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    Clinical Trial Results:
    Efficacy of regorafenib as maintenance therapy in non-adipocytic soft tissue sarcoma having received first-line doxorubicin-based chemotherapy

    Summary
    EudraCT number
    		 2018-001574-22
    Trial protocol
    		 FR  
    Global end of trial date
    26 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EREMISS-1801
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03793361
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre Oscar Lambret
    Sponsor organisation address
    3 rue Frédéric Combemale – BP307, Lille, France, 59020
    Public contact
    Sponsor unit, Centre Oscar lambret, +33 03 20 29 59 18, promotion@o-lambret.fr
    Scientific contact
    Sponsor unit, Centre Oscar lambret, +33 03 20 29 59 18, promotion@o-lambret.fr
    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 Sep 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal objective of the trial is to assess the efficacy, in terms of PFS, of regorafenib compared to placebo as maintenance therapy in metastatic soft-tissue, non-adipocytic sarcomas experiencing stable disease or partial tumor response after 6 cycles of doxorubicin-based chemotherapy as 1st line chemotherapy
    Protection of trial subjects
    First IDMC (23/03/2021) => No major safety concerns. Expected AEs with regorafenib, to be further investigated during next IDMC (limited number of patients, 15). IDMC members advice to avoid waivers on inclusion criteria especially related to expected AEs. Second IDMC (02/04/2024) => The IDMC has considered the present data and agrees with the conclusions of the study team that available data are sufficient to conclude without the need to restart recruitment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2019
    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
    France: 127
    Worldwide total number of subjects
    127
    EEA total number of subjects
    127
    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)
    82
    From 65 to 84 years
    43
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 127 patients from 17 centres were included between 16/05/2019 and 28/11/2022: Placebo, N=62; Regorafenib, N=65. In the regorafenib group, 1 patient was excluded from all analyses, because the pathological review corrected the diagnosis to melanoma, leading to an early study withdrawal. => Study population: Placebo N=62 Regorafenib N=64

    Pre-assignment
    Screening details
    		 134 patients screened but only 127 patients included in the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Patients, investigators and radiologists of the independent review committee were all blinded to treatment allocation. At the treating sites, only pharmacists were aware of the allocated treatment. Unblinding could be done by the sponsor on request of the investigator in case of emergency (safety issue), progression confirmed by central review and need to know the treatment received to continue medical care, or for any reason justified by the investigator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo arm
    Arm description
    		 Placebo (3 tablets) once daily, 3 weeks on / 1 week off plus Best Supportive Care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Regorafenib arm
    Arm description
    		 Regorafenib (120 mg, 3 tablets) once daily, 3 weeks on / 1 week off plus Best Supportive Care (BSC)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Regorafenib (120 mg, 3 tablets) once daily, 3 weeks on / 1 week off plus Best Supportive Care (BSC)

    Number of subjects in period 1 [1]
    		Placebo arm Regorafenib arm
    Started
    62
    64
    Completed
    62
    64
    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: In the regorafenib group, one patient was excluded because the pathological review corrected the diagnosis to melanoma, leading to an early study withdrawal. This patient has been excluded from all analyses, leading to a study population of 126 patients

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo arm
    Reporting group description
    		 Placebo (3 tablets) once daily, 3 weeks on / 1 week off plus Best Supportive Care

    Reporting group title
    Regorafenib arm
    Reporting group description
    		 Regorafenib (120 mg, 3 tablets) once daily, 3 weeks on / 1 week off plus Best Supportive Care (BSC)

    Reporting group values
    		 Placebo arm Regorafenib arm Total
    Number of subjects
    		 62 64 126
    Age categorical
    Age (Years)
    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)
    		 36 46 82
        From 65-84 years
    		 25 18 43
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 61.5 (22 to 85) 55.5 (17 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 33 36 69
        Male
    		 29 28 57
    Histological subtype
    Histological subtype
    Units: Subjects
        Leiomyosarcoma
    		 37 37 74
        Synovial-sarcoma
    		 2 4 6
        Other sarcoma
    		 23 23 46
    Disease staging at study entry
    Disease staging at study entry
    Units: Subjects
        Locally advanced without metastases
    		 8 2 10
        Metastatic disease only
    		 20 22 42
        Locally advanced with metastases
    		 34 40 74
    Metastases at study entry
    Metastases at study entry
    Units: Subjects
        No
    		 8 2 10
        Yes
    		 54 62 116
    Time from end doxorubicin to inclusion
    Time from end doxorubicin to inclusion
    Units: days
        median (full range (min-max))
    		 38 (15 to 54) 39.5 (20 to 56) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo arm
    Reporting group description
    		 Placebo (3 tablets) once daily, 3 weeks on / 1 week off plus Best Supportive Care

    Reporting group title
    Regorafenib arm
    Reporting group description
    		 Regorafenib (120 mg, 3 tablets) once daily, 3 weeks on / 1 week off plus Best Supportive Care (BSC)

    Primary: Progression free survival (central review)

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    End point title
    		 Progression free survival (central review)
    End point description
    Progression-free survival (PFS), defined as the time between randomisation and first disease progression, based on central radiological review using RECIST 1.1 criteria, or death from any cause. For this estimate, we have censored the observation at the date of last tumour evaluation that was reviewed before start of another anticancer treatment if any, or at the date of last reviewed evaluation if the patient was alive at last follow-up with a stable disease according to central review. In each group, the PFS curve was estimated using the Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Tumour evaluation was planned every 8 weeks during the first 6 cycles and then every 3 months. Patients were followed-up until the end of the study, planned at least 8 months after last patient recruitment. All radiological imaging were centrally reviewed
    End point values
    		 Placebo arm Regorafenib arm
    Number of subjects analysed
    62
    60 [1]
    Units: Survival estimate (%)
    number (confidence interval 95%)
        PFS at 6 months (IC95%)
    14.6 (7.0 to 24.9)
    49.5 (36.0 to 61.7)
        PFS at 12 months (IC95%)
    7.3 (2.4 to 16.0)
    14.7 (6.7 to 25.6)
        PFS at 24 months (IC95%)
    2.7 (0.3 to 11.0)
    2.8 (0.3 to 11.8)
    Notes
    [1] - In the Rego arm, exclusion of 4 patients for whom imaging was not available for central radio review
    Statistical analysis title
    		 Progression free survival - adjusted HR
    Statistical analysis description
    Cox models were used to estimate the hazard ratios (HR) and 95% confidence intervals (95%CI) associated with the treatment effect (regorafenib versus placebo) after testing the proportional hazards assumption, using the scaled Schoenfeld residuals method
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.78
    Notes
    [2] - Effect of treatment (Regorafenib versus placebo) Cox model: adjusted HR (IC95%) HR adjusted on minimisation factors: histological subtypes (leiomyosarcoma versus synovial sarcoma versus other histological subtype), response to doxorubicin-based chemotherapy (partial response versus stable disease) and centres (after pooling centres with less than 8 patients). The p-value of the test for proportional hazards assumption (based on Schoenfeld residuals) is not significant p=0.09.
    Statistical analysis title
    		 Progression free survival - not adjusted HR
    Statistical analysis description
    Effect of treatment (Regorafenib versus placebo)
    Comparison groups
    Placebo arm v Regorafenib arm
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Not applicable
    Confidence interval
    Notes
    [3] - The HR was not estimated in the Cox model because the assumption of proportional hazards was violated (Schoenfeld residuals test, p-value=0.01) P-value of the logrank test, p-value = 0.002
    Statistical analysis title
    		 Progression free survival - RMSTD
    Statistical analysis description
    Effect of treatment (Regorafenib versus placebo)
    Comparison groups
    Placebo arm v Regorafenib arm
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.006 [5]
    Method
    		 restricted mean survival time difference
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 4.82
    Notes
    [4] - The mean absolute gain in survival times (PFS and OS, respectively) was estimated and tested using the rmstd method (restricted mean survival time difference, as published by Royston and Parmar in 2011) which remains valid if the proportional hazard assumption appears violated or questionable.
    [5] - The curve has been truncated at the maximum time observed, i.e. 26 months.

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    OS, defined as the time interval from the date of randomisation to the date of death from any cause In each group, the OS curve was estimated using the Kaplan-Meier method
    End point type
    Secondary
    End point timeframe
    Until the end of the study.
    End point values
    		 Placebo arm Regorafenib arm
    Number of subjects analysed
    62
    64
    Units: Survival estimate (%)
    number (confidence interval 95%)
        OS at 6 months (IC95%)
    87.1 (75.9 to 93.3)
    87.5 (76.6 to 93.5)
        OS at 12 months (IC95%)
    69.4 (56.3 to 79.2)
    70.3 (57.5 to 79.9)
        OS at 24 months (IC95%)
    41.4 (28.3 to 53.9)
    53.1 (39.3 to 65.0)
    Statistical analysis title
    		 Overall survival - adjusted HR
    Statistical analysis description
    Cox models were used to estimate the hazard ratios (HR) and 95% confidence intervals (95%CI) associated with the treatment effect (regorafenib versus placebo) after testing the proportional hazards assumption, using the scaled Schoenfeld residuals method.
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.28
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.22
    Notes
    [6] - Effect of treatment (Regorafenib versus placebo) Cox model: adjusted HR (IC95%) HR adjusted on minimisation factors: histological subtypes (leiomyosarcoma versus synovial sarcoma versus other histological subtype), response to doxorubicin-based chemotherapy (partial response versus stable disease) and centres (after pooling centres with less than 8 patients). The p-value of the test for proportional hazards assumption (based on Schoenfeld residuals) is not significant p=0.09.
    Statistical analysis title
    		 Overall survival - not adjusted HR
    Statistical analysis description
    Effect of treatment (Regorafenib versus placebo)
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.3
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.23
    Notes
    [7] - The p-value of the test for proportional hazards assumption (based on Schoenfeld residuals) is not significant p=0.97.
    Statistical analysis title
    		 Overall survival - RMSTD
    Statistical analysis description
    Effect of treatment (Regorafenib versus placebo)
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.32 [9]
    Method
    		 restricted mean survival time difference
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 7.36
    Notes
    [8] - The mean absolute gain in survival times (PFS and OS, respectively) was estimated and tested using the rmstd method (restricted mean survival time difference, as published by Royston and Parmar in 2011) which remains valid if the proportional hazard assumption appears violated or questionable
    [9] - The curve has been truncated at the maximum time observed, i.e. 41 months

    Secondary: Cumulative incidence of next systemic treatment.

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    End point title
    		 Cumulative incidence of next systemic treatment.
    End point description
    The cumulative incidence of next systemic treatment (NST) has been estimated from the time to start a subsequent line of systemic anticancer therapy, considering death as a competing event. In each group, the cumulative incidence curve has been estimated using the Kalbfleish and Prentice method to consider competing event. Fine and Gray models were used to estimate the subdistribution HR (sub-HR) associated with treatment effect.
    End point type
    Secondary
    End point timeframe
    Cumulative incidence of next systemic treatment
    End point values
    		 Placebo arm Regorafenib arm
    Number of subjects analysed
    62
    64
    Units: Cumulative incidence (%)
    number (confidence interval 95%)
        Cumulative incidence at 6 months (95%CI)
    54.8 (41.7 to 66.2)
    29.7 (19.1 to 41.1)
        Cumulative incidence at 12 months (95%CI)
    80.7 (68.4 to 88.5)
    59.4 (46.4 to 70.2)
        Cumulative incidence at 24 months (95%CI)
    87.1 (75.9 to 93.3)
    79.0 (66.5 to 87.3)
    Statistical analysis title
    		 Adjusted subdistribution hazard ratio (sub-HR)
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.003 [11]
    Method
    		 Fine & Gray model
    Parameter type
    		 Sub-HR
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.82
    Notes
    [10] - Sub-HR adjusted on minimisation factors: histological subtypes (leiomyosarcoma versus synovial sarcoma versus other histological subtype), response to doxorubicin-based chemotherapy (partial response versus stable disease) and centres (after pooling centres with less than 8 patients).
    [11] - Adjusted on minimisation factors: histological subtypes (leiomyosarcoma versus synovial sarcoma versus other histological subtype), response to doxorubicin-based chemotherapy (partial response versus stable disease) and centres
    Statistical analysis title
    		 Not adjusted subdistribution hazard ratio (sub-HR)
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.008
    Method
    		 Fine & Gray model
    Parameter type
    		 Sub-HR
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.87
    Notes
    [12] - Sub-HR: Subdistribution Hazard Ratio, estimated in a Fine and Gray model considering deaths without start of another systemic treatment as competing events

    Post-hoc: Progression free survival (according to the local investigator)

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    End point title
    		 Progression free survival (according to the local investigator)
    End point description
    Progression-free survival (PFS), defined as the time between randomisation and first disease progression, assessed by the local investigator using RECIST 1.1 criteria, or death from any cause. In each group, the PFS curve was estimated using the Kaplan-Meier method
    End point type
    Post-hoc
    End point timeframe
    Tumour evaluation was planned every 8 weeks during the first six cycles and then every 3 months. Patients were followed-up until the end of the study, planned at least 8 months after last patient recruitment.
    End point values
    		 Placebo arm Regorafenib arm
    Number of subjects analysed
    62
    64
    Units: Survival estimate (%)
    number (confidence interval 95%)
        PFS at 6 months (IC95%)
    27.4 (17.0 to 38.8)
    51.6 (38.8 to 63.0)
        PFS at 12 months (IC95%)
    9.7 (3.9 to 18.5)
    17.2 (9.2 to 27.3)
        PFS at 24 months (IC95%)
    6.5 (2.1 to 14.4)
    2.4 (0.7 to 10.8)
    Statistical analysis title
    		 PFS according to the site - adjusted HR
    Statistical analysis description
    Effect of treatment (Regorafenib versus placebo)
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Post-hoc
    Analysis type
    		 other [13]
    P-value
    		 = 0.005
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.85
    Notes
    [13] - Cox model: adjusted HR (IC95%) HR adjusted on minimisation factors: histological subtypes (leiomyosarcoma versus synovial sarcoma versus other histological subtype), response to doxorubicin-based chemotherapy (partial response versus stable disease) and centres (after pooling centres with less than 8 patients). The p-value of the test for proportional hazards assumption (based on Schoenfeld residuals) is not significant p=0.32.
    Statistical analysis title
    		 PFS according to the site - not adjusted HR
    Statistical analysis description
    Effect of treatment (Regorafenib versus placebo)
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.03 [14]
    Method
    		 Regression, Cox
    Parameter type
    		 Not applicable
    Confidence interval
    Notes
    [14] - The HR was not estimated in the Cox model because the assumption of proportional hazards was violated (Schoenfeld residuals test, p-value=0.03) P-value of the logrank test, p-value = 0.03
    Statistical analysis title
    		 PFS according to the site - RMSTD
    Statistical analysis description
    Effect of treatment (Regorafenib versus placebo)
    Comparison groups
    Regorafenib arm v Placebo arm
    Number of subjects included in analysis
    126
    Analysis specification
    Post-hoc
    Analysis type
    		 other [15]
    P-value
    		 = 0.051 [16]
    Method
    		 restricted mean survival time difference
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 4.58
    Notes
    [15] - The mean absolute gain in survival times (PFS and OS, respectively) was estimated and tested using the rmstd method (restricted mean survival time difference, as published by Royston and Parmar in 2011) which remains valid if the proportional hazard assumption appears violated or questionable.
    [16] - The curve has been truncated at the maximum time observed, i.e. 32 months

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety was evaluated during the whole treatment duration up to the visit performed 30 (+/- 7) days after permanent treatment discontinuation. We did not collect adverse events (AEs) unequivocally related to sarcoma progression.
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo arm
    Reporting group description
    		 -

    Reporting group title
    Regorafenib arm
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo arm Regorafenib arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 62 (1.61%)
    15 / 64 (23.44%)
         number of deaths (all causes)
    41
    39
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
    Additional description: Haemorrhage
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
    Additional description: Acute coronary syndrome
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failure
    Additional description: Heart failure
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
    Additional description: Ejection fraction decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
    Additional description: Syncope
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
    Additional description: Fever
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Rash
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
    Additional description: Rash maculo-papular
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    Additional description: Infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo arm Regorafenib arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 62 (77.42%)
    61 / 64 (95.31%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
    Additional description: Tumour pain
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    Vascular disorders
    Haemorrhage
    Additional description: Haemorrhage
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 64 (6.25%)
         occurrences all number
    2
    5
    Hot flashes
    Additional description: Hot flashes
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    1 / 62 (1.61%)
    13 / 64 (20.31%)
         occurrences all number
    3
    20
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    Phlebitis
    Additional description: Phlebitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Anorexia
    Additional description: Anorexia
         subjects affected / exposed
    3 / 62 (4.84%)
    15 / 64 (23.44%)
         occurrences all number
    3
    21
    Face oedema
    Additional description: Face oedema
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    21 / 62 (33.87%)
    40 / 64 (62.50%)
         occurrences all number
    30
    68
    Fever
    Additional description: Fever
         subjects affected / exposed
    2 / 62 (3.23%)
    6 / 64 (9.38%)
         occurrences all number
    2
    7
    General disorders and administration site conditions - other
    Additional description: General disorders and administration site conditions - other
         subjects affected / exposed
    1 / 62 (1.61%)
    6 / 64 (9.38%)
         occurrences all number
    1
    6
    Non-cardiac chest pain
    Additional description: Non-cardiac chest pain
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Oedema
    Additional description: Oedema
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 64 (4.69%)
         occurrences all number
    2
    3
    Pain
    Additional description: Pain
         subjects affected / exposed
    13 / 62 (20.97%)
    19 / 64 (29.69%)
         occurrences all number
    18
    25
    Weight decreased
    Additional description: Weight decreased
         subjects affected / exposed
    3 / 62 (4.84%)
    13 / 64 (20.31%)
         occurrences all number
    4
    15
    Reproductive system and breast disorders
    Vaginal discharge
    Additional description: Vaginal discharge
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 64 (6.25%)
         occurrences all number
    2
    4
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 64 (7.81%)
         occurrences all number
    6
    6
    Hiccups
    Additional description: Hiccups
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Voice alteration
    Additional description: Voice alteration
         subjects affected / exposed
    2 / 62 (3.23%)
    12 / 64 (18.75%)
         occurrences all number
    2
    17
    Psychiatric disorders
    Anxiety
    Additional description: Anxiety
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 64 (3.13%)
         occurrences all number
    2
    3
    Depression
    Additional description: Depression
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    3 / 62 (4.84%)
    2 / 64 (3.13%)
         occurrences all number
    3
    2
    Psychiatric disorders - other
    Additional description: Psychiatric disorders - other
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Blood bilirubin increased
    Additional description: Blood bilirubin increased
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 64 (4.69%)
         occurrences all number
    2
    3
    Gamma-glutamyltransferase increased
    Additional description: Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    Hematuria
    Additional description: Hematuria
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hyperglycaemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    3
    Hyperthyroidism
    Additional description: Hyperthyroidism
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hypertriglyceridemia
    Additional description: Hypertriglyceridemia
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Hyperuricaemia
    Additional description: Hyperuricaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hypoalbuminemia
    Additional description: Hypoalbuminemia
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    Hypocalcemia
    Additional description: Hypocalcemia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
    Additional description: Hypoglycaemia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 64 (3.13%)
         occurrences all number
    1
    2
    Hyponatraemia
    Additional description: Hyponatraemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hypothyroidism
    Additional description: Hypothyroidism
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Investigations - other
    Additional description: Investigations - other
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 64 (6.25%)
         occurrences all number
    6
    5
    Lipase increased
    Additional description: Lipase increased
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Proteinuria
    Additional description: Proteinuria
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    Reduced creatinine clearance
    Additional description: Reduced creatinine clearance
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Transaminases increased
    Additional description: Transaminases increased
         subjects affected / exposed
    3 / 62 (4.84%)
    15 / 64 (23.44%)
         occurrences all number
    7
    33
    Injury, poisoning and procedural complications
    Fall
    Additional description: Fall
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications - other
    Additional description: Injury, poisoning and procedural complications - other
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Wound
    Additional description: Wound
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Cardiac disorders
    Conduction disorder
    Additional description: Conduction disorder
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Cardiac disorders - other
    Additional description: Cardiac disorders - other
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    3
    Ejection fraction decreased
    Additional description: Ejection fraction decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Heart failure
    Additional description: Heart failure
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Pericarditis
    Additional description: Pericarditis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Cognitive disturbance
    Additional description: Cognitive disturbance
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    2 / 62 (3.23%)
    6 / 64 (9.38%)
         occurrences all number
    2
    6
    Headache
    Additional description: Headache
         subjects affected / exposed
    2 / 62 (3.23%)
    8 / 64 (12.50%)
         occurrences all number
    9
    8
    Peripheral neuropathy
    Additional description: Peripheral neuropathy
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 64 (4.69%)
         occurrences all number
    3
    5
    Somnolence
    Additional description: Somnolence
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    3 / 62 (4.84%)
    2 / 64 (3.13%)
         occurrences all number
    3
    2
    Blood disorder - other
    Additional description: Blood disorder - other
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Lymphocyte count decreased
    Additional description: Lymphocyte count decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Neutrophil count decreased
    Additional description: Neutrophil count decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    5
    Platelet count decreased
    Additional description: Platelet count decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    7 / 64 (10.94%)
         occurrences all number
    0
    9
    Ear and labyrinth disorders
    Tinnitus
    Additional description: Tinnitus
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    5
    Vertigo
    Additional description: Vertigo
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Dry eye
    Additional description: Dry eye
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Eye disorders - other
    Additional description: Eye disorders - other
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    3 / 62 (4.84%)
    6 / 64 (9.38%)
         occurrences all number
    8
    9
    Anal fissure
    Additional description: Anal fissure
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    5 / 62 (8.06%)
    13 / 64 (20.31%)
         occurrences all number
    7
    19
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    13 / 62 (20.97%)
    24 / 64 (37.50%)
         occurrences all number
    17
    33
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    4 / 62 (6.45%)
    10 / 64 (15.63%)
         occurrences all number
    4
    11
    Cheilitis
    Additional description: Cheilitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders - other
    Additional description: Gastrointestinal disorders - other
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 64 (1.56%)
         occurrences all number
    3
    2
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    3
    Mucositis oral
    Additional description: Mucositis oral
         subjects affected / exposed
    5 / 62 (8.06%)
    26 / 64 (40.63%)
         occurrences all number
    5
    38
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    10 / 62 (16.13%)
    8 / 64 (12.50%)
         occurrences all number
    12
    11
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 64 (6.25%)
         occurrences all number
    4
    5
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Dry skin
    Additional description: Dry skin
         subjects affected / exposed
    6 / 62 (9.68%)
    4 / 64 (6.25%)
         occurrences all number
    7
    4
    Eczema
    Additional description: Eczema
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hyperkeratosis
    Additional description: Hyperkeratosis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Nail disorder
    Additional description: Nail disorder
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 64 (1.56%)
         occurrences all number
    5
    1
    Palmar-plantar erythrodysaesthesia syndrome
    Additional description: Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    7 / 62 (11.29%)
    30 / 64 (46.88%)
         occurrences all number
    9
    48
    Rash
    Additional description: Rash
         subjects affected / exposed
    1 / 62 (1.61%)
    12 / 64 (18.75%)
         occurrences all number
    1
    19
    Urticaria
    Additional description: Urticaria
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Urinary frequency
    Additional description: Urinary frequency
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
    Additional description: Urinary incontinence
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Urinary tract obstruction
    Additional description: Urinary tract obstruction
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
    Additional description: Hyperthyroidism
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hypothyroidism
    Additional description: Hypothyroidism
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    4
    Thyroid disorder
    Additional description: Thyroid disorder
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders - other
    Additional description: Musculoskeletal and connective tissue disorders - other
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    4 / 62 (6.45%)
    18 / 64 (28.13%)
         occurrences all number
    4
    24
    Osteonecrosis of jaw
    Additional description: Osteonecrosis of jaw
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Infection
    Additional description: Infection
         subjects affected / exposed
    2 / 62 (3.23%)
    8 / 64 (12.50%)
         occurrences all number
    2
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2018
    Compliance with Regulation (EU) No. 2016/79 (RGPD) and the CNIL reference methodology, MR001 of May 3, 2018, and clarification of the statistical methodology, data studied, and bibliography. Addition of a clarification for the declaration of SAEs.
    31 Dec 2018
    The patient diary (monthly and quarterly): containing useful information on taking the treatment, the study schedule, and a table for recording daily doses of the treatment. The BP monitoring sheet: A sheet for recording hypertension measurements taken at home by the patient, a nurse, or their treating physician. Update of the list of investigators
    04 Feb 2019
    Update on the BI of regorafenib and impact on the protocol
    16 Oct 2019
    Update of selection criteria , TTT blinding procedures, update of schedule and update of CP list + update of BI
    24 Mar 2020
    MSI - recruitment suspended due to the health situation
    14 Apr 2020
    MUS for the possibility of sending TTT to the patient's home, remote consultations,
    25 May 2020
    MSI - resumption of recruitment
    09 Oct 2020
    Modification of sample size determination with extension of the recruitment period, update of the study schedule, list of CP and BI
    22 Feb 2021
    Protocol modification: clarification of an inclusion criterion, treatment administration procedures, procedures for lifting the blind, addition of the COVID-19 vaccine to the list of authorized treatments + synopsis + update of the list of CP + BI + NICE (clarification on treatment administration and duration of contraception after stopping treatment)
    03 Feb 2022
    Extension of the recruitment period by 6 months following a 2-month suspension of recruitment due to a problem with the supply of TTT and update of the CP list.
    28 Sep 2022
    Extension of the recruitment period by 5 months + Update of the CP list + Modification of NICE following BI update + RGPD info
    17 Apr 2023
    Protocol modification: addition of exploratory objective, clarification of centralized review procedures List of CP: update
    04 Sep 2023
    Update of the CP list => modification of the CP list Update of the Regorafenib IB => modification of the protocol: Rare AE

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/40210087
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