, Cmin AUC, clearance, accumulation ratio and time dependency) [ Time Frame: Blood samples will be collected on day 9 (24 hours) of dosing in Cycle 1. An additional two samples will be taken on the day of the optional tumour biopsy (pre-dose and at the time of the tumour biopsy) for each analyte ]
  • Pharmacodynamic markers to assess correlations with disease activity, effects of study drug and clinical outcomes. [ Time Frame: At baseline, Day 15, treatment discontinuation, expected average 6 months ]
    Biopsy samples will be collected at screening (optional for Part A dose escalation), Day 15 (optional for Part A dose escalation and expansion) and treatment discontinuation at a selected clinical dose.
  • Pharmacodynamic markers to assess correlations with disease activity, effects of study drug and clinical outcomes. [ Time Frame: At baseline, Week 6 post cycle 1, Week 12 post cycle 1 and treatment discontinuation, expected average 6 months ]
    Blood samples for investigation of blood-borne biomarkers will be taken to provide one sample of plasma and one sample of serum at screening, Week 6 post cycle 1 (optional), Week 12 post cycle 1 (optional) and treatment discontinuation.
  • Pharmacodynamic markers to assess correlations with disease activity, effects of study drug and clinical outcomes. [ Time Frame: At baseline, Week 6 post cycle, Week 12 post cycle, treatment discontinuation, expected average 6 months ]
    Plasma samples for extraction and analysis of circulating free tumour DNA (cfDNA) will be taken at screening, Week 6 post cycle 1 (optional), Week 12 post cycle 1 (optional) and treatment discontinuation
  • Tumour response as assessed by RECIST 1.1 [ Time Frame: At beaseline and every 6 weeks thereafter until disease progression or withdrawal from study treatment, expected average 6 months ]
    Tumour assessment at baseline (no more than 28 days before the start of study treatment) and every 6 weeks thereafter until disease progression as defined by RECIST 1.1 or withdrawal from study treatment and study.
  • Pharmacodynamic markers in EGFRm+ T790M+ tumours at selective endpoints [ Time Frame: At baseline, Day 15 and treatment discontinuation, expected average 6 months ]
    At screening (optional for Part A dose escalation), Day 15 (optional for Part A dose escalation and expansion) and treatment discontinuation (optional) at a selected clinical dose.
  • Patient reported outcomes: EORTC QLQ C-30 and QLQ-LC13 [ Time Frame: Part B only- at the at baseline, on Day 1 of each cycle,from cycle 2 onwards at treatment discontinuation and at the safety follow-up visit 28 days after their last dose of study drug, expected average 6 months ]
  • Pharmacogenetics [ Time Frame: At baseline (prior prior to the first administration of AZD9291) until the las study visit, within the expected average of 6 months ]
    If for any reason the sample is not drawn prior to dosing it may be taken at any visit until the last study visit. If a patient agrees to participate in the host pharmacogenetics research component of the study a blood sample will be collected during the study.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE AZD9291 First Time In Patients Ascending Dose Study
Official Title  ICMJE Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent
Brief Summary This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.
Detailed Description A Phase I/II, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Ascending Doses of AZD9291 in Patients with Advanced Non Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent (AURA)
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Non Small Cell Lung Cancer
  • Advanced (Inoperable) Non Small Cell Lung Cancer
Intervention  ICMJE Drug: AZD9291
Starting dose 20 mg, administered once daily. If tolerated subsequent cohorts will test increasing doses of AZD9291, until a maximum tolerated dose or maximum feasible dose is defined
Study Arms  ICMJE Experimental: Daily dose of AZD9291
Daily oral dose of AZD9291
Intervention: Drug: AZD9291
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 Completed
Actual Enrollment  ICMJE
 (submitted: November 8, 2017)		 603
Original Estimated Enrollment  ICMJE
 (submitted: February 28, 2013)		 158
Actual Study Completion Date  ICMJE December 13, 2023
Actual Primary Completion Date May 1, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
  • Aged at least 18 years. Patients from Japan aged at least 20 years.
  • Histological or cytological confirmation diagnosis of Non Small Cell Lung Cancer (NSCLC).
  • Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. gefitinib or erlotinib (with the exception of 1st line expansion cohort). In addition other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.

  • Patients (with the exception of 1st line expansion cohort) must fulfil one of the following:

    • Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR
    • Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI.
  • Previous treatment with a single-agent EGFR TKI (e.g. gefitinib or erlotinib).
  • Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing or evidence of non-child bearing potential.
  • Male patients should be willing to use barrier contraception.
  • For 1st Line expansion cohort ONLY, confirmation that the tumour is EGFRm+ve and have had no prior therapy for their advanced disease (for 1st line patients biopsy will be at time of diagnosis of advanced disease).
  • For dose expansion and extension cohorts, patients must also have confirmation of tumour T790M mutation status (confirmed positive or negative) from a biopsy sample taken after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy).

Prior to entry a result from the central analysis of the patient's T790M mutation status must be obtained.

- World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.

Exclusion Criteria:

  • Treatment with an EGFR TKI (erlotinib or gefitinib) within 8 days (approximately 5x half-life) of the first dose of study treatment.
  • Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment.
  • AZD9291 in the present study (ie, dosing with AZD9291 previously initiated in this study).
  • Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection.
  • Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
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,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Spain,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01802632
Other Study ID Numbers  ICMJE D5160C00001
2012-004628-39 ( EudraCT Number )
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.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
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
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Yuri Rukazenkov AstraZeneca
PRS Account AstraZeneca
Verification Date January 2024

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