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    Summary
    EudraCT Number:2018-001061-16
    Sponsor's Protocol Code Number:D5160C00048
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-04-14
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2018-001061-16
    A.3Full title of the trial
    A Phase III, randomized, double-blind, placebo-controlled, multicenter, international study of Osimertinib as maintenance therapy in patients with locally advanced, unresectable EGFR mutation-positive Non-Small Cell Lung Cancer (Stage III) whose disease has not progressed following definitive platinum-based chemoradiation therapy (LAURA).
    III. fázisú, randomizált, kettős vak, placebokontrollos, multicentrikus, nemzetközi vizsgálat a fenntartó kezelésként alkalmazott oszimertinib értékelésére olyan, lokálisan előrehaladott, nem operálható, EGFR-mutációra pozitív (III. stádiumú) nem kissejtes tüdőrákos betegeknél, akiknek betegsége a definitív platinaalapú kemoradiáció után nem progrediált (LAURA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A global study to assess the effects of osimertinib following chemoradiation in patients with Stage III unresectable non-small cell lung cancer (LAURA).
    A.3.2Name or abbreviated title of the trial where available
    LAURA
    A.4.1Sponsor's protocol code numberD5160C00048
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03521154
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact pointClinical Trial Transparency
    B.5.3 Address:
    B.5.3.1Street AddressSödertälje
    B.5.3.2Town/ citySödertälje
    B.5.3.3Post code151 85
    B.5.3.4CountrySweden
    B.5.6E-mailClinicalTrialTransparency@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tagrisso
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAZD9291 80 mg film-coated tablet
    D.3.2Product code AZD9291
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOsimertinib mesylate
    D.3.9.1CAS number 1421373-66-1
    D.3.9.2Current sponsor codeAZD9291 mesylate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tagrisso
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAZD9291 40 mg film-coated tablet
    D.3.2Product code AZD9291
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOsimertinib mesylate
    D.3.9.1CAS number 1421373-66-1
    D.3.9.2Current sponsor codeAZD9291 mesylate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Histologically documented non-small cell lung cancer of predominantly non-squamous pathology who present with locally advanced, unresectable (Stage III) disease, whose tumor tissue has EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, either alone or in combination with other EGFR mutations, as detected by cobas® EGFR Mutation Test v2 (Roche Diagnostics) and whose disease has not progressed following definitive platinum-based chemoradiation.
    E.1.1.1Medical condition in easily understood language
    Stage III EGFR mutation-positive Non-Small Cell Lung Cancer that cannot be removed by surgery (unresectable) whose disease has not worsened (progressed) following chemoradiation treatment.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10029519
    E.1.2Term Non-small cell lung cancer stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of osimertinib treatment compared with placebo as measured by progression free survival (PFS).
    E.2.2Secondary objectives of the trial
    1. To assess the efficacy of osimertinib treatment compared with placebo by assessment of PFS in patients with:
    EGFR Ex19del or L858R mutation
    EGFRm+ Ex19del or
    L858R detectable in plasma-derived ctDNA
    2. To assess the efficacy of osimertinib versus placebo on CNS PFS
    3. To further assess the efficacy of osimertinib compared with placebo as measured by OS, ORR, DoR, DCR and tumor shrinkage, time to death or distant metastases ( TTDM) and Time to treatment discontinuation (TTD)
    4. To further assess the efficacy of osimertinib compared to placebo post progression (as measured by Second progression free survival on a subsequent treatment (PFS2), Time to first subsequent therapy (TFST) and Time to second subsequent therapy (TSST)
    5. To assess disease-related symptoms and health-related QoL in patients treated with osimertinib compared with placebo
    6. To assess the safety and tolerability profile of osimertinib compared with placebo
    7. To assess the PK of osimertinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female aged at least 18 years
    2. Patients with histologically documented NSCLC of predominantly non-squamous Pathology who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology)
    3. The tumor harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by cobas® EGFR Mutation Test v2 (Roche Diagnostics) in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing.
    4. Patients must have received either concurrent chemoradiation or sequential chemoradiation including at least 2 cycles of platinum based chemotherapy and a total dose of radiation of 60 Gy ±10% (54 to 66 Gy)
    5. Chemoradiation must be completed ≤6 weeks prior to randomization.
    6. Patients must not have had disease progression during or following definitive platinum-based, chemoradiation therapy
    7. World Health Organization (WHO) performance status of 0 or 1
    8. Life expectancy >12 weeks at Day 1
    9. Female patients who are not abstinent (in line with the preferred and usual lifestyle choice) must be using adequate contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-childbearing potential
    E.4Principal exclusion criteria
    1. Mixed small cell and non-small cell lung cancer histology

    2. History of interstitial lung disease (ILD) prior to chemoradiation

    3. Symptomatic pneumonitis following chemoradiation

    4. Any unresolved toxicity Common Terminology Criteria for Adverse Events (CTCAE) > Grade 2 from the prior chemoradiation therapy

    5. Any of the following cardiac criteria:
    • Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs
    • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG
    • Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes

    6. Inadequate bone marrow reserve or organ function

    7. History of other malignancies, except: adequately treated non-melanoma skin cancer or lentigo maligna , curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of disease for > 5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy.

    8. 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).

    9. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib

    10. Prior treatment with any prior chemotherapy, radiation therapy, immunotherapy or investigational agents for NSCLC outside of that received in the definitive setting for Stage III disease (chemotherapy and radiotherapy in SCRT and CCRT regimens is allowed for treatment of Stage III disease).

    11. Prior treatment with EGFR-TKI therapy

    12. Major surgery as defined by the investigator within 4 weeks of the first dose of study drug.

    13. Patients currently receiving (unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior to receiving the first dose of study drug).

    14. Contraindication to MRI, including but not limited to, claustrophobia, pace makers, metal implants, intracranial surgical clips and metal foreign bodies
    E.5 End points
    E.5.1Primary end point(s)
    PFS using BICR assessment according to RECIST v1.1

    Sensitivity analysis of PFS using Investigator assessment according to RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Q3 2022
    E.5.2Secondary end point(s)
    1. PFS in patients with EGFR Ex19del or L858R mutation and Patients with EGFRm+ Ex19del or L858R detectable in plasma-derived ctDNA using BICR assessment according to RECIST v1.1; Sensitivity analysis of PFS using Investigator assessment according to RECIST v1.1.
    2. Time to CNS PFS (time to the earliest of CNS progression or death) using BICR assessments according to RECIST v1.1; Cumulative incidence rate of CNS PFS by BICR at 12 and 24 months.
    3. OS, ORR, DoR, DCR and tumor shrinkage, TTDM using BICR assessments according to RECIST v1.1, Time to treatment discontinuation (TTD).
    4. Second progression free survival on a subsequent treatment (PFS2), Time to first subsequent therapy (TFST), Time to second subsequent therapy (TSST).
    5. Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 items (EORTC QLQ-C30): Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Lung Cancer 13 items (EORTC QLQ-LC13).
    6. Adverse Events (graded by CTCAE v5); Clinical chemistry, hematology and urinalysis; Vital signs (pulse and blood pressure), physical examination, weight; ECG parameters; Left ventricular ejection fraction; WHO Performance Status.
    7. Trough plasma concentrations of osimertinib, and its metabolite AZ5104 If conducted, PK Parameters (CLss/F, Css, min and Css, max, AUCss) may be derived using population PK analysis and reported separately to the CSR. Data from this study may form part of a pooled analysis with data from other studies.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Overall Survival: Q3 2022, and again at Q2 2026
    The rest of secondary endpoints: Q3, 2022
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Brazil
    China
    Hungary
    India
    Japan
    Korea, Republic of
    Malaysia
    Mexico
    Peru
    Russian Federation
    Spain
    Taiwan
    Thailand
    Turkey
    United States
    Vietnam
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the last expected visit/contact of the last patient undergoing the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 110
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    legally acceptable representative will provide consent on behalf of patient
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following discontinuation of study medication standard of care therapy as judged by the study doctor will be given. After study completion AstraZeneca will tell the study doctor which treatment those patients still receiving study medication are taking. Patients receiving osimertinib may continue to receive osimertinib at the discretion of the study doctor. Patients receiving placebo will discontinue placebo treatment and will be given standard of care therapy, as judged by the study doctor.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-02
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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