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    Summary
    EudraCT Number:2013-003156-21
    Sponsor's Protocol Code Number:ETOP_5-12/EORTC_08111
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-01
    Trial results View 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 ConcernedAustria - BASG
    A.2EudraCT number2013-003156-21
    A.3Full title of the trial
    A randomised, open-label phase III trial evaluating the addition of
    denosumab to standard first-line anticancer treatment in advanced
    NSCLC
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to investigate how well the standard treatment (chemotherapy) in combination with denosumab works compared with the standard treatment alone in patients with advanced NSCLC.
    A.3.2Name or abbreviated title of the trial where available
    SPLENDOUR: Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy
    A.4.1Sponsor's protocol code numberETOP_5-12/EORTC_08111
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02129699
    A.5.4Other Identifiers
    Name:Amgen numberNumber:20080166
    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 SponsorETOP (European Thoracic Oncology Platform)
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAmgen Ltd., Cambridge
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportEuropean Organization for Research and Treatment of Cancer EORTC, Brussels
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationETOP
    B.5.2Functional name of contact pointETOP Coordinating Office
    B.5.3 Address:
    B.5.3.1Street AddressEffingerstrasse 40
    B.5.3.2Town/ cityBern
    B.5.3.3Post code3008
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41 31511 94 00
    B.5.5Fax number+41 31 511 94 01
    B.5.6E-mailSPLENDOUR@etop-eu.org
    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 XGEVA
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V., Breda, The Netherlands
    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 nameDenosumab
    D.3.2Product code AMG 162
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDENOSUMAB
    D.3.9.1CAS number 615258-40-7
    D.3.9.3Other descriptive nameDENOSUMAB
    D.3.9.4EV Substance CodeSUB29173
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number70
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    advanced NSCLC

    E.1.1.1Medical condition in easily understood language
    Lung cancer called "non small cell lung cancer (NSCLC)” that has spread to other parts of your body (metastatic)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025055
    E.1.2Term Lung cancer non-small cell stage IV
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate whether the addition of denosumab to standard firstline chemotherapy in advanced NSCLC improves overall survival.
    E.2.2Secondary objectives of the trial
    - to compare progression free survival (PFS) and response rate (RR, based on RECIST 1.1) in patients treated with standard first-line chemotherapy with or without denosumab
    - to assess the tolerability of the two regimens
    - to evaluate potential predictive biomarkers for denosumab activity
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Histologically or cytologically confirmed advanced stage IV non-small cell lung carcinoma (NSCLC), according to 7th TNM classification
    - Age ≥ 18 years
    - ECOG performance status 0-2
    - Measurable or evaluable disease (according to RECIST 1.1 criteria) assessed within 28 days from randomization
    - Availability of tumour tissue (as assessed by the local pathologist) for translational research:
    - preferred: FFPE block from primary tumour or metastasis,
    - alternatively: cell block
    - if no block available: 10 freshly cut unstained slides.
    - Adequate haematological function: neutrophils ≥ 1.5 ×109/L, platelets ≥ 100×109/L, and hemoglobin ≥ 9 g/dL
    - Adequate liver function:
    - ALT ≤ 3 × ULN ( ≤ 5 × ULN if liver metastasis are present)
    - Total bilirubin < 2 x ULN
    - Adequate renal function: calculated renal creatinine clearance (CrCl) ≥ 30 mL/min (according to the formula of Cockroft-Gault; please refer to the protocol section 6.1.8 for this formula)
    - Life expectancy of at least 3 months
    - Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before enrolment. Pregnancy test has to be repeated within 14 days before treatment start.
    - All sexually active men and women of childbearing potential must use an effective contraceptive method during the study treatment and for a period of at least 6 months following the last administration of trial treatment
    - Written Informed Consent must be signed and dated by the patient and the investigator prior to any trial-related intervention for
    a) Trial treatment
    b) Submission of biomaterial for central testing
    E.4Principal exclusion criteria
    - Patients with presence of documented sensitizing EGFR activating mutation or ALK rearrangements (screening following local standards is optional, but strongly encouraged in non-squamous histology)

    Note: EGFR and ALK testing is not mandatory but recommended to be done. If test has been ordered, investigator is encouraged to wait for the result before enrolment. Once the patient is enrolled, if an EGFR mutation/ALK alteration is confirmed, no EGFR or ALK TKi treatment respectively should be started until PD to first-line platinum-based chemotherapy.

    - Patients with documented brain metastases (systematic screening of patients not mandatory; however, if the patient is symptomatic, brain metastases screening is recommended)
    - Prior chemotherapy or molecular targeted therapy for metastatic disease.
    Exceptions:
    - Neoadjuvant or adjuvant chemotherapy or radio-chemotherapy are allowed if terminated more than 6 months before registration.
    - Previous radical radiotherapy without systemic treatment is allowed.
    - One previous line of systemic immunotherapy by checkpoint inhibitors is allowed and needs to be documented

    - Concomitant treatment with immune checkpoint inhibitors
    - Any investigational agent(s) within 30 days prior to randomisation
    - Concurrent bisphosphonate administration
    - Oral/ dental conditions (by visual inspection):
    - Prior history or current evidence of osteomyelitis / osteonecrosis of the jaw
    - Active dental or jaw condition which requires oral surgery
    - Planned invasive dental procedure for the course of the trial
    - Non-healed dental or oral surgery
    - Evidence of any medical condition which would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease, active infection, uncontrolled diabetes mellitus; uncontrolled arterial hypertension ≥ 160/100 mmHg, history of myocardial infarction in the last 3 months)
    - Documented active infection with Hepatitis B virus or Hepatitis C virus, known infection with human immunodeficiency virus (HIV)
    - Known hypersensitivity to any of the components of the treatment
    - Severe, uncorrected hypocalcaemia or hypercalcaemia
    - hypercalcaemia: total calcium >3.1 mmol/l or corrected calcium (with albumin level) >3 mmol/l
    - hypocalcaemia: total calcium <2 mmol/l or corrected calcium (with albumin level) < 1.9 mmol/l
    - Legal incapacity or limited legal capacity
    - Medical or psychological condition including uncontrolled arterial hypertension (>160/110) despite adequate medication which in the opinion of the investigator would not permit the patient to complete the trial or sign meaningful informed consent
    - Women who are pregnant or breastfeeding
    - Any concurrent malignancy other than adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma, or prostate cancer Gleason score < 6. (Patients with a previous malignancy but without evidence of disease for ≥ 2 years will be allowed to enter the trial)
    - Any previous exposure to denosumab, with the exception of a maximum of 2 previous doses of denosumab (Prolia®) more than 6 month before enrolment for osteoporosis treatment/prevention
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time from the date of randomisation until death from any cause.
    E.5.2Secondary end point(s)
    - Progression-free survival (PFS) based on RECIST 1.1
    - Response based on RECIST 1.1
    - Toxicity profile of denosumab
    - Evaluation of potential predictive biomarkers for denosumab activity
    E.5.2.1Timepoint(s) of evaluation of this end point
    - PFS: time from date of randomisation until objective
    disease progression or death, whichever occurs first

    - Response of the tumour is defined according to RECIST 1.1 criteria

    - Toxicity profile of denosumab: Adverse events classified according to NCI CTCAE V4

    - Evaluation of potential predictive biomarkers for denosumab activity: collection of tumor at randomisation and collection of serum samples at baseline, at day 1 of cycles 3 and at first progression
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Stratifications: Bone mets, Region, ECOG PS, Histology
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard chemotherapy
    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 EEA65
    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
    Austria
    Belgium
    France
    Germany
    Ireland
    Israel
    Italy
    Poland
    Slovenia
    Spain
    Switzerland
    United Kingdom
    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
    End of trial occurs when all of the following criteria have been satisfied:
    - All patients have been off protocol-specified treatment for at least thirty days, or a maximum of 2 years after the final analysis, estimated to be done at month 56 after inclusion of the first patient.
    - Trial is mature for the analysis of the primary endpoint (observation of 847 deaths)
    - Database has been fully cleaned and frozen for the final analysis
    Note: follow-up will be life-long for all patients.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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: 550
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 450
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state53
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 850
    F.4.2.2In the whole clinical trial 1000
    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)
    Beyond primary analysis, all subjects randomised to ARM B and still benefitting from denosumab will be offered denosumab at a dose of 120 mg s.c. every 3 to 4 weeks until patient or physician elect to discontinue denosumab for any reason, and for a maximum of 2 years after the required number of 847 deaths for the final analysis has been reached.
    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 Decision2014-11-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-02-29
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