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    Clinical Trial Results:
    A Phase II, randomised, open-label study of Gemcitabine/Carboplatin first-line chemotherapy in combination with or without the antisense oligonucleotide Apatorsen (OGX-427) in advanced squamous cell lung cancers.

    Summary
    EudraCT number
    2014-000199-25
    Trial protocol
    GB  
    Global end of trial date
    24 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jun 2019
    First version publication date
    29 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    009436
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02423590
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    QM Innovation Building, 5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    CECM Trials Team, Queen Mary University of London , +44 02078828197, bci-cecmmonitoring@qmul.ac.uk
    Scientific contact
    CECM Trials Team, Queen Mary University of London , +44 02078829187, bci-cecmmonitoring@qmul.ac.uk
    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
    31 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To estimate the clinical benefit of gemcitabine/carboplatin plus Apatorsen (OGX-427) relative to gemcitabine /carboplatin alone, as measured by investigator-assessed progression-free survival (PFS).
    Protection of trial subjects
    The study design aims to minimise potential risks. Eligibility criteria were selected to enhance the safety of patients in this trial and a number of exclusion criteria were specifically based on the known safety profiles of the study drug treatments. A dose modification strategy for management of toxicity and monitoring was in place for those risks deemed to be most likely or serious.
    Background therapy
    All patients received gemcitabine and carboplatin, which were used within their licensed indications and were therefore regarded as non-investigational products. Commercial gemcitabine and carboplatin was sourced locally by the investigational sites in keeping with standard local practice. Commercial brands of gemcitabine and carboplatin were permitted for use.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    27 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 86
    Worldwide total number of subjects
    86
    EEA total number of subjects
    86
    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)
    35
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    From June 2014 to December 2016 86 patients with advanced squamous cell lung cancer were recruited from 21 UK centres.

    Pre-assignment
    Screening details
    Patients with newly diagnosed cytologically or histologically confirmed Stage IIIB/IV squamous cell carcinoma, with no symptomatic CNS involvement or CNS involvement requiring steroids. ECOG perfomance status 0 - 2. Adequate organ and bone marrow function, with no history of significant cardiovascular disease or polyneuropathy > Grade 2. .

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Gemcitabine/Carboplatin
    Arm description
    Gemcitabine/carboplatin will be administered as standard 21-day treatment cycles according to normal clinical practice. Gemcitabine (1250 mg/m2) will be given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Following the administration of gemcitabine on Day 1, carboplatin (AUC5) will be given by infusion over 30-60 minutes.
    Arm type
    Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m2 given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following the administration of gemcitabine on Day 1, carboplatin (AUC5) will be given by infusion over 30-60 minutes. AUC dose was calculated as per local guidelines. Sites could use the Calvert formula as a guide.

    Arm title
    Apatorsen plus gemcitabine/carboplatin
    Arm description
    Gemcitabine/carboplatin was administered as standard 21-day treatment cycles according to normal clinical practice. Apatorsen (OGX-427) was administered prior to gemcitabine/carboplatin chemotherapy. Apatorsen (OGX-427) treatment began with a loading dose period prior to the initiation of chemotherapy. Patients received three loading doses of 400 mg by 2 hour intravenous infusions within a 9-day period (with at least 48 hours between start times of infusions and between the start of the last infusion and the initiation of chemotherapy); following the loading dose period and upon initiation of the 21-day treatment cycles, 400mg Apatorsen (OGX-427) was given weekly by approximately 2 hour intravenous infusions. Gemcitabine was given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Carboplatin was given by 30 to 60 minute infusion on Day 1 of each 21-day Cycle. Chemotherapy was initiated within 7 calendar days following completion of the loading dose period.
    Arm type
    Experimental

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m2 given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following the administration of gemcitabine on Day 1, carboplatin (AUC5) will be given by infusion over 30-60 minutes. AUC dose was calculated as per local guidelines. Sites could use the Calvert formula as a guide.

    Investigational medicinal product name
    Apatorsen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Apatorsen (OGX-427) treatment began with a loading dose period prior to the initiation of chemotherapy. Patients received three loading doses of 400 mg by 2 hour intravenous infusions within a 9-day period (with at least 48 hours between start times of infusions and between the start of the last infusion and the initiation of chemotherapy); following the loading dose period and upon initiation of the 21-day treatment cycles, 400mg Apatorsen (OGX-427) was given weekly by approximately 2 hour intravenous infusions.

    Number of subjects in period 1 [1]
    Gemcitabine/Carboplatin Apatorsen plus gemcitabine/carboplatin
    Started
    41
    42
    Completed
    41
    42
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 3 of the 86 randomised patients did not receive any treatment and were excluded from the analysis cohort.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gemcitabine/Carboplatin
    Reporting group description
    Gemcitabine/carboplatin will be administered as standard 21-day treatment cycles according to normal clinical practice. Gemcitabine (1250 mg/m2) will be given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Following the administration of gemcitabine on Day 1, carboplatin (AUC5) will be given by infusion over 30-60 minutes.

    Reporting group title
    Apatorsen plus gemcitabine/carboplatin
    Reporting group description
    Gemcitabine/carboplatin was administered as standard 21-day treatment cycles according to normal clinical practice. Apatorsen (OGX-427) was administered prior to gemcitabine/carboplatin chemotherapy. Apatorsen (OGX-427) treatment began with a loading dose period prior to the initiation of chemotherapy. Patients received three loading doses of 400 mg by 2 hour intravenous infusions within a 9-day period (with at least 48 hours between start times of infusions and between the start of the last infusion and the initiation of chemotherapy); following the loading dose period and upon initiation of the 21-day treatment cycles, 400mg Apatorsen (OGX-427) was given weekly by approximately 2 hour intravenous infusions. Gemcitabine was given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Carboplatin was given by 30 to 60 minute infusion on Day 1 of each 21-day Cycle. Chemotherapy was initiated within 7 calendar days following completion of the loading dose period.

    Reporting group values
    Gemcitabine/Carboplatin Apatorsen plus gemcitabine/carboplatin Total
    Number of subjects
    41 42 83
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    17 16 33
        From 65-84 years
    24 26 50
        85 years and over
    0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    66 (50 to 80) 67.5 (45 to 77) -
    Gender categorical
    Units: Subjects
        Female
    10 21 31
        Male
    31 21 52
    ECOG
    Units: Subjects
        0 - Fully Active
    5 7 12
        1 - Ambulatory, capable of light work
    32 31 63
        2 - Up and about >50% of time
    4 4 8
    Tumour stage
    Units: Subjects
        IIIB
    11 12 23
        IV
    30 30 60

    End points

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    End points reporting groups
    Reporting group title
    Gemcitabine/Carboplatin
    Reporting group description
    Gemcitabine/carboplatin will be administered as standard 21-day treatment cycles according to normal clinical practice. Gemcitabine (1250 mg/m2) will be given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Following the administration of gemcitabine on Day 1, carboplatin (AUC5) will be given by infusion over 30-60 minutes.

    Reporting group title
    Apatorsen plus gemcitabine/carboplatin
    Reporting group description
    Gemcitabine/carboplatin was administered as standard 21-day treatment cycles according to normal clinical practice. Apatorsen (OGX-427) was administered prior to gemcitabine/carboplatin chemotherapy. Apatorsen (OGX-427) treatment began with a loading dose period prior to the initiation of chemotherapy. Patients received three loading doses of 400 mg by 2 hour intravenous infusions within a 9-day period (with at least 48 hours between start times of infusions and between the start of the last infusion and the initiation of chemotherapy); following the loading dose period and upon initiation of the 21-day treatment cycles, 400mg Apatorsen (OGX-427) was given weekly by approximately 2 hour intravenous infusions. Gemcitabine was given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Carboplatin was given by 30 to 60 minute infusion on Day 1 of each 21-day Cycle. Chemotherapy was initiated within 7 calendar days following completion of the loading dose period.

    Primary: Progression-free survival (PFS)

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    End point title
    Progression-free survival (PFS)
    End point description
    End point type
    Primary
    End point timeframe
    PFS is defined as the time from date of randomisation to the date of first documented tumour progression or death from any cause, whichever occurs first.
    End point values
    Gemcitabine/Carboplatin Apatorsen plus gemcitabine/carboplatin
    Number of subjects analysed
    41
    42
    Units: months
        median (confidence interval 95%)
    6.47 (5.32 to 7.33)
    5.19 (3.25 to 5.82)
    Statistical analysis title
    Log-rank test and Cox proportional hazards
    Comparison groups
    Gemcitabine/Carboplatin v Apatorsen plus gemcitabine/carboplatin
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.174
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    2.27

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    OS is defined as the time from date of randomisation to the date of death from any cause.
    End point values
    Gemcitabine/Carboplatin Apatorsen plus gemcitabine/carboplatin
    Number of subjects analysed
    41
    42
    Units: months
        median (confidence interval 95%)
    12.98 (8.18 to 18.83)
    9.10 (5.39 to 10.68)
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR)

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    End point title
    Objective response rate (ORR)
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with at least one confirmed complete response (CR) or partial response (PR) based on investigator assessment using RECIST v1.1.
    End point values
    Gemcitabine/Carboplatin Apatorsen plus gemcitabine/carboplatin
    Number of subjects analysed
    41
    42
    Units: Percentage
        number (confidence interval 95%)
    21.95 (10.56 to 37.61)
    19.05 (8.60 to 34.12)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events will be recorded from the day of written informed consent until 30 days after the last dose of study treatment. Prior to initiation of study medications, only SAEs caused by a protocol-mandated interventions will be reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Gemcitabine/Carboplatin
    Reporting group description
    Gemcitabine/carboplatin will be administered as standard 21-day treatment cycles according to normal clinical practice. Gemcitabine (1250 mg/m2) will be given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Following the administration of gemcitabine on Day 1, carboplatin (AUC5) will be given by infusion over 30-60 minutes.

    Reporting group title
    Apatorsen plus gemcitabine/carboplatin
    Reporting group description
    Gemcitabine/carboplatin was administered as standard 21-day treatment cycles according to normal clinical practice. Apatorsen (OGX-427) was administered prior to gemcitabine/carboplatin chemotherapy. Apatorsen (OGX-427) treatment began with a loading dose period prior to the initiation of chemotherapy. Patients received three loading doses of 400 mg by 2 hour intravenous infusions within a 9-day period (with at least 48 hours between start times of infusions and between the start of the last infusion and the initiation of chemotherapy); following the loading dose period and upon initiation of the 21-day treatment cycles, 400mg Apatorsen (OGX-427) was given weekly by approximately 2 hour intravenous infusions. Gemcitabine was given by 30 minute intravenous infusions on Day 1 and Day 8 of each 21-day Cycle. Carboplatin was given by 30 to 60 minute infusion on Day 1 of each 21-day Cycle. Chemotherapy was initiated within 7 calendar days following completion of the loading dose period.

    Serious adverse events
    Gemcitabine/Carboplatin Apatorsen plus gemcitabine/carboplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 41 (41.46%)
    30 / 42 (71.43%)
         number of deaths (all causes)
    31
    32
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Pancytopenia
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    6 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrilation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 41 (0.00%)
    6 / 42 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Unresponsiveness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small bowel obstruction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vomiting
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 41 (9.76%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia
         subjects affected / exposed
    4 / 41 (9.76%)
    6 / 42 (14.29%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Gemcitabine/Carboplatin Apatorsen plus gemcitabine/carboplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 41 (100.00%)
    42 / 42 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 41 (12.20%)
    7 / 42 (16.67%)
         occurrences all number
    17
    31
    Hypotension
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 42 (9.52%)
         occurrences all number
    2
    5
    Thromboembolic event
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 42 (7.14%)
         occurrences all number
    3
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    31 / 41 (75.61%)
    25 / 42 (59.52%)
         occurrences all number
    51
    55
    Pain
         subjects affected / exposed
    25 / 41 (60.98%)
    18 / 42 (42.86%)
         occurrences all number
    33
    38
    Fever
         subjects affected / exposed
    7 / 41 (17.07%)
    11 / 42 (26.19%)
         occurrences all number
    10
    15
    Edema
         subjects affected / exposed
    9 / 41 (21.95%)
    4 / 42 (9.52%)
         occurrences all number
    9
    6
    Chills
         subjects affected / exposed
    2 / 41 (4.88%)
    6 / 42 (14.29%)
         occurrences all number
    3
    8
    Dysphonia
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 42 (7.14%)
         occurrences all number
    2
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 41 (17.07%)
    6 / 42 (14.29%)
         occurrences all number
    7
    8
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 42 (7.14%)
         occurrences all number
    5
    3
    Investigations
    Thrombocytopenia
         subjects affected / exposed
    14 / 41 (34.15%)
    21 / 42 (50.00%)
         occurrences all number
    50
    88
    Neutropenia
         subjects affected / exposed
    9 / 41 (21.95%)
    18 / 42 (42.86%)
         occurrences all number
    37
    75
    Leucopenia
         subjects affected / exposed
    5 / 41 (12.20%)
    12 / 42 (28.57%)
         occurrences all number
    28
    52
    Liver function test abnormal
         subjects affected / exposed
    6 / 41 (14.63%)
    7 / 42 (16.67%)
         occurrences all number
    14
    36
    Hypocalcaemia
         subjects affected / exposed
    4 / 41 (9.76%)
    5 / 42 (11.90%)
         occurrences all number
    7
    10
    Weight loss
         subjects affected / exposed
    3 / 41 (7.32%)
    6 / 42 (14.29%)
         occurrences all number
    4
    8
    Lymphopenia
         subjects affected / exposed
    3 / 41 (7.32%)
    5 / 42 (11.90%)
         occurrences all number
    13
    19
    Creatinine increased
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 42 (9.52%)
         occurrences all number
    6
    11
    Hypokalaemia
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 42 (7.14%)
         occurrences all number
    2
    5
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    3 / 41 (7.32%)
    7 / 42 (16.67%)
         occurrences all number
    3
    17
    Chest pain
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 42 (9.52%)
         occurrences all number
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    25 / 41 (60.98%)
    29 / 42 (69.05%)
         occurrences all number
    41
    61
    Cough
         subjects affected / exposed
    23 / 41 (56.10%)
    21 / 42 (50.00%)
         occurrences all number
    28
    32
    Epistaxis
         subjects affected / exposed
    7 / 41 (17.07%)
    7 / 42 (16.67%)
         occurrences all number
    13
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 41 (51.22%)
    24 / 42 (57.14%)
         occurrences all number
    92
    145
    Localized edema
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    7 / 41 (17.07%)
    7 / 42 (16.67%)
         occurrences all number
    8
    9
    Headache
         subjects affected / exposed
    4 / 41 (9.76%)
    7 / 42 (16.67%)
         occurrences all number
    5
    20
    Dizziness
         subjects affected / exposed
    3 / 41 (7.32%)
    7 / 42 (16.67%)
         occurrences all number
    7
    7
    Neuropathy
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 42 (9.52%)
         occurrences all number
    3
    4
    Tremor
         subjects affected / exposed
    2 / 41 (4.88%)
    5 / 42 (11.90%)
         occurrences all number
    2
    5
    Lethargy
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 42 (7.14%)
         occurrences all number
    5
    3
    Paraesthesia
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 42 (4.76%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    21 / 41 (51.22%)
    23 / 42 (54.76%)
         occurrences all number
    32
    31
    Nausea
         subjects affected / exposed
    12 / 41 (29.27%)
    20 / 42 (47.62%)
         occurrences all number
    17
    33
    Mucositis
         subjects affected / exposed
    11 / 41 (26.83%)
    12 / 42 (28.57%)
         occurrences all number
    16
    15
    Diarrhoea
         subjects affected / exposed
    8 / 41 (19.51%)
    7 / 42 (16.67%)
         occurrences all number
    11
    16
    Vomiting
         subjects affected / exposed
    3 / 41 (7.32%)
    7 / 42 (16.67%)
         occurrences all number
    3
    12
    Dyspepsia
         subjects affected / exposed
    5 / 41 (12.20%)
    4 / 42 (9.52%)
         occurrences all number
    5
    4
    Haemoptysis
         subjects affected / exposed
    2 / 41 (4.88%)
    7 / 42 (16.67%)
         occurrences all number
    2
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 41 (21.95%)
    8 / 42 (19.05%)
         occurrences all number
    9
    9
    Alopecia
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 42 (14.29%)
         occurrences all number
    1
    6
    Dry skin
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Hyperhidrosis
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 42 (9.52%)
         occurrences all number
    1
    4
    Pruritus
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 42 (9.52%)
         occurrences all number
    3
    7
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    12 / 41 (29.27%)
    18 / 42 (42.86%)
         occurrences all number
    19
    25
    Arthralgia
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 42 (7.14%)
         occurrences all number
    4
    4
    Muscular weakness
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 42 (7.14%)
         occurrences all number
    2
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    14 / 41 (34.15%)
    17 / 42 (40.48%)
         occurrences all number
    18
    22
    Hypomagnesaemia
         subjects affected / exposed
    6 / 41 (14.63%)
    8 / 42 (19.05%)
         occurrences all number
    12
    43
    Hyperglycaemia
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 42 (7.14%)
         occurrences all number
    4
    10
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 42 (7.14%)
         occurrences all number
    8
    5
    Hypercalcaemia
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 42 (4.76%)
         occurrences all number
    6
    3
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 42 (7.14%)
         occurrences all number
    4
    4
    Infections and infestations
    Infection
         subjects affected / exposed
    24 / 41 (58.54%)
    26 / 42 (61.90%)
         occurrences all number
    43
    52

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2014
    - Clarification of adverse reaction expectdness listed in the Protocol - List of prohibited medications amended to include live vaccines because they are not recommended in patients treated with gemcitabine. - Pharmacovigilance reporting clarification - Due to the gemcitabine cardiotoxic potential, ECG added at screening and when clinically indicated to the safety assessments. - As per SmPC requirements, neurological evaluation and an assessment of hearing must be performed on a regular basis in patients treated with carboplatin. - Contraception updates
    18 Aug 2015
    - Addition of exploratory objective to investigate any apatorsen benefit in a study subpopulation defined as having poor prognostic features.
    15 Mar 2016
    - Change to the dose of IMP from 600mg to 400mg following review of data provided by the IMP manufacturer on recently completed studies. - Expansion of inclusion criteria to better suit recent advances in treatment. Patients who have received previous first-line immunotherapy (without chemotherapy) were now eligible for the trial. Patients with cytological diagnosis of squamous cell cancer were also eligible following this amendment, previously only patients with a histological diagnosis were elligible. - Length of chemotherapy amended from ‘6 cycles’ to ‘4-6 cycles’ to reflect differences in local practice across all research sites.
    21 Feb 2017
    Reduction of sample size from 140 to 86 patients due to unavailability of IMP.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Jan 2017
    Halt to recruitment while preparing amendment to reduce protocol sample size.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Not applicable.
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