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    Clinical Trial Results:
    An Open-label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With Fulvestrant in Women With ER-Positive/HER2- Negative Advanced or Metastatic Breast Cancer That Has Progressed During or After Aromatase Inhibitor Therapy

    Summary
    EudraCT number
    		 2015-003612-20
    Trial protocol
    		 ES  
    Global end of trial date
    25 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Dec 2020
    First version publication date
    06 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C31006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02756364
    WHO universal trial number (UTN)
    		 U1111-1174-2165
    Sponsors
    Sponsor organisation name
    Millennium Pharmaceuticals, Inc.
    Sponsor organisation address
    40 Lansdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to compare the progression free survival (PFS) of participants treated with the combination of fulvestrant plus daily sapanisertib and fulvestrant plus weekly sapanisertib versus participants treated with single-agent fulvestrant.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 90
    Country: Number of subjects enrolled
    United States: 51
    Worldwide total number of subjects
    141
    EEA total number of subjects
    90
    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)
    96
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 50 investigative sites in Spain and the United States from 28 July 2016 to 25 November 2019. After all data was collected and participants were transitioned to post-trial access, the Sponsor stopped the study site, defined as 'Site terminated by the Sponsor'.

    Pre-assignment
    Screening details
    		 Female participants with a diagnosis of estrogen receptor (ER)-positive/human epidermal growth factor receptor-2 (HER2)-negative advanced or metastatic breast cancer that has progressed during or after aromatase inhibitor therapy were enrolled in 1:1:1 ratio to receive fulvestrant, fulvestrant + sapanisertib QD and fulvestrant + sapanisertib QW.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Fulvestrant 500 mg
    Arm description
    		 Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant IM injection.

    Arm title
    		 Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Arm description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant IM injection.

    Investigational medicinal product name
    Sapanisertib 4 mg QD
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsule.

    Arm title
    		 Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Arm description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulvestrant 500 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant IM injection.

    Investigational medicinal product name
    Sapanisertib 30 mg QW
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsule.

    Number of subjects in period 1
    		Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Started
    46
    47
    48
    Completed
    0
    0
    0
    Not completed
    46
    47
    48
         Adverse event, serious fatal
    20
    15
    18
         Site Terminated by Sponsor
    24
    30
    21
         Withdrawal by Patient
    2
    1
    8
         Lost to follow-up
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Fulvestrant 500 mg
    Reporting group description
    		 Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).

    Reporting group title
    Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Reporting group description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).

    Reporting group title
    Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Reporting group description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).

    Reporting group values
    		 Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW Total
    Number of subjects
    		 46 47 48 141
    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)
    		 30 32 34 96
        From 65-84 years
    		 16 15 14 45
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.3 ( 10.10 ) 60.3 ( 10.92 ) 57.9 ( 12.04 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 46 47 48 141
        Male
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 4 7 16
        Not Hispanic or Latino
    		 37 41 40 118
        Unknown or Not Reported
    		 4 2 1 7
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 0 1 2
        White
    		 44 45 44 133
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 1 2 3 6
    Region of Enrollment
    Units: Subjects
        Spain
    		 23 34 33 90
        United States
    		 23 13 15 51

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Fulvestrant 500 mg
    Reporting group description
    		 Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).

    Reporting group title
    Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Reporting group description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).

    Reporting group title
    Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Reporting group description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Full Analysis Set included all randomized participants.
    End point type
    Primary
    End point timeframe
    Up to 40 months
    End point values
    		 Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects analysed
    46
    47
    48
    Units: months
        median (confidence interval 95%)
    3.5 (1.9 to 5.6)
    7.2 (3.9 to 10.6)
    5.6 (4.1 to 9.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.537
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.26
    Notes
    [1] - HR obtained by stratified Cox proportional hazard model with treatment arm, original interactive response technology (IRT) stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.849
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.45
    Notes
    [2] - HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death. 9999 indicates the median and upper limit of CI was not estimable due to fewer number of participants with event. 99999 indicates the upper limit of confidence interval (CI) was not estimable due to fewer number of participants with event. Full Analysis Set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Up to 164 weeks
    End point values
    		 Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects analysed
    46
    47
    48
    Units: months
        median (confidence interval 95%)
    30.5 (21.5 to 99999)
    9999 (29.9 to 9999)
    34.2 (20.0 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.276
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.4
    Notes
    [3] - HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.47
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.68
    Notes
    [4] - HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    TTP was defined as the time from the date of randomization to the date of first documentation of progression. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Full Analysis Set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Up to 40 months
    End point values
    		 Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects analysed
    46
    47
    48
    Units: months
        median (confidence interval 95%)
    3.5 (1.9 to 5.6)
    7.2 (5.5 to 10.6)
    5.6 (4.1 to 9.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.495
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.25
    Notes
    [5] - HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.646
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.38
    Notes
    [6] - HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants who achieve a best response of complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 40 months
    End point values
    		 Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects analysed
    46
    47
    47
    Units: percentage of participants
        number (not applicable)
    10.9
    21.3
    12.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 7.29
    Notes
    [7] - The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 4.39
    Notes
    [8] - The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR was defined as the percentage of participants who achieved a best response of CR, PR, or stable disease (SD) of any duration. CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 40 months
    End point values
    		 Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects analysed
    46
    47
    47
    Units: percentage of participants
        number (not applicable)
    60.9
    74.5
    66.0
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW v Arm A: Fulvestrant 500 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 4.44
    Notes
    [9] - The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Fulvestrant 500 mg v Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 6.94
    Notes
    [10] - The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).

    Secondary: Percentage of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Percentage of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 164 weeks
    End point values
    		 Arm A: Fulvestrant 500 mg Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Number of subjects analysed
    46
    47
    47
    Units: percentage of participants
        number (not applicable)
    89.1
    100.0
    100.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 164 weeks
    Adverse event reporting additional description
    At each visit investigator had to document any occurrence of adverse events and abnormal laboratory findings.Any event spontaneously reported by participant or observed by investigator was recorded,irrespective of relation to study treatment.All-cause Mortality(deaths) were collected in FAS population.AEs were collected in Safety Analysis Set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Arm A: Fulvestrant 500 mg
    Reporting group description
    		 Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-days cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).

    Reporting group title
    Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
    Reporting group description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-days cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-days treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).

    Reporting group title
    Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Reporting group description
    		 Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-days treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).

    Serious adverse events
    		 Arm A: Fulvestrant 500 mg Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 46 (17.39%)
    8 / 47 (17.02%)
    13 / 47 (27.66%)
         number of deaths (all causes)
    20
    18
    15
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis acute
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Fulvestrant 500 mg Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 46 (82.61%)
    47 / 47 (100.00%)
    47 / 47 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 46 (15.22%)
    5 / 47 (10.64%)
    4 / 47 (8.51%)
         occurrences all number
    26
    16
    8
    Hot flush
         subjects affected / exposed
    5 / 46 (10.87%)
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    5
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 46 (23.91%)
    21 / 47 (44.68%)
    13 / 47 (27.66%)
         occurrences all number
    14
    99
    30
    Pyrexia
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 47 (8.51%)
    4 / 47 (8.51%)
         occurrences all number
    3
    7
    5
    Fatigue
         subjects affected / exposed
    10 / 46 (21.74%)
    11 / 47 (23.40%)
    17 / 47 (36.17%)
         occurrences all number
    11
    29
    27
    Injection site pain
         subjects affected / exposed
    5 / 46 (10.87%)
    2 / 47 (4.26%)
    2 / 47 (4.26%)
         occurrences all number
    6
    2
    2
    Pain
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 47 (2.13%)
    3 / 47 (6.38%)
         occurrences all number
    1
    2
    3
    Malaise
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 47 (8.51%)
    1 / 47 (2.13%)
         occurrences all number
    0
    25
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 46 (15.22%)
    2 / 47 (4.26%)
    5 / 47 (10.64%)
         occurrences all number
    10
    2
    6
    Cough
         subjects affected / exposed
    5 / 46 (10.87%)
    1 / 47 (2.13%)
    7 / 47 (14.89%)
         occurrences all number
    6
    1
    9
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 46 (10.87%)
    2 / 47 (4.26%)
    5 / 47 (10.64%)
         occurrences all number
    5
    2
    5
    Depression
         subjects affected / exposed
    3 / 46 (6.52%)
    3 / 47 (6.38%)
    4 / 47 (8.51%)
         occurrences all number
    3
    3
    5
    Insomnia
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 47 (8.51%)
    3 / 47 (6.38%)
         occurrences all number
    0
    4
    3
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 46 (2.17%)
    6 / 47 (12.77%)
    11 / 47 (23.40%)
         occurrences all number
    1
    17
    22
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 46 (4.35%)
    6 / 47 (12.77%)
    6 / 47 (12.77%)
         occurrences all number
    2
    8
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 46 (4.35%)
    4 / 47 (8.51%)
    6 / 47 (12.77%)
         occurrences all number
    3
    7
    10
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 47 (6.38%)
    5 / 47 (10.64%)
         occurrences all number
    1
    8
    7
    Blood cholesterol increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    5 / 47 (10.64%)
         occurrences all number
    0
    2
    6
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 47 (2.13%)
    3 / 47 (6.38%)
         occurrences all number
    1
    1
    4
    Neutrophil count decreased
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 47 (4.26%)
    3 / 47 (6.38%)
         occurrences all number
    0
    8
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 46 (19.57%)
    10 / 47 (21.28%)
    4 / 47 (8.51%)
         occurrences all number
    10
    20
    4
    Dizziness
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 47 (10.64%)
    4 / 47 (8.51%)
         occurrences all number
    1
    5
    10
    Dysgeusia
         subjects affected / exposed
    0 / 46 (0.00%)
    7 / 47 (14.89%)
    8 / 47 (17.02%)
         occurrences all number
    0
    7
    8
    Somnolence
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    0
    0
    4
    Tremor
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    3 / 47 (6.38%)
         occurrences all number
    0
    1
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 47 (4.26%)
    3 / 47 (6.38%)
         occurrences all number
    3
    4
    7
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 46 (19.57%)
    41 / 47 (87.23%)
    23 / 47 (48.94%)
         occurrences all number
    10
    118
    40
    Vomiting
         subjects affected / exposed
    4 / 46 (8.70%)
    33 / 47 (70.21%)
    14 / 47 (29.79%)
         occurrences all number
    5
    152
    26
    Diarrhoea
         subjects affected / exposed
    1 / 46 (2.17%)
    13 / 47 (27.66%)
    24 / 47 (51.06%)
         occurrences all number
    2
    28
    71
    Stomatitis
         subjects affected / exposed
    3 / 46 (6.52%)
    15 / 47 (31.91%)
    16 / 47 (34.04%)
         occurrences all number
    3
    26
    25
    Constipation
         subjects affected / exposed
    8 / 46 (17.39%)
    6 / 47 (12.77%)
    4 / 47 (8.51%)
         occurrences all number
    8
    6
    5
    Dry mouth
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 47 (6.38%)
    12 / 47 (25.53%)
         occurrences all number
    1
    3
    13
    Abdominal pain upper
         subjects affected / exposed
    1 / 46 (2.17%)
    9 / 47 (19.15%)
    5 / 47 (10.64%)
         occurrences all number
    1
    10
    18
    Abdominal pain
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 47 (8.51%)
    4 / 47 (8.51%)
         occurrences all number
    3
    4
    6
    Dyspepsia
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 47 (6.38%)
    4 / 47 (8.51%)
         occurrences all number
    0
    4
    4
    Gastritis
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 47 (4.26%)
    3 / 47 (6.38%)
         occurrences all number
    0
    2
    5
    Odynophagia
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 47 (6.38%)
    1 / 47 (2.13%)
         occurrences all number
    0
    3
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 46 (0.00%)
    7 / 47 (14.89%)
    14 / 47 (29.79%)
         occurrences all number
    0
    13
    34
    Pruritus
         subjects affected / exposed
    0 / 46 (0.00%)
    8 / 47 (17.02%)
    15 / 47 (31.91%)
         occurrences all number
    0
    13
    24
    Dry skin
         subjects affected / exposed
    2 / 46 (4.35%)
    3 / 47 (6.38%)
    3 / 47 (6.38%)
         occurrences all number
    2
    3
    5
    Alopecia
         subjects affected / exposed
    2 / 46 (4.35%)
    3 / 47 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    2
    3
    2
    Erythema
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 47 (4.26%)
    3 / 47 (6.38%)
         occurrences all number
    0
    6
    3
    Rash maculo-papular
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    3 / 47 (6.38%)
         occurrences all number
    0
    1
    5
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 47 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    0
    3
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 46 (15.22%)
    2 / 47 (4.26%)
    6 / 47 (12.77%)
         occurrences all number
    10
    3
    7
    Pain in extremity
         subjects affected / exposed
    6 / 46 (13.04%)
    4 / 47 (8.51%)
    3 / 47 (6.38%)
         occurrences all number
    7
    4
    5
    Arthralgia
         subjects affected / exposed
    5 / 46 (10.87%)
    3 / 47 (6.38%)
    4 / 47 (8.51%)
         occurrences all number
    6
    5
    4
    Bone pain
         subjects affected / exposed
    4 / 46 (8.70%)
    4 / 47 (8.51%)
    2 / 47 (4.26%)
         occurrences all number
    4
    4
    2
    Myalgia
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 47 (8.51%)
    2 / 47 (4.26%)
         occurrences all number
    0
    9
    3
    Musculoskeletal pain
         subjects affected / exposed
    4 / 46 (8.70%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    4
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    3
    1
    1
    Flank pain
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 47 (6.38%)
    0 / 47 (0.00%)
         occurrences all number
    0
    3
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 46 (4.35%)
    7 / 47 (14.89%)
    7 / 47 (14.89%)
         occurrences all number
    2
    9
    7
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 47 (2.13%)
    5 / 47 (10.64%)
         occurrences all number
    2
    1
    5
    Nasopharyngitis
         subjects affected / exposed
    4 / 46 (8.70%)
    3 / 47 (6.38%)
    5 / 47 (10.64%)
         occurrences all number
    4
    4
    5
    Respiratory tract infection
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 47 (2.13%)
    2 / 47 (4.26%)
         occurrences all number
    3
    1
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    10 / 46 (21.74%)
    26 / 47 (55.32%)
    27 / 47 (57.45%)
         occurrences all number
    15
    115
    185
    Decreased appetite
         subjects affected / exposed
    5 / 46 (10.87%)
    19 / 47 (40.43%)
    15 / 47 (31.91%)
         occurrences all number
    5
    30
    21
    Dehydration
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 47 (6.38%)
    1 / 47 (2.13%)
         occurrences all number
    0
    4
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2016
    The primary purpose of this amendment was to make typographical changes.
    07 Mar 2017
    The primary purposes of this amendment were to update the dosing conditions for participants receiving QW sapanisertib in Arm C, to update the PK sampling schedule to reflect the dosing change in Arm C, to update the window for baseline disease assessment, to clarify procedures and/or timing for imaging collection and clinical laboratory evaluations, to update the inclusion and exclusion criteria, to update the safety reporting contact information, to clarify the guidance relating to dose modifications, to update the list of investigator responsibilities, to update references to study manuals throughout the protocol, and to update the participant enrollment plan.
    02 Oct 2017
    The primary purposes of this amendment were to update those sections affected by new nonclinical data for sapanisertib metabolism by specific cytochrome P-450 (CYP) isoforms. The study’s exclusion criteria, list of prohibited concomitant medications, list of relevant CYP inhibitors and inducers, and dietary restrictions related to CYP inhibitors and inducers were updated accordingly. The number of study sites, recommendations for initiation of crossover treatment, and guidance for fasting serum glucose post-dose collection were also updated.

    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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