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    Clinical Trial Results:
    Open-Label Access Protocol of Denosumab for Subjects with Advanced Cancer

    Summary
    EudraCT number
    		 2011-002114-36
    Trial protocol
    		 HU   CZ   AT   FR   ES   PL   BE   LV   LT   IT  
    Global end of trial date
    10 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Aug 2019
    First version publication date
    17 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20110113
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01419717
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    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
    10 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to facilitate the access of denosumab until denosumab was approved and available for sale for subjects with advanced cancer who had participated in a denosumab phase 3 study.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The protocol, proposed informed consent form, other written subject information, and any proposed advertising material were submitted to the Independent Ethics Committee/Institutional Review Board (IEC/IRB) for written approval before recruitment of subjects into the study and shipment of Amgen investigational product. Before a subject’s participation in the clinical study, the investigator was responsible for obtaining written informed consent from the subject after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures or any investigational products were administered.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Nov 2011
    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
    Russian Federation: 13
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Latvia: 8
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Brazil: 16
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    South Africa: 1
    Worldwide total number of subjects
    129
    EEA total number of subjects
    58
    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)
    60
    From 65 to 84 years
    64
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 65 centers in Europe, Latin America, Japan, and South Africa. Participants were enrolled from 22 November 2011 to 27 October 2014.

    Pre-assignment
    Screening details
    		 Adults with advanced cancer who had been previously enrolled in an Amgen denosumab phase 3 study and had participated in the open-label extension portion of that study were eligible to enroll in this study.

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

    Arms
    Arm title
    		 Denosumab
    Arm description
    		 Participants were offered 120 milligrams of denosumab injected subcutaneously every 4 weeks until denosumab was approved and available for sale.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Xgeva
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 4 weeks (Q4W) at a dose of 120 mg.

    Number of subjects in period 1
    		Denosumab
    Started
    129
    Received Denosumab
    128
    Completed
    4
    Not completed
    125
         Adverse event, serious fatal
    17
         Consent withdrawn by subject
    10
         Adverse event, non-fatal
    19
         Other
    4
         Administrative Decision
    1
         Lost to follow-up
    2
         Protocol-specified Criteria
    62
         Disease Progression
    9
         Noncompliance
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants were offered 120 milligrams of denosumab injected subcutaneously every 4 weeks until denosumab was approved and available for sale.

    Reporting group values
    		 Denosumab Total
    Number of subjects
    		 129 129
    Age, Customized
    Units: Subjects
        18 - 64 years
    		 60 60
        65 - 74 years
    		 36 36
        75 - 84 years
    		 28 28
        ≥ 85 years
    		 5 5
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.74 ± 11.48 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 97 97
        Male
    		 32 32
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 103 103
        Asian
    		 15 15
        Black or African American
    		 6 6
        Other
    		 4 4
        Unknown
    		 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 28 28
        Not Hispanic or Latino
    		 101 101
        Unknown or Not Reported
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants were offered 120 milligrams of denosumab injected subcutaneously every 4 weeks until denosumab was approved and available for sale.

    Primary: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events [1]
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. The event does not necessarily have a causal relationship with study treatment. Each AE was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where Grade 1 = Mild AE Grade 2 = Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE. Treatment-related adverse events (TRAEs) includes events for which the investigator indicated there was a reasonable possibility they may have been caused by investigational product.
    End point type
    Primary
    End point timeframe
    From first dose of denosumab in Study 20110113 to end of study. Median (minimum, maximum) time on study was 13.93 (0.0, 74.7) months.
    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: The statistical analysis in this study was entirely descriptive; no formal statistical hypothesis was tested or estimated.
    End point values
    		 Denosumab
    Number of subjects analysed
    128 [2]
    Units: participants
        All adverse events
    98
        Serious adverse events
    45
        AE leading to discontinuation of denosumab
    28
        AE leading to discontinuation from study
    22
        Fatal adverse events
    18
        AE grade 3, 4, or 5
    46
        Treatment-related adverse event
    26
        Treatment-related serious adverse event
    10
        TRAE leading to discontinuation of denosumab
    18
        TRAE leading to discontinuation from study
    16
        Treatment-related fatal adverse events
    0
        Treatment-related AE grade 3, 4, or 5
    8
    Notes
    [2] - Participants who received at least 1 dose of denosumab in study 20110113.
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-denosumab Binding Antibodies

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    End point title
    		 Number of Participants with Anti-denosumab Binding Antibodies
    End point description
    A blood sample was collected at the end of study visit for the measurement of anti-denosumab binding antibodies.
    End point type
    Secondary
    End point timeframe
    Assessed at end of study; the median (minimum, maximum) time on study for all enrolled participants was 13.9 (0.0, 74.7) months.
    End point values
    		 Denosumab
    Number of subjects analysed
    86 [3]
    Units: participants
    0
    Notes
    [3] - Participants who received at least 1 dose of denosumab and with at least 1 antibody result.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of denosumab in Study 20110113 to end of study. Median (minimum, maximum) time on study was 13.93 (0.0, 74.7) months
    Adverse event reporting additional description
    Participants who received at least one dose of denosumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants received 120 milligrams of denosumab injected subcutaneously every 4 weeks until denosumab was approved and available for sale.

    Serious adverse events
    		 Denosumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 128 (35.16%)
         number of deaths (all causes)
    18
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Cardiac myxoma
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neoplasm malignant
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    General physical health deterioration
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Pleurisy
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Paraplegia
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Melaena
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    7 / 128 (5.47%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myelitis
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Pulpitis dental
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Hypoglycaemia
         subjects affected / exposed
    1 / 128 (0.78%)
         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
    		 Denosumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 128 (51.56%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 128 (6.25%)
         occurrences all number
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 128 (11.72%)
         occurrences all number
    18
    Fatigue
         subjects affected / exposed
    12 / 128 (9.38%)
         occurrences all number
    18
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 128 (7.03%)
         occurrences all number
    10
    Diarrhoea
         subjects affected / exposed
    11 / 128 (8.59%)
         occurrences all number
    17
    Nausea
         subjects affected / exposed
    15 / 128 (11.72%)
         occurrences all number
    23
    Toothache
         subjects affected / exposed
    9 / 128 (7.03%)
         occurrences all number
    11
    Vomiting
         subjects affected / exposed
    11 / 128 (8.59%)
         occurrences all number
    16
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 128 (5.47%)
         occurrences all number
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 128 (11.72%)
         occurrences all number
    26
    Back pain
         subjects affected / exposed
    16 / 128 (12.50%)
         occurrences all number
    18
    Osteonecrosis of jaw
         subjects affected / exposed
    8 / 128 (6.25%)
         occurrences all number
    8
    Pain in extremity
         subjects affected / exposed
    13 / 128 (10.16%)
         occurrences all number
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 128 (10.94%)
         occurrences all number
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2013
    Summary of changes: • Clarify that serious adverse events must be reported within 24 hours • Clarify how serious adverse events reported to Amgen will be reported to regulators and investigators • Provide lactation notification worksheet in the protocol

    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
    For support, Contact us.
    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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