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    Clinical Trial Results:
    ENGOT-EN1/FANDANGO: A randomized phase II trial of first-line combination chemotherapy with nintedanib / placebo for patients with advanced or recurrent endometrial cancer.

    Summary
    EudraCT number
    		 2016-000193-38
    Trial protocol
    		 SE   DK   DE   FI   BE   FR  
    Global end of trial date
    01 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2023
    First version publication date
    20 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENGOT-EN1/FANDANGO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02730416
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nordic Society of Gynaecological Oncology - Clinical Trial Unit (NSGO-CTU)
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, København, Denmark, 2100
    Public contact
    Medical Director, Mansoor Raza Mirza, Nordic Society of Gynaecological Oncology - Clinical Trial Unit (NSGO-CTU), +45 35453311, Mansoor.Raza.Mirza@regionh.dk
    Scientific contact
    Medical Director, Mansoor Raza Mirza, Nordic Society of Gynaecological Oncology - Clinical Trial Unit (NSGO-CTU), +45 35453311, Mansoor.Raza.Mirza@regionh.dk
    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
    26 May 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objective: To compare Progression free survival (PFS) between arms. Progression Free Survival (PFS) is defined as the time from randomization until disease progression or death by any cause. The progression events are defined by RECIST 1.1 criteria
    Protection of trial subjects
    All study subjects were required to read and sign the informed consent form. The IDMC was established to provide independent review and assessment of the efficacy and safety data in a systematic manner and to safeguard the interest and safety of the participating patients in the study. The IDMC consisted of 3 independent individuals, and made recommendations to the sponsor, based on their review, to continue or stop the trial based on their assessment of safety information. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the ICH-GCP guidelines. The local principal investigators were responsible for ensuring that the study was conducted in accordance with the protocol, the ethical principles of the Declaration of Helsinki, current ICH guidelines on Good Clinical practice (GCP) and applicable local regulatory requirements.
    Background therapy
    		 Carboplatin AUC 5 Q3W and paclitaxel 175 mg/m2 Q3W for up to 6 cycles.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Dec 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 52
    Country: Number of subjects enrolled
    Germany: 31
    Worldwide total number of subjects
    146
    EEA total number of subjects
    146
    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)
    63
    From 65 to 84 years
    83
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential candidates for the trial was identified by a member of the treatment team, by referrals from other departments/hospitals/GP. Investigator screened patients’ medical records for suitability to enroll in the trial. Enrollment occured only after the patient gav written informed consent. Recruitment from Q4 2016 to Q1 2019

    Pre-assignment
    Screening details
    		 All patients had to commence treatment within 28 days of start of screening. Patients who failed screening, could be be rescreened at a later date, at the Investigators discretion, upon discussion with and approval by sponsor.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Nintedanib and placebo treatment was blinded. The study medication was labeled using a unique Kit ID number, which was linked to the randomization scheme. The active and placebo tablets were identical and presented in the same packaging to ensure blinding of the study medication. The treatment assignment was kept separate from the trial team up to database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Treatment with 1L chemotherapy for endometrial cancer with Paclitaxel/Carboplatin, incl. IMP Nintedanib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg orally twice daily, on day 2-21 of each 21 day cycle

    Arm title
    		 Arm B
    Arm description
    		 Treatment with 1L chemotherapy for endometrial cancer with Paclitaxel/Carboplatin, incl. Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg orally twice daily, on day 2-21 of each 21 day cycle

    Number of subjects in period 1
    		Arm A Arm B
    Started
    72
    74
    End of treatment with nintedanib/placebo
    72
    74
    Completed
    0
    0
    Not completed
    72
    74
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    4
         Physician decision
    10
    16
         Adverse event, non-fatal
    15
    7
         Intercurrent disease
    -
    1
         Pt. requested to stop
    6
    2
         Lack of efficacy
    40
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Treatment with 1L chemotherapy for endometrial cancer with Paclitaxel/Carboplatin, incl. IMP Nintedanib

    Reporting group title
    Arm B
    Reporting group description
    		 Treatment with 1L chemotherapy for endometrial cancer with Paclitaxel/Carboplatin, incl. Placebo

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 72 74 146
    Age categorical
    Age of participating subjects
    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)
    		 30 33 63
        From 65-84 years
    		 42 41 83
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 72 74 146
        Male
    		 0 0 0
    Race
    Race of participating subjects
    Units: Subjects
        other
    		 2 0 2
        white
    		 52 56 108
        unknown
    		 0 1 1
        not reporting
    		 18 17 35
    Previous cancer
    Number of subjects with previous cancer
    Units: Subjects
        No
    		 63 65 128
        Yes
    		 9 9 18
    Diabetes
    Subjects with diabetes
    Units: Subjects
        No
    		 68 60 128
        Yes
    		 4 14 18
    Hypertension
    Subjects with hypertension
    Units: Subjects
        No
    		 44 46 90
        Yes
    		 28 28 56
    Previous surgery
    Units: Subjects
        No
    		 42 48 90
        Yes
    		 30 26 56
    Any ongoing condition
    Subjects with ongoing conditions
    Units: Subjects
        No
    		 32 25 57
        Yes
    		 40 49 89
    IHD
    Subjects with IHD
    Units: Subjects
        No
    		 72 70 142
        Yes
    		 0 4 4
    Any comorbidity
    Subjects with any comorbidities
    Units: Subjects
        No
    		 70 68 138
        Yes
    		 2 6 8
    Stage of disease
    Stage of disease
    Units: Subjects
        Stage 3C2
    		 11 15 26
        Stage 4
    		 31 30 61
        Recurrent disease
    		 30 29 59
    Prior adjuvant chemotherapy
    Subjects who have received any prior adjuvant chemotherapy
    Units: Subjects
        No
    		 57 58 115
        Yes
    		 15 16 31
    Disease status RECIST
    Disease status according to RECIST
    Units: Subjects
        Non-measurable
    		 13 10 23
        Measurable
    		 59 64 123

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Treatment with 1L chemotherapy for endometrial cancer with Paclitaxel/Carboplatin, incl. IMP Nintedanib

    Reporting group title
    Arm B
    Reporting group description
    		 Treatment with 1L chemotherapy for endometrial cancer with Paclitaxel/Carboplatin, incl. Placebo

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) or modified intention-to-treat population comprises all patients receiving at least one dose of study medication irrespective of their further compliance to the planned course of treatment. The FAS is the primary analysis population and will be used for evaluation of all endpoints.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression Free Survival (PFS) of patients treated with chemotherapy plus Nintedanib against chemotherapy plus placebo. The progression events are defined by RECIST 1.1 criteria. PFS was censored if the patient was lost to follow-up or refused to continue in the study (i.e. withdraws consent). For patients alive and without progression at the time of analysis, PFS was censored. In any case of censoring, the date of censoring will be the last time point documenting survival status.
    End point type
    Primary
    End point timeframe
    Progression Free Survival (PFS) is defined as the time from randomization until disease progression or death by any cause.
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    72
    74
    146
    Units: month
        number (confidence interval 95%)
    8.23 (5.77 to 10.27)
    7.07 (5.40 to 9.10)
    7.93 (6.0 to 8.6)
    Statistical analysis title
    		 Survival endpoints analyses (PFS)
    Statistical analysis description
    Survival end-points incl. PFS was tested using a Cox proportional hazard model adjusted for the stratification factors. Visual inspection of the Kaplan-Meier plots were used to ensure that no major deviation from the proportional hazard’s assumption was present. If, however, such a deviation was observed the analysis was adapted accordingly.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 cox-proportional hazard
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.9981
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6952
         upper limit
    		 1.433
    Variability estimate
    Standard deviation

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival (OS) is defined as the time from start of treatment until date of death by any cause or until the trial was stopped prematurely. Overall survival was censored if the patient was lost to follow-up or refused to continue in the study (i.e. withdraws consent). For patients alive at the time of analysis, overall survival was censored. In any case of censoring, the date of censoring was the last time point documenting survival status.
    End point type
    Secondary
    End point timeframe
    Overall Survival (OS) is defined as the time from start of treatment until date of death by any cause or until the trial was stopped prematurely.
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    72
    74
    146
    Units: month
        number (confidence interval 95%)
    26 (19.10 to 47.83)
    25.27 (18.6 to 30.7)
    25.27 (20.03 to 30.7)
    Statistical analysis title
    		 Survival endpoints analyses (OS)
    Statistical analysis description
    Survival end-points incl. OS was tested using a Cox proportional hazard model adjusted for the stratification factors. Visual inspection of the Kaplan-Meier plots was used to ensure that no major deviation from the proportional hazard’s assumption is present. If, however, such a deviation was observed the analysis was adapted accordingly.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 COX-proportional hazard
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.8239
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5417
         upper limit
    		 1.2531
    Variability estimate
    Standard deviation

    Secondary: Progression-free survival after consecutive treatment (PFS2)

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    End point title
    		 Progression-free survival after consecutive treatment (PFS2)
    End point description
    PFS2 is defined along the same timelines as PFS but accounts for the time from randomization to progression or death by any cause on any subsequent line of anticancer therapy.
    End point type
    Secondary
    End point timeframe
    PFS2 is defined along the same timelines as PFS but accounts for the time from randomization to progression or death by any cause on any subsequent line of anticancer therapy.
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    40
    36
    76
    Units: day
        median (inter-quartile range (Q1-Q3))
    504.5 (353.5 to 770.5)
    416 (345 to 570)
    459.5 (349.5 to 646.5)
    No statistical analyses for this end point

    Secondary: Disease Specific Survival (DSS)

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    End point title
    		 Disease Specific Survival (DSS)
    End point description
    DSS was censored if the patient was lost to follow-up or refuses to continue in the study (i.e. withdraws consent). For patients alive at the time of analysis, DSS was censored. In any case of censoring, the date of censoring was the last time point documenting survival status.
    End point type
    Secondary
    End point timeframe
    Disease Specific Survival (DSS) is defined as the time from start of treatment until date of death from endometrial cancer.
    End point values
    		 Full analysis set
    Number of subjects analysed
    146 [1]
    Units: days
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    Notes
    [1] - DSS is not reported due to incomplete data collection
    No statistical analyses for this end point

    Secondary: Time to first subsequent therapy (TFST)

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    End point title
    		 Time to first subsequent therapy (TFST)
    End point description
    TFST was censored if the patient was lost to follow-up or refused to continue in the study (i.e. withdraws consent). For patients alive and without initiation of second-line treatment at the time of analysis, TFST was censored. In any case of censoring, the date of censoring will be the last time point documenting survival status.
    End point type
    Secondary
    End point timeframe
    Time to first subsequent therapy (TFST) is defined as the time from enrolment/randomization until initiation of second-line anti-cancer treatment following study treatment discontinuation or death.
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    42
    37
    79
    Units: day
        median (inter-quartile range (Q1-Q3))
    308.5 (252 to 468)
    296 (231 to 355)
    304 (232 to 420)
    No statistical analyses for this end point

    Secondary: Time to second subsequent therapy (TSST)

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    End point title
    		 Time to second subsequent therapy (TSST)
    End point description
    TSST was censored if the patient was lost to follow-up or refuses to continue in the study (i.e. withdraws consent). For patients alive and without initiation of third-line treatment at the time of analysis, TSST was censored. In any case of censoring, the date of censoring was the last time point documenting survival status.
    End point type
    Secondary
    End point timeframe
    Time to second subsequent therapy (TSST) is defined as the time from enrolment/randomization until initiation of third-line anti-cancer treatment or death.
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    42
    37
    79
    Units: days
        median (inter-quartile range (Q1-Q3))
    587.5 (441 to 1163)
    608 (347 to 801)
    602 (377 to 903)
    No statistical analyses for this end point

    Secondary: Response Rate (RR)

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    End point title
    		 Response Rate (RR)
    End point description
    End point type
    Secondary
    End point timeframe
    The analysis of the Response Rate (RR) was performed for each treatment by calculating the point estimate of the percentage of patients in who have achieved complete response or partial response, assessed according to RECIST 1.1 criteria.
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    72
    74
    146
    Units: percent
        number (not applicable)
    65.27
    55.4
    60.27
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    The analysis of disease control rate was performed for each treatment arm by calculating the point estimate of the percentage of patients who have achieved complete response or partial response or stable disease for at least 12 weeks, assessed according to RECIST 1.1 criteria.
    End point type
    Secondary
    End point timeframe
    Disease Control Rate (DCR = Complete Response, Partial Respons or Stable Disease for at least 12 weeks).
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    72
    74
    146
    Units: percent
        number (not applicable)
    88.88
    79.72
    84.24
    No statistical analyses for this end point

    Secondary: Quality of life (QoL)

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    End point title
    		 Quality of life (QoL)
    End point description
    Quality of Life (QoL) scores, assessed by EORTC’s general EORTC-QLQ-C30 questionnaire and disease specific questionnaire EORTC-QLQ-EN-24, will be calculated using EORTC’s Scoring Manual.
    End point type
    Secondary
    End point timeframe
    Quality of Life (QoL) scores will be calculated for each individual patient at selected visits.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    72 [2]
    74 [3]
    Units: patients
        median (standard deviation)
    0 ± 0
    0 ± 0
    Attachments
    		 QoL scores and graphs
    Notes
    [2] - No significant main effects on the general health score could be shown, see attachment.
    [3] - No significant main effects on the general health score could be shown, see attachment.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were collected from inf. consent until 30 days after last dose/study discont. AEs were recorded from 1. dose until treatment discont. AEs were followed for 30 days after last dose of investigational drug.
    Adverse event reporting additional description
    AEs could be informed upon spontaneously by the patient or discovered by study staff during physical investigation or when wording opn & non-leading questions. Nature of AE, date of onset/resolution, actions taken, severity and causality to study drugs/procedures as assessed by investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Arm A (Nintedanib group)
    Reporting group description
    		 Carboplatin + paclitaxel + nintedanib

    Reporting group title
    Arm B (control group)
    Reporting group description
    		 Carboplatin + paclitaxel + placebo

    Serious adverse events
    		 Arm A (Nintedanib group) Arm B (control group)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 72 (43.06%)
    21 / 74 (28.38%)
         number of deaths (all causes)
    42
    46
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter related infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    9 / 72 (12.50%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    8 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Blood alanine aminotransferase increased
         subjects affected / exposed
    11 / 72 (15.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    10 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 72 (8.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (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
    Dyspnoea
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Febrile neutropenia
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GGT increased
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A (Nintedanib group) Arm B (control group)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 72 (100.00%)
    70 / 74 (94.59%)
    Vascular disorders
    Edema limbs
         subjects affected / exposed
    1 / 72 (1.39%)
    9 / 74 (12.16%)
         occurrences all number
    2
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    17 / 72 (23.61%)
    13 / 74 (17.57%)
         occurrences all number
    22
    23
    Fatigue
         subjects affected / exposed
    27 / 72 (37.50%)
    22 / 74 (29.73%)
         occurrences all number
    41
    32
    Pain
         subjects affected / exposed
    9 / 72 (12.50%)
    13 / 74 (17.57%)
         occurrences all number
    20
    18
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    6 / 72 (8.33%)
    8 / 74 (10.81%)
         occurrences all number
    7
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 72 (6.94%)
    3 / 74 (4.05%)
         occurrences all number
    5
    4
    Dyspnoea
         subjects affected / exposed
    13 / 72 (18.06%)
    12 / 74 (16.22%)
         occurrences all number
    16
    15
    Epistaxis
         subjects affected / exposed
    4 / 72 (5.56%)
    2 / 74 (2.70%)
         occurrences all number
    4
    5
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 74 (5.41%)
         occurrences all number
    3
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 72 (9.72%)
    4 / 74 (5.41%)
         occurrences all number
    7
    5
    Insomnia
         subjects affected / exposed
    4 / 72 (5.56%)
    5 / 74 (6.76%)
         occurrences all number
    6
    5
    Peripheral motor neuropathy
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 74 (2.70%)
         occurrences all number
    6
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    42 / 72 (58.33%)
    37 / 74 (50.00%)
         occurrences all number
    63
    47
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 72 (40.28%)
    27 / 74 (36.49%)
         occurrences all number
    48
    59
    Leukopenia
         subjects affected / exposed
    10 / 72 (13.89%)
    10 / 74 (13.51%)
         occurrences all number
    19
    18
    Neutropenia
         subjects affected / exposed
    32 / 72 (44.44%)
    26 / 74 (35.14%)
         occurrences all number
    58
    52
    Thrombocytopenia
         subjects affected / exposed
    25 / 72 (34.72%)
    19 / 74 (25.68%)
         occurrences all number
    51
    21
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    12 / 72 (16.67%)
    17 / 74 (22.97%)
         occurrences all number
    13
    26
    Anorexia
         subjects affected / exposed
    10 / 72 (13.89%)
    6 / 74 (8.11%)
         occurrences all number
    14
    7
    Constipation
         subjects affected / exposed
    13 / 72 (18.06%)
    13 / 74 (17.57%)
         occurrences all number
    20
    16
    Diarrhoea
         subjects affected / exposed
    47 / 72 (65.28%)
    22 / 74 (29.73%)
         occurrences all number
    110
    44
    Taste disorder
    Additional description: Dysguesia
         subjects affected / exposed
    6 / 72 (8.33%)
    6 / 74 (8.11%)
         occurrences all number
    6
    6
    Dyspepsia
         subjects affected / exposed
    6 / 72 (8.33%)
    4 / 74 (5.41%)
         occurrences all number
    7
    4
    Mucositis oral
         subjects affected / exposed
    0 / 72 (0.00%)
    6 / 74 (8.11%)
         occurrences all number
    0
    7
    Nausea
         subjects affected / exposed
    35 / 72 (48.61%)
    22 / 74 (29.73%)
         occurrences all number
    55
    34
    Vomiting
         subjects affected / exposed
    22 / 72 (30.56%)
    9 / 74 (12.16%)
         occurrences all number
    39
    16
    Hepatobiliary disorders
    Alanine aminotransferase increased
         subjects affected / exposed
    30 / 72 (41.67%)
    6 / 74 (8.11%)
         occurrences all number
    47
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 72 (30.56%)
    5 / 74 (6.76%)
         occurrences all number
    32
    8
    ggt
         subjects affected / exposed
    13 / 72 (18.06%)
    2 / 74 (2.70%)
         occurrences all number
    19
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    34 / 72 (47.22%)
    26 / 74 (35.14%)
         occurrences all number
    37
    28
    Rash
         subjects affected / exposed
    7 / 72 (9.72%)
    6 / 74 (8.11%)
         occurrences all number
    7
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 72 (12.50%)
    6 / 74 (8.11%)
         occurrences all number
    10
    9
    Myalgia
         subjects affected / exposed
    10 / 72 (13.89%)
    11 / 74 (14.86%)
         occurrences all number
    15
    16
    Pain in extremity
         subjects affected / exposed
    2 / 72 (2.78%)
    8 / 74 (10.81%)
         occurrences all number
    4
    12
    Infections and infestations
    Fever
         subjects affected / exposed
    4 / 72 (5.56%)
    5 / 74 (6.76%)
         occurrences all number
    5
    6
    Urinary tract infection
         subjects affected / exposed
    8 / 72 (11.11%)
    11 / 74 (14.86%)
         occurrences all number
    13
    15
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    12 / 72 (16.67%)
    8 / 74 (10.81%)
         occurrences all number
    17
    17
    Hypomagnesaemia
         subjects affected / exposed
    15 / 72 (20.83%)
    9 / 74 (12.16%)
         occurrences all number
    24
    15
    GGT increased
         subjects affected / exposed
    13 / 72 (18.06%)
    2 / 74 (2.70%)
         occurrences all number
    19
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 72 (18.06%)
    2 / 74 (2.70%)
         occurrences all number
    20
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2019
    Substantial changes to the protocol incl. changes in inclusion and exclusion criteriae, clarification that treatment with radiotherapy will result in EOS, clarification on testing in relation to the trial incl. blood/urin tests, CT-scans. Added GDPR section and specification on when to start the TR-section, will be made, when the primary endpoint is mature. The tissue samples for translational research shall be kept at sites until it is decided to conduct a TR project. Specifikation of TFST, SUSARs.

    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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