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    Clinical Trial Results:
    EVINEC: Safety and Tolerability of Everolimus as second-line treatment in poorly differentiated neuroendocrine carcinoma / neuroendocrine carcinoma G3 according to WHO 2010 and neuroendocrine tumor G3 - an investigtor initiated Phase II study.

    Summary
    EudraCT number
    2012-004550-28
    Trial protocol
    DE  
    Global end of trial date
    04 May 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Nov 2022
    First version publication date
    01 Nov 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AIO-NET-0112
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02113800
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Novartis-Nr: : CRAD001KDE55T
    Sponsors
    Sponsor organisation name
    AIO-Studien-gGmbH
    Sponsor organisation address
    Kuno-Fischer-Str. 8, Berlin, Germany, 14057
    Public contact
    AIO-Studien-gGmbH, AIO-Studien-gGmbH, +49 30814534431, info@aio-studien-ggmbh.de
    Scientific contact
    AIO-Studien-gGmbH, AIO-Studien-gGmbH, +49 30814534431, info@aio-studien-ggmbh.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate tolerability and safety of everolimus in second-line treatment of poorly differentiated neuroendocrine carcinoma / neuroendocrine carcinoma G3 according to WHO 2010 and neuroendocrine tumors G3. Safety and tolerability of Everolimus can be inferred if type, frequency and seriousness of observed AEs is comparable to those determined in previous Everolimus trials in NET (Radiant-1,2 and 3).
    Protection of trial subjects
    This study was planned, analyzed and conducted according to the study protocol and in accordance with the International Conference on Harmonization (ICH) ‚Guideline for Good Clinical Practice E6(R1)‘, CPMP/ICH/135/95, based on the principles of the Declaration of Helsinki (1964) and its October 1996 amendment (Somerset West, South Africa). The study was duly conducted in compliance with the German Arzneimittelgesetz (AMG; German Drug Law), and the corresponding Directive 2001/20/EC. Subjects were fully informed regarding all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    28
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    42 patients were screened for study participation, 39 of whon were found eligible.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Everolimus 10 mg/d
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A dose of 10 mg was to be administered orally once daily at the same time every day, consistently either with or without food, swallowed whole with a glass of water.

    Number of subjects in period 1
    Everolimus 10 mg/d
    Started
    39
    Completed
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    -

    Reporting group values
    Treatment Total
    Number of subjects
    39 39
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    57.0 (33 to 77) -
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    23 23

    End points

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    End points reporting groups
    Reporting group title
    Everolimus 10 mg/d
    Reporting group description
    -

    Subject analysis set title
    Per protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Of 39 treated patients, 9 were excluded from the per protocol analysis set. Reasons were the retroactive histological tumor diagnosis as non-NEN by central pathology (3 patients), and major protocol violations (6 patients).

    Primary: Overall survival

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    End point title
    Overall survival [1]
    End point description
    Primary objective of this study was limted to safety and tolerability. Hence, no primary efficacy endpoint was definded. One of the secondary endpoints, overall survival (OS), is given instead. The median OS was 12.0 months for all NEN G3 patients together (95%-CI 7.0-23-9). A lower OS occurred in NEC G3 patients with 5.6 months (95%-CI 1.3-20.1) and for MANEC patients with 7.0 months (95%-CI 1.0-11.1) compared to NET G3 patients with 23.9 months (95%-CI 12.0-NC). OS rate at 12 months in the PP Population was 49.0% (95%-CI 30.2%-65.4%). OS at 12 months was lowest in MANEC patients with 14.3% (95%-CI 0.7%-46.5%) and in NEC G3 patients with 30.0% (95%-CI 7.1%-57.8%) compared to NET G3 patients with 83.9% (95%-CI 49.4%-95.7%).
    End point type
    Primary
    End point timeframe
    Overall survival (OS) was defined as the time from the date of first treatment to the date of death. Patients for whom not date of death was recorded were censored at the date of last contact.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since the study had no primary efficacy endpoint, OS is given for this data field instead. No in-depth statistical analysis was perfomed.
    End point values
    Per protocol
    Number of subjects analysed
    30
    Units: Months
        median (confidence interval 95%)
    12.0 (7.0 to 23.9)
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    Progression-free survival
    End point description
    The median progressive free survival (PFS) was 2.2 months for all NEN G3 patients together (95%-CI 1.8-4.8). PFS was shorter in NEC G3 with a median of 1.8 months (95% CI 0.9-2.0) and in MANEC with 2.2 months (95% CI 0.7-4.1) as compared to NET G3 patients with 5.2 months (95% CI 1.6-7.3). PFS rate at 6 months was lowest in MANEC patients with 14.3% (95%-CI 0.7%-46.5%) and NEC G3 patients with 20.0% (95%-CI 3.1%-47.5%) compared to NET G3 patients with 41.7% (95%-CI 15.2%-66.5%).
    End point type
    Secondary
    End point timeframe
    Progression-Free Survival (PFS) was defined as the time from first treatment to PD or death. Patients who had no PD and did not die were censored at the time of the last tumor assessment.
    End point values
    Everolimus 10 mg/d
    Number of subjects analysed
    30
    Units: Months
        median (confidence interval 95%)
    2.2 (1.8 to 4.8)
    No statistical analyses for this end point

    Secondary: Best overall response, ORR and DCR

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    End point title
    Best overall response, ORR and DCR
    End point description
    Partial remission was observed for one patient, resulting in an Objective Response Rate (ORR) of 3.3%, [95%CI 0.6%-16.7%]. Disease control was documented for 14 NEN G3 patients, resulting in a disease control rate (DCR) of 46.7% [95%CI 30.2%-63.9%].
    End point type
    Secondary
    End point timeframe
    Best response among all available response assessments
    End point values
    Everolimus 10 mg/d
    Number of subjects analysed
    30
    Units: CR, PR, SD and PD
        Complete Remission (CR)
    0
        Partial Remission (PR)
    1
        Stable Disease (SD)
    13
        Progressive Disease (PD)
    13
        No assessment
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Reporting of all adverse events started at the first treatment visit and ended on the EoT visit.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Everolimus 10 mg/d
    Reporting group description
    -

    Serious adverse events
    Everolimus 10 mg/d
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 39 (12.82%)
         number of deaths (all causes)
    29
         number of deaths resulting from adverse events
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Melaena
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Everolimus 10 mg/d
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    6
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Fatigue
         subjects affected / exposed
    14 / 39 (35.90%)
         occurrences all number
    16
    General physical health deterioration
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Influenza like illness
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    4
    Oedema peripheral
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Pain
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    7
    Pyrexia
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Swelling face
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    5
    Epistaxis
         subjects affected / exposed
    8 / 39 (20.51%)
         occurrences all number
    9
    Pneumonitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Depression
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    C-reactive protein increased
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Platelet count decreased
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    7
    Weight decreased
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    8
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Atrial tachycardia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Atrioventricular block
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Dysgeusia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Headache
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Taste disorder
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    5
    Anaemia of malignant disease
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Increased tendency to bruise
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Lymphopenia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Neutropenia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Visual impairment
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Abdominal mass
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    11
    Abdominal pain lower
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Aphthous ulcer
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    10
    Diarrhoea
         subjects affected / exposed
    11 / 39 (28.21%)
         occurrences all number
    14
    Dry mouth
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Dyspepsia
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    14 / 39 (35.90%)
         occurrences all number
    14
    Stomatitis
         subjects affected / exposed
    16 / 39 (41.03%)
         occurrences all number
    20
    Toothache
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    9
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Dry skin
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Erythema
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Erythema multiforme
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Night sweats
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    8
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    9
    Flank pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Uninary tract infection
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    10
    Hypercalcaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Hyperglycaemia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Hypophosphataemia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Iron deficiency
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2015
    Addition of IMP package sizes

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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