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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients with Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF).

    Summary
    EudraCT number
    		 2018-001991-39
    Trial protocol
    		 GB   BE   NL   DE   IT  
    Global end of trial date
    17 Oct 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

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    Trial identification
    Sponsor protocol code
    NIR-DT-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03785964
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 138207
    Sponsors
    Sponsor organisation name
    SpringWorks Therapeutics
    Sponsor organisation address
    100 Washington Blvd, Stamford, United States, CT 06902
    Public contact
    Clinical Operations, SpringWorks Subsidiary 2, PBC, clinical@springworkstx.com
    Scientific contact
    Clinical Operations, SpringWorks Subsidiary 2, PBC, clinical@springworkstx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    07 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to determine the efficacy (as defined by progression free survival [PFS]) of nirogacestat in adult participants with progressing DT/AF.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and with all applicable laws and regulations of the locales and countries where the study was conducted, and in compliance with Good Clinical Practice Guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Apr 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
    Netherlands: 8
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United States: 90
    Worldwide total number of subjects
    142
    EEA total number of subjects
    39
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    136
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multicenter study with a total of 52 sites across 7 countries (Belgium, Canada, Germany, Italy, Netherlands, United Kingdom, and United States of America). A total of 201 participants were screened and 142 participants were enrolled and randomised.

    Pre-assignment
    Screening details
    		 All eligible participants must have had histologically confirmed Desmoid Tumor /Aggressive Fibromatosis (by local pathologist prior to informed consent) that had progressed by ≥ 20% as measured by Response Evaluation Criteria in Solid Tumors version 1.1 within 12 months of the screening visit scan.

    Period 1
    Period 1 title
    Double-Blind Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind Phase - Nirogacestat
    Arm description
    		 Nirogacestat 150 mg twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nirogacestat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nirogacestat 50 mg tablets (3 tablets; 150 mg) twice daily (BID) orally continuously for 28-day cycles.

    Arm title
    		 Double-Blind Phase - Placebo
    Arm description
    		 Placebo twice daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 50mg (sugar pill manufactured to mimic nirogacestat 50 mg tablet) (3 tablets) BID orally continuously for 28-day cycles.

    Number of subjects in period 1
    		Double-Blind Phase - Nirogacestat Double-Blind Phase - Placebo
    Started
    70
    72
    Treated (Safety Population)
    69
    72
    Completed
    12
    35
    Not completed
    58
    37
         Adverse event, serious fatal
    -
    1
         Unqualified clinical progression
    1
    1
         Adverse event, non-fatal
    14
    -
         Ongoing (still on treatment)
    36
    23
         Other reason
    5
    11
         Participant non-compliance
    1
    1
         Not treated
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Phase - Nirogacestat
    Reporting group description
    		 Nirogacestat 150 mg twice daily

    Reporting group title
    Double-Blind Phase - Placebo
    Reporting group description
    		 Placebo twice daily.

    Reporting group values
    		 Double-Blind Phase - Nirogacestat Double-Blind Phase - Placebo Total
    Number of subjects
    		 70 72 142
    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)
    		 67 69 136
        From 65-84 years
    		 3 3 6
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.5 ( 14.43 ) 37.0 ( 12.89 ) -
    Gender categorical
    Units: Subjects
        Female
    		 45 47 92
        Male
    		 25 25 50
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat Population - Nirogacestat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat Population consisted of all participants who were enrolled and randomized to study treatment.

    Subject analysis set title
    Intent-to-treat Population - Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat Population consisted of all participants who were enrolled and randomized to study treatment.

    Subject analysis set title
    Safety Population - Nirogacestat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.

    Subject analysis set title
    Safety Population - Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.

    Subject analysis sets values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo Safety Population - Nirogacestat Safety Population - Placebo
    Number of subjects
    70
    72
    69
    72
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    67
    69
    66
    69
        From 65-84 years
    3
    3
    3
    3
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.5 ( 14.43 )
    37.0 ( 12.89 )
    37.3 ( 14.48 )
    37.0 ( 12.89 )
    Gender categorical
    Units: Subjects
        Female
    45
    47
    44
    47
        Male
    25
    25
    25
    25

    End points

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    End points reporting groups
    Reporting group title
    Double-Blind Phase - Nirogacestat
    Reporting group description
    		 Nirogacestat 150 mg twice daily

    Reporting group title
    Double-Blind Phase - Placebo
    Reporting group description
    		 Placebo twice daily.

    Subject analysis set title
    Intent-to-treat Population - Nirogacestat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat Population consisted of all participants who were enrolled and randomized to study treatment.

    Subject analysis set title
    Intent-to-treat Population - Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat Population consisted of all participants who were enrolled and randomized to study treatment.

    Subject analysis set title
    Safety Population - Nirogacestat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.

    Subject analysis set title
    Safety Population - Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.

    Primary: Efficacy: Progression Free Survival (PFS)

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    End point title
    		 Efficacy: Progression Free Survival (PFS)
    End point description
    Progression will be determined radiographically using RECIST v1.1 (Eisenhauer, 2009) or clinically as assessed by the investigator. Clinical progression is defined as the onset or worsening of symptoms resulting in a global deterioration of health status causing the permanent discontinuation from study treatment and the initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for DT/AF. Events of clinical progression will be adjudicated by an independent blinded central Endpoint Adjudication Committee (EAC) which will qualify events of clinical progression for inclusion in the PFS endpoint prior to study unblinding according to an EAC Review Charter.
    End point type
    Primary
    End point timeframe
    On the first day of every 3 cycles (each cycle is 28 days) until disease progression is observed or death, whichever comes first, assessed up to approximately 2 years.
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70 [1]
    72 [2]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    15.1 (8.4 to 99999)
    Notes
    [1] - 99999 denotes not evaluated as < 50% of the participants had events in Nirogacestat treatment arm
    [2] - 99999 denotes that upper 95% CI is not reached
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio was estimated from stratified Cox proportional hazards model using the exact method for ties, stratified by tumor location. Placebo was the reference treatment.
    Comparison groups
    Intent-to-treat Population - Nirogacestat v Intent-to-treat Population - Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.55
    Notes
    [3] - p-value was from a one-sided stratified log-rank test with placebo as reference.

    Secondary: Efficacy: Objective Response Rate Using RECIST Version 1.1 Criteria

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    End point title
    		 Efficacy: Objective Response Rate Using RECIST Version 1.1 Criteria
    End point description
    Objective response rate (ORR) is defined as the proportion of participants having a confirmed Best Overall Response (BOR) of CR or PR by central reader using RECIST v1.1 criteria. Responses obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of ORR. However, any responses, which occurred after a new anticancer therapy was received, will not be included. ORR is presented by percentages of responders.
    End point type
    Secondary
    End point timeframe
    On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years.
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70
    72
    Units: Percentage of participants
        number (confidence interval 95%)
    41 (29.8 to 53.8)
    8 (3.1 to 17.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cochran-Mantel-Haenszel test for general association stratified by tumor location. Placebo was reference treatment.
    Comparison groups
    Intent-to-treat Population - Nirogacestat v Intent-to-treat Population - Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Two-sided p-value

    Secondary: Efficacy: Change From Baseline at Cycle 10 in the Brief Pain Inventory (BPI) Average Pain Intensity (API) Score

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    End point title
    		 Efficacy: Change From Baseline at Cycle 10 in the Brief Pain Inventory (BPI) Average Pain Intensity (API) Score
    End point description
    The Brief Pain Inventory consists of 9 questions and utilizes a 11-point Numerical pain Rating Scale from 0-10 measuring severity from "no pain" to "pain as bad as you can imagine," with a 24-hour recall period. Average Pain Intensity is calculated as the 7-day average (when results on at least 4 days for a VISIT are available) of Brief Pain Inventory Question #3 - Worst Pain in last 24 hours. The minimum and maximum of the actual score are (0, 8) for Nirogacestat and (0,9) for Placebo, respectively. A positive change from Baseline value indicates worsening of Average Pain Intensity and a negative change from Baseline value indicates improvement of Average Pain Intensity. The minimum and maximum of change from baseline score are (-7, 3) for Nirogacestat and (-5, 5) for Placebo, respectively.
    End point type
    Secondary
    End point timeframe
    Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70
    72
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -1.583 (-2.157 to -1.009)
    -0.241 (-0.822 to 0.340)
    Statistical analysis title
    		 Superiority Mixed Models Analysis
    Statistical analysis description
    Mixed model with repeated measures (MMRM) with treatment and visit as factors, Baseline Brief Pain Inventory Short Form score and primary tumor location (intra-abdominal or extra-abdominal) as covariates, included baseline by visit and treatment by visit interactions. Only participants with a Baseline and at least one post-baseline score were included in the analysis. 40 and 31 participants contributed to this analysis at Cycle 10 from Nirogacestat and Placebo respectively
    Comparison groups
    Intent-to-treat Population - Nirogacestat v Intent-to-treat Population - Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - An unstructured covariance structure was used and degrees of freedom were estimated using the Kenward-Roger approximation.

    Secondary: Efficacy: Change From Baseline at Cycle 10 in the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Tumor Symptom Scale (DTSS) - Total Score

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    End point title
    		 Efficacy: Change From Baseline at Cycle 10 in the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Tumor Symptom Scale (DTSS) - Total Score
    End point description
    The DEsmoid Tumor Symptom Scale is an 11-point, numeric rating scale from 0 to 10 to measure severity from "none" to "as bad as you can imagine," with a 24-hour recall period. The Total Symptom Score is calculated as the mean of Pain items (Items 1-3) as a single score, then a mean of this with items 4-7). Weekly summary scores will be created by averaging the daily scores over the 7 days period prior to each visit. A weekly score will be derived only if 4 or more out of 7 days period have non-missing scores. The weekly summary score will be used in analyses. If no weekly summary score is calculable, the participant will have data considered as missing at that visit. Higher scores represent worse symptom severity. The minimum and maximum of the actual score are (0,7) for Nirogacestat and (0,10) for Placebo. A positive change from Baseline value indicated worsening of symptoms. The minimum and maximum of change from baseline are (-6,1) for Nirogacestat and (-4,5) for Placebo.
    End point type
    Secondary
    End point timeframe
    Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years.
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70
    72
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -1.110 (-1.569 to -0.651)
    0.457 (-0.009 to 0.923)
    Statistical analysis title
    		 Superiority Mixed Models Analysis
    Statistical analysis description
    Mixed model with repeated measures (MMRM) with treatment and visit as factors, Baseline DEsmoid Tumor Symptom Scale score and primary tumor location (intra-abdominal or extra-abdominal) as covariates, included baseline by visit and treatment by visit interactions. Only participants with a Baseline and at least one post-baseline score were included in the analysis. 40 and 32 participants contributed to this analysis at Cycle 10 from Nirogacestat and Placebo respectively.
    Comparison groups
    Intent-to-treat Population - Nirogacestat v Intent-to-treat Population - Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [6] - An unstructured covariance structure was used and degrees of freedom were estimated using the Kenward-Roger approximation.

    Secondary: Efficacy: Change From Baseline in the GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Tumor Impact Scale (DTIS) - Physical Functioning Domain Score

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    End point title
    		 Efficacy: Change From Baseline in the GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Tumor Impact Scale (DTIS) - Physical Functioning Domain Score
    End point description
    The items are evaluated on a 5-point Likert Scale ranging from "none of the time" to "all of the time" to measure frequency, with a 7-day recall period. The Physical Function Domain Score are calculated as the average Item 01 Moving, Item 02 Reaching (Freq), Item 06 Vigorous Activity, Item 7 Moderate Activity, and Item 08 Accomplished Less. Higher scores represent worst impact severity. The minimum and maximum of the actual score are (1, 5) for Nirogacestat and (1,5) for Placebo, respectively. A positive change from baseline value indicates worsening impact and a negative change from baseline value indicates improvement in impact. The minimum and maximum of change from baseline score are (-3, 0) for Nirogacestat and (-1, 2) for Placebo, respectively.
    End point type
    Secondary
    End point timeframe
    On the last day of every cycle (each cycle is 28 days) through study completion, average of 2 years.
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70
    72
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.613 (-0.808 to -0.418)
    0.094 (-0.113 to 0.300)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed model with repeated measures (MMRM) with treatment and visit as factors, Baseline score and primary tumor location (intra-abdominal or extra-abdominal) as covariates, included baseline by visit and treatment by visit interactions. Only participants with a Baseline and at least one post-baseline score were included in the analysis. 39 and 28 participants contributed to this analysis at Cycle 10 from Nirogacestat and Placebo respectively.
    Comparison groups
    Intent-to-treat Population - Nirogacestat v Intent-to-treat Population - Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [7] - An unstructured covariance structure was used and degrees of freedom were estimated using the Kenward-Roger approximation.

    Secondary: Efficacy: Change From Baseline at Cycle10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale

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    End point title
    		 Efficacy: Change From Baseline at Cycle10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale
    End point description
    The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A high score for the global health status/QoL represents a high QoL. The minimum and maximum of the actual score are (33, 100) for Nirogacestat and (8,92) for Placebo, respectively. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of global health status. The minimum and maximum of change from baseline score are (-58, 67) for Nirogacestat and (-67, 42) for Placebo, respectively.
    End point type
    Secondary
    End point timeframe
    Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70
    72
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    2.935 (-3.115 to 8.985)
    -8.466 (-15.065 to -1.867)
    Statistical analysis title
    		 Superiority Mixed Models Analysis
    Statistical analysis description
    Mixed model with repeated measures (MMRM) with treatment and visit as factors, Baseline score and primary tumor location (intra-abdominal or extra-abdominal) as covariates, included baseline by visit and treatment by visit interactions. Only participants with a Baseline and at least one post-baseline score were included in the analysis. 38 and 27 participants contributed to this analysis at Cycle 10 from Nirogacestat and Placebo respectively.
    Comparison groups
    Intent-to-treat Population - Placebo v Intent-to-treat Population - Nirogacestat
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.006
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [8] - An unstructured covariance structure was used and degrees of freedom were estimated using the Kenward-Roger approximation.

    Secondary: Efficacy: Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning

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    End point title
    		 Efficacy: Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning
    End point description
    e EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A high score for a Physical functional scale represents a high/healthy level of functioning. The minimum and maximum of the actual score are (27, 100) for Nirogacestat and (7,100) for Placebo, respectively. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of physical functioning scores. The minimum and maximum of change from baseline score are (-7, 40) for Nirogacestat and (-40, 27) for Placebo, respectively.
    End point type
    Secondary
    End point timeframe
    Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70
    72
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    9.143 (5.619 to 12.668)
    -5.225 (-9.060 to -1.390)
    Statistical analysis title
    		 Superiority Mixed Models Analysis
    Statistical analysis description
    Mixed model with repeated measures (MMRM) with treatment and visit as factors, Baseline score and primary tumor location (intra-abdominal or extra-abdominal) as covariates, included baseline by visit and treatment by visit interactions. Only participants with a Baseline and at least one post-baseline score were included in the analysis. 38 and 28 participants contributed to this analysis at Cycle 10 from Nirogacestat and Placebo respectively.
    Comparison groups
    Intent-to-treat Population - Nirogacestat v Intent-to-treat Population - Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - An unstructured covariance structure was used and degrees of freedom were estimated using the Kenward-Roger approximation.

    Secondary: Efficacy: Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Role Functioning

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    End point title
    		 Efficacy: Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Role Functioning
    End point description
    The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of global health status and functioning scores. The minimum and maximum of change from baseline score are (-17, 83) for Nirogacestat and (-100, 50) for Placebo, respectively. The minimum and maximum of the actual score are (33, 100) for Nirogacestat and (0,100) for Placebo, respectively.
    End point type
    Secondary
    End point timeframe
    Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
    End point values
    		 Intent-to-treat Population - Nirogacestat Intent-to-treat Population - Placebo
    Number of subjects analysed
    70
    72
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    13.293 (7.080 to 19.506)
    -5.590 (-12.320 to 1.139)
    Statistical analysis title
    		 Superiority Mixed Models Analysis
    Statistical analysis description
    Mixed model with repeated measures (MMRM) with treatment and visit as factors, Baseline score and primary tumor location (intra-abdominal or extra-abdominal) as covariates, included baseline by visit and treatment by visit interactions. Only participants with a Baseline and at least one post-baseline score were included in the analysis. 38 and 28 participants contributed to this analysis at Cycle 10 from Nirogacestat and Placebo respectively.
    Comparison groups
    Intent-to-treat Population - Nirogacestat v Intent-to-treat Population - Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [10] - An unstructured covariance structure was used and degrees of freedom were estimated using the Kenward-Roger approximation.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All SAEs and AEs were collected from the time of signing ICF until 30 days after the last dose of study treatment, an average of 1 years and 4 months and up to 2 years and 10 months.
    Adverse event reporting additional description
    One patient randomized to Nirogacestat arm, discontinued prior to receiving any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Safety Population - Nirogacestat
    Reporting group description
    		 One patient randomized to Nirogacestat arm, discontinued prior to receiving any study drug.

    Reporting group title
    Safety Population- Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Safety Population - Nirogacestat Safety Population- Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 69 (20.29%)
    8 / 72 (11.11%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Spindle cell sarcoma
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal fistula
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian failure
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature menopause
         subjects affected / exposed
    3 / 69 (4.35%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
         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
    Rash maculo-papular
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (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
    Abdominal abscess
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 69 (0.00%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population - Nirogacestat Safety Population- Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 69 (100.00%)
    69 / 72 (95.83%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    5 / 69 (7.25%)
    12 / 72 (16.67%)
         occurrences all number
    5
    16
    Vascular disorders
    Hot flush
         subjects affected / exposed
    13 / 69 (18.84%)
    4 / 72 (5.56%)
         occurrences all number
    14
    4
    Hypertension
         subjects affected / exposed
    10 / 69 (14.49%)
    8 / 72 (11.11%)
         occurrences all number
    18
    11
    Hypotension
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 72 (1.39%)
         occurrences all number
    6
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    Fatigue
         subjects affected / exposed
    35 / 69 (50.72%)
    26 / 72 (36.11%)
         occurrences all number
    56
    31
    Influenza like illness
         subjects affected / exposed
    7 / 69 (10.14%)
    2 / 72 (2.78%)
         occurrences all number
    7
    2
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 69 (7.25%)
    5 / 72 (6.94%)
         occurrences all number
    5
    5
    Oedema peripheral
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    Pyrexia
         subjects affected / exposed
    5 / 69 (7.25%)
    6 / 72 (8.33%)
         occurrences all number
    7
    10
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    5 / 69 (7.25%)
    0 / 72 (0.00%)
         occurrences all number
    5
    0
    Menstruation irregular
         subjects affected / exposed
    6 / 69 (8.70%)
    4 / 72 (5.56%)
         occurrences all number
    6
    4
    Ovarian failure
         subjects affected / exposed
    12 / 69 (17.39%)
    0 / 72 (0.00%)
         occurrences all number
    14
    0
    Premature menopause
         subjects affected / exposed
    8 / 69 (11.59%)
    0 / 72 (0.00%)
         occurrences all number
    11
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 69 (15.94%)
    3 / 72 (4.17%)
         occurrences all number
    18
    3
    Dysphonia
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 72 (0.00%)
         occurrences all number
    4
    0
    Dyspnoea
         subjects affected / exposed
    11 / 69 (15.94%)
    4 / 72 (5.56%)
         occurrences all number
    15
    4
    Epistaxis
         subjects affected / exposed
    10 / 69 (14.49%)
    1 / 72 (1.39%)
         occurrences all number
    11
    1
    Nasal congestion
         subjects affected / exposed
    7 / 69 (10.14%)
    2 / 72 (2.78%)
         occurrences all number
    11
    2
    Oropharyngeal pain
         subjects affected / exposed
    5 / 69 (7.25%)
    3 / 72 (4.17%)
         occurrences all number
    5
    3
    Productive cough
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 72 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 69 (8.70%)
    5 / 72 (6.94%)
         occurrences all number
    8
    6
    Insomnia
         subjects affected / exposed
    6 / 69 (8.70%)
    8 / 72 (11.11%)
         occurrences all number
    11
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 69 (17.39%)
    6 / 72 (8.33%)
         occurrences all number
    17
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 69 (15.94%)
    8 / 72 (11.11%)
         occurrences all number
    16
    12
    Blood follicle stimulating hormone increased
         subjects affected / exposed
    7 / 69 (10.14%)
    1 / 72 (1.39%)
         occurrences all number
    9
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    8 / 69 (11.59%)
    10 / 72 (13.89%)
         occurrences all number
    8
    10
    Weight decreased
         subjects affected / exposed
    6 / 69 (8.70%)
    7 / 72 (9.72%)
         occurrences all number
    10
    8
    Weight increased
         subjects affected / exposed
    11 / 69 (15.94%)
    5 / 72 (6.94%)
         occurrences all number
    19
    12
    White blood cell count decreased
         subjects affected / exposed
    2 / 69 (2.90%)
    5 / 72 (6.94%)
         occurrences all number
    3
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 69 (11.59%)
    4 / 72 (5.56%)
         occurrences all number
    10
    5
    Headache
         subjects affected / exposed
    20 / 69 (28.99%)
    11 / 72 (15.28%)
         occurrences all number
    25
    15
    Memory impairment
         subjects affected / exposed
    4 / 69 (5.80%)
    2 / 72 (2.78%)
         occurrences all number
    5
    2
    Paraesthesia
         subjects affected / exposed
    1 / 69 (1.45%)
    4 / 72 (5.56%)
         occurrences all number
    1
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 69 (10.14%)
    8 / 72 (11.11%)
         occurrences all number
    16
    18
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 69 (5.80%)
    3 / 72 (4.17%)
         occurrences all number
    4
    4
    Abdominal pain
         subjects affected / exposed
    11 / 69 (15.94%)
    9 / 72 (12.50%)
         occurrences all number
    16
    18
    Abdominal pain upper
         subjects affected / exposed
    5 / 69 (7.25%)
    1 / 72 (1.39%)
         occurrences all number
    6
    1
    Constipation
         subjects affected / exposed
    7 / 69 (10.14%)
    7 / 72 (9.72%)
         occurrences all number
    9
    8
    Diarrhoea
         subjects affected / exposed
    58 / 69 (84.06%)
    25 / 72 (34.72%)
         occurrences all number
    129
    32
    Dry mouth
         subjects affected / exposed
    8 / 69 (11.59%)
    3 / 72 (4.17%)
         occurrences all number
    9
    3
    Dyspepsia
         subjects affected / exposed
    0 / 69 (0.00%)
    6 / 72 (8.33%)
         occurrences all number
    0
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 69 (8.70%)
    3 / 72 (4.17%)
         occurrences all number
    6
    3
    Mouth ulceration
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 72 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    37 / 69 (53.62%)
    28 / 72 (38.89%)
         occurrences all number
    53
    32
    Stomatitis
         subjects affected / exposed
    20 / 69 (28.99%)
    3 / 72 (4.17%)
         occurrences all number
    43
    3
    Vomiting
         subjects affected / exposed
    14 / 69 (20.29%)
    14 / 72 (19.44%)
         occurrences all number
    21
    17
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    13 / 69 (18.84%)
    1 / 72 (1.39%)
         occurrences all number
    13
    1
    Dermatitis acneiform
         subjects affected / exposed
    15 / 69 (21.74%)
    0 / 72 (0.00%)
         occurrences all number
    22
    0
    Dry skin
         subjects affected / exposed
    11 / 69 (15.94%)
    5 / 72 (6.94%)
         occurrences all number
    13
    5
    Hidradenitis
         subjects affected / exposed
    6 / 69 (8.70%)
    0 / 72 (0.00%)
         occurrences all number
    12
    0
    Pruritus
         subjects affected / exposed
    9 / 69 (13.04%)
    6 / 72 (8.33%)
         occurrences all number
    12
    6
    Rash
         subjects affected / exposed
    13 / 69 (18.84%)
    5 / 72 (6.94%)
         occurrences all number
    15
    6
    Rash maculo-papular
         subjects affected / exposed
    22 / 69 (31.88%)
    4 / 72 (5.56%)
         occurrences all number
    40
    8
    Hyperhidrosis
         subjects affected / exposed
    4 / 69 (5.80%)
    2 / 72 (2.78%)
         occurrences all number
    5
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 69 (11.59%)
    9 / 72 (12.50%)
         occurrences all number
    9
    9
    Back pain
         subjects affected / exposed
    9 / 69 (13.04%)
    7 / 72 (9.72%)
         occurrences all number
    10
    9
    Flank pain
         subjects affected / exposed
    2 / 69 (2.90%)
    4 / 72 (5.56%)
         occurrences all number
    2
    5
    Muscular weakness
         subjects affected / exposed
    5 / 69 (7.25%)
    2 / 72 (2.78%)
         occurrences all number
    7
    2
    Muscle spasms
         subjects affected / exposed
    4 / 69 (5.80%)
    4 / 72 (5.56%)
         occurrences all number
    6
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 69 (2.90%)
    4 / 72 (5.56%)
         occurrences all number
    2
    5
    Myalgia
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 72 (0.00%)
         occurrences all number
    4
    0
    Pain in extremity
         subjects affected / exposed
    5 / 69 (7.25%)
    6 / 72 (8.33%)
         occurrences all number
    6
    6
    Infections and infestations
    COVID-19
         subjects affected / exposed
    12 / 69 (17.39%)
    11 / 72 (15.28%)
         occurrences all number
    12
    13
    Folliculitis
         subjects affected / exposed
    9 / 69 (13.04%)
    0 / 72 (0.00%)
         occurrences all number
    25
    0
    Sinusitis
         subjects affected / exposed
    6 / 69 (8.70%)
    0 / 72 (0.00%)
         occurrences all number
    9
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 69 (7.25%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 69 (15.94%)
    8 / 72 (11.11%)
         occurrences all number
    13
    11
    Hypokalaemia
         subjects affected / exposed
    8 / 69 (11.59%)
    1 / 72 (1.39%)
         occurrences all number
    12
    1
    Hypocalcaemia
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 72 (0.00%)
         occurrences all number
    6
    0
    Hypophosphataemia
         subjects affected / exposed
    29 / 69 (42.03%)
    5 / 72 (6.94%)
         occurrences all number
    66
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Nov 2018
    Protocol Amendment 1 • The MD Anderson Symptom Inventory PRO was replaced with the EORTC QLQ 30 because it more accurately captured concepts important to patients with desmoid tumors. • The PROMIS PF and the 3 additional questions were added to supplement the DTIS. • Stratification by target tumor location was changed from “favorable” versus “unfavorable” to “intra-abdominal” versus “extra-abdominal” to more accurately reflect the way these tumors are described in clinical practice. • Situations where breaking the blind would be acceptable were further detailed and broken out into 3 distinct categories: emergency situations, confirmed progressive disease, and all estimated number of PFS events have been observed. • The language regarding the calculation and analysis of the secondary endpoint of duration of response was revised for clarity.
    14 Oct 2019
    Protocol Amendment 2 • The sample size was increased for screened and randomized patients. • Updated inclusion/exclusion criteria. • Added potential risk of nirogacestat to interact with drugs that are substrates of cytochrome P450 3A4. • Added potential risk of gastric acid reducing agents to reduce absorption and lower exposure prior to dosing of nirogacestat. • Added new section for AESIs. • Changed serial PK draw and observation period from 2 hours to 3 hours. • Updated the methodology for selecting target lesions to specify that target lesions will be selected by the investigator. The location of the target tumor(s) selected by the investigators as the basis for inclusion in the study were documented on the Pre Randomization RECIST v1.1 Calculation Worksheet.
    27 Jan 2020
    Protocol Amendment 3 • Clarification to ensure menstrual irregularities/infertility were captured as part of the medical history. • Added blood sampling for hormone levels from males and females. • Added risks of Notch-related effects on reproductive function and fertility. • Reproductive system disorders including amenorrhea and premature menopause/primary ovarian insufficiency were added as AESIs to enable additional safety follow-up while gastrointestinal events including nausea, vomiting/dyspepsia, and diarrhea were removed as these were known and expected events related to nirogacestat.
    09 Feb 2021
    Protocol Amendment 5 No participants were initially consented under Protocol Amendment 5 as screening had previously closed. • Revised the definition of PFS to include events of clinical progression in the analysis of PFS for the primary endpoint.

    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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