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    Clinical Trial Results:
    A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Single-Agent MLN0128 and the Combination of MLN0128+MLN1117 Compared With Everolimus in the Treatment of Adult Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma That Has Progressed on Vascular Endothelial Growth Factor-Targeted Therapy

    Summary
    EudraCT number
    		 2015-002133-22
    Trial protocol
    		 ES   FR   PL   GB   IT  
    Global end of trial date
    13 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2021
    First version publication date
    29 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C31005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02724020
    WHO universal trial number (UTN)
    		 U1111-1172-1808
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, MA, United States, 02421
    Public contact
    Study Director , Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director , Takeda, TrialDisclosures@takeda.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
    13 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the efficacy and safety of single-agent MLN0128 and the combination of MLN0128 + MLN1117 compared with everolimus in the treatment of participants with metastatic clear-cell renal cell carcinoma (mccRCC) that have progressed on vascular endothelial growth factor (VEGF)-targeted therapy.
    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
    30 Jun 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
    Canada: 5
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    96
    EEA total number of subjects
    60
    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)
    49
    From 65 to 84 years
    47
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at approximately 60-70 investigative sites in Czech Republic, France, Italy, Poland, Spain, United Kingdom, Canada and United States from 30 June 2016 to 13 October 2020.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of metastatic clear-cell renal cell carcinoma were randomised at a ratio of 1 :1 :1 to open label treatment period with single-agent MLN0128 and the combination of MLN0128 and MLN1117 compared with single-agent everolimus.

    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: Single-agent Everolimus 10 mg QD
    Arm description
    		 Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to end of study).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus capsules.

    Arm title
    		 Arm B: Single-agent MLN0128 30 mg QW
    Arm description
    		 MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to end of study).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MLN0128
    Investigational medicinal product code
    Other name
    TAK-228, INK0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MLN0128 capsules.

    Arm title
    		 Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Arm description
    		 MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to end of study).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MLN0128
    Investigational medicinal product code
    Other name
    TAK-228, INK0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MLN0128 capsules.

    Investigational medicinal product name
    MLN1117
    Investigational medicinal product code
    Other name
    TAK-117, INK1117
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MLN1117 capsules.

    Number of subjects in period 1
    		Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Started
    32
    32
    32
    Treated (Safety Analysis Set)
    32
    32
    31
    Completed
    0
    0
    0
    Not completed
    32
    32
    32
         Death
    16
    18
    19
         Withdrawal by Subject
    1
    3
    5
         Site Terminated by Sponsor
    15
    8
    8
         Lost to follow-up
    -
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Single-agent Everolimus 10 mg QD
    Reporting group description
    		 Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to end of study).

    Reporting group title
    Arm B: Single-agent MLN0128 30 mg QW
    Reporting group description
    		 MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to end of study).

    Reporting group title
    Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Reporting group description
    		 MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to end of study).

    Reporting group values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD Total
    Number of subjects
    		 32 32 32 96
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 15 20 14 49
        From 65-84 years
    		 17 12 18 47
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ( 11.41 ) 61.6 ( 8.90 ) 63.3 ( 9.06 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 10 7 23
        Male
    		 26 22 25 73
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 2 2
        Not Hispanic or Latino
    		 28 30 27 85
        Unknown or Not Reported
    		 4 2 3 9
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 1 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 1 1
        White
    		 27 29 27 83
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 4 3 4 11
    Region of Enrollment
    Units: Subjects
        Czech Republic
    		 1 1 2 4
        France
    		 4 2 2 8
        Italy
    		 11 9 4 24
        Poland
    		 2 2 1 5
        Spain
    		 6 6 7 19
        United Kingdom
    		 4 4 9 17
        Canada
    		 2 1 2 5
        United States
    		 2 7 5 14
    Height
    Number analyzed is the number of participants with data available for height at Baseline. n= 31, 32, 31.
    Units: cm
        arithmetic mean (standard deviation)
    		 170.23 ( 8.489 ) 171.16 ( 10.626 ) 172.01 ( 8.349 ) -
    Weight
    Number analyzed is the number of participants with data available for weight at Baseline. n= 31, 32, 32.
    Units: kg
        arithmetic mean (standard deviation)
    		 75.69 ( 12.449 ) 78.12 ( 15.473 ) 80.40 ( 17.896 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Single-agent Everolimus 10 mg QD
    Reporting group description
    		 Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to end of study).

    Reporting group title
    Arm B: Single-agent MLN0128 30 mg QW
    Reporting group description
    		 MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to end of study).

    Reporting group title
    Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Reporting group description
    		 MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to end of study).

    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 occurs first. Per Response Evaluation Criteria in Solid Tumors (RECIST) v1 .1 criteria. 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 randomised participants.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to disease progression or death (up to 51 months)
    End point values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects analysed
    32
    32
    32
    Units: months
        median (confidence interval 95%)
    3.8 (2.0 to 5.4)
    3.6 (1.9 to 5.7)
    3.1 (1.9 to 5.4)
    Statistical analysis title
    		 Statistical Analysis 1 for PFS
    Statistical analysis description
    HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm B: Single-agent MLN0128 30 mg QW
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.388
    Method
    		 Stratified Log-rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 2.36
    Statistical analysis title
    		 Statistical Analysis 2 for PFS
    Statistical analysis description
    HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
    Comparison groups
    Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD v Arm A: Single-agent Everolimus 10 mg QD
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.667
    Method
    		 Stratified Log-rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 2.52

    Secondary: Number of Participants with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An AE was defined as any untoward medical occurrence in participants administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. TEAE was defined as the event that occur after administration of the first dose of study drug and through 30 days after the last dose of study drug. Safety Analysis Set included participants who receive at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through 30 days after the last dose of study drug (approximately up to 31 months)
    End point values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects analysed
    32
    32
    31
    Units: participants
    32
    30
    31
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival in months was defined as the time from the date of randomisation to the date of death. Full Analysis Set included all randomised participants. 99999 indicates upper limit of 95% CI was not estimable due to fewer number of participants with events.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through 30 days after the last dose of study drug (up to 51 months)
    End point values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects analysed
    32
    32
    32
    Units: months
        median (confidence interval 95%)
    22.4 (8.2 to 99999)
    16.2 (9.0 to 19.9)
    18.1 (6.2 to 23.4)
    Statistical analysis title
    		 Statistical Analysis 1 for OS
    Statistical analysis description
    HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm B: Single-agent MLN0128 30 mg QW
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.212
    Method
    		 Stratified Log-rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 3.49
    Statistical analysis title
    		 Statistical Analysis 2 for OS
    Statistical analysis description
    HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.546
    Method
    		 Stratified Log-rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 2.98

    Secondary: Time-to-progression (TTP)

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    End point title
    		 Time-to-progression (TTP)
    End point description
    TTP in months is defined as the time from the date of randomisation 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 randomised participants.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to disease progression or death (up to 51 months)
    End point values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects analysed
    32
    32
    32
    Units: months
        median (confidence interval 95%)
    3.8 (2.0 to 15.6)
    3.5 (1.9 to 7.4)
    3.7 (1.9 to 10.5)
    Statistical analysis title
    		 Statistical Analysis 1 for TTP
    Statistical analysis description
    HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm B: Single-agent MLN0128 30 mg QW
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.156
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 3.05
    Statistical analysis title
    		 Statistical Analysis 2 for TTP
    Statistical analysis description
    HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.667
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.79

    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 among response evaluable analysis set who achieve a best overall response of complete response (CR) or partial response (PR) based on investigators assessment of response following RECIST 1 .1. 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. Response Evaluable Analysis Set included participants who receive at least 1 dose of study drug, have measurable disease at Baseline and have 1 postbaseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to disease progression or death (up to 51 months)
    End point values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects analysed
    32
    32
    31
    Units: percentage of participants
        number (not applicable)
    15.6
    0
    6.5
    Statistical analysis title
    		 Statistical Analysis for ORR
    Statistical analysis description
    Odds ratio and 95% CI was obtained using a stratified Cochran–Mantel–Haenszel (CMH) model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category. As prespecified in protocol, the statistical analysis was performed between arms - Arm A: Single-agent Everolimus 10 mg QD and Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD only.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.08
         upper limit
    		 2.22

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR is defined as the percentage of participants who achieve 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. Response Evaluable Analysis Set included participants who receive at least 1 dose of study drug, have measurable disease at Baseline and have 1 postbaseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to disease progression or death (up to 51 months)
    End point values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects analysed
    32
    32
    31
    Units: percentage of participants
        number (not applicable)
    62.5
    50.0
    54.8
    Statistical analysis title
    		 Statistical Analysis 1 for CBR
    Statistical analysis description
    Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm B: Single-agent MLN0128 30 mg QW
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 1.69
    Statistical analysis title
    		 Statistical Analysis 2 for CBR
    Statistical analysis description
    Odds ratio and 95% Cl was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 2.21

    Secondary: CBR with SD Duration of at least 16 Weeks

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    End point title
    		 CBR with SD Duration of at least 16 Weeks
    End point description
    CBR with SD duration of at least 4 months (CBR-16) was defined as the percentage of participants who achieve CR or PR of any duration or have SD with duration of at least 16 weeks. 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. Response Evaluable Analysis Set included participants who receive at least 1 dose of study drug, have measurable disease at Baseline and have 1 postbaseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects analysed
    32
    32
    31
    Units: percentage of participants
        number (not applicable)
    40.6
    25.0
    29.0
    Statistical analysis title
    		 Statistical Analysis 1 for CBR (16 weeks)
    Statistical analysis description
    Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm B: Single-agent MLN0128 30 mg QW
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 1.38
    Statistical analysis title
    		 Statistical Analysis 2 for CBR (16 weeks)
    Statistical analysis description
    Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
    Comparison groups
    Arm A: Single-agent Everolimus 10 mg QD v Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 1.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths: From first dose of study drug through end of the study (up to 51 months); Serious and other (non-serious) AEs: From first dose of study drug through 30 days after the last dose of study drug (up to 31 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of AEs and abnormal laboratory findings to report irrespective of relation to study treatment. Deaths: Data is reported for FAS: all randomised participants. Adverse Events: Data for is reported for Safety Analysis Set: participants who received >=1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Arm A: Single-agent Everolimus 10 mg QD
    Reporting group description
    		 Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to end of study).

    Reporting group title
    Arm B: Single-agent MLN0128 30 mg QW
    Reporting group description
    		 MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to end of study).

    Reporting group title
    Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Reporting group description
    		 MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to end of study).

    Serious adverse events
    		 Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 32 (59.38%)
    13 / 32 (40.63%)
    15 / 31 (48.39%)
         number of deaths (all causes)
    16
    18
    19
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    T-cell lymphoma
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infarction
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pyrexia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Hiccups
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Femur fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Pelvic fracture
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (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
    Road traffic accident
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (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
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (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
    Stomatitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Urinary retention
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (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
    Muscular weakness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Pathological fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Abscess jaw
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (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
    Pulmonary sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (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
    Dehydration
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 32 (100.00%)
    29 / 32 (90.63%)
    31 / 31 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 32 (18.75%)
    3 / 32 (9.38%)
    4 / 31 (12.90%)
         occurrences all number
    8
    4
    4
    Hypotension
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    5
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 32 (59.38%)
    12 / 32 (37.50%)
    9 / 31 (29.03%)
         occurrences all number
    27
    19
    11
    Fatigue
         subjects affected / exposed
    10 / 32 (31.25%)
    6 / 32 (18.75%)
    12 / 31 (38.71%)
         occurrences all number
    12
    9
    16
    Pyrexia
         subjects affected / exposed
    10 / 32 (31.25%)
    3 / 32 (9.38%)
    5 / 31 (16.13%)
         occurrences all number
    24
    4
    8
    Chest pain
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 32 (9.38%)
    1 / 31 (3.23%)
         occurrences all number
    2
    3
    1
    Influenza like illness
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    4
    1
    1
    Chills
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    2
    2
    1
    Oedema peripheral
         subjects affected / exposed
    4 / 32 (12.50%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    6
    0
    0
    Pain
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         occurrences all number
    1
    1
    2
    Peripheral swelling
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    10 / 32 (31.25%)
    10 / 32 (31.25%)
    5 / 31 (16.13%)
         occurrences all number
    12
    14
    5
    Cough
         subjects affected / exposed
    11 / 32 (34.38%)
    10 / 32 (31.25%)
    3 / 31 (9.68%)
         occurrences all number
    24
    12
    5
    Dyspnoea exertional
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    0
    Epistaxis
         subjects affected / exposed
    4 / 32 (12.50%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    0
    Nasal dryness
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
         occurrences all number
    4
    2
    2
    Insomnia
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
         occurrences all number
    3
    2
    2
    Investigations
    Weight decreased
         subjects affected / exposed
    4 / 32 (12.50%)
    9 / 32 (28.13%)
    5 / 31 (16.13%)
         occurrences all number
    4
    9
    5
    Blood creatinine increased
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 32 (9.38%)
    2 / 31 (6.45%)
         occurrences all number
    2
    4
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    4 / 31 (12.90%)
         occurrences all number
    0
    1
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    4 / 31 (12.90%)
         occurrences all number
    0
    2
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0
    Amylase increased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    5
    Haemoglobin decreased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    5
    0
    0
    Lipase increased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 32 (18.75%)
    4 / 32 (12.50%)
    4 / 31 (12.90%)
         occurrences all number
    8
    5
    5
    Dizziness
         subjects affected / exposed
    3 / 32 (9.38%)
    4 / 32 (12.50%)
    0 / 31 (0.00%)
         occurrences all number
    5
    4
    0
    Dysgeusia
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    3
    0
    3
    Presyncope
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    0
    Tremor
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    2
    Memory impairment
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 32 (12.50%)
    6 / 32 (18.75%)
    4 / 31 (12.90%)
         occurrences all number
    4
    7
    5
    Leukocytosis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 32 (21.88%)
    22 / 32 (68.75%)
    17 / 31 (54.84%)
         occurrences all number
    12
    43
    28
    Vomiting
         subjects affected / exposed
    7 / 32 (21.88%)
    14 / 32 (43.75%)
    13 / 31 (41.94%)
         occurrences all number
    9
    32
    23
    Diarrhoea
         subjects affected / exposed
    13 / 32 (40.63%)
    8 / 32 (25.00%)
    11 / 31 (35.48%)
         occurrences all number
    20
    15
    17
    Constipation
         subjects affected / exposed
    9 / 32 (28.13%)
    12 / 32 (37.50%)
    5 / 31 (16.13%)
         occurrences all number
    11
    19
    6
    Stomatitis
         subjects affected / exposed
    12 / 32 (37.50%)
    6 / 32 (18.75%)
    3 / 31 (9.68%)
         occurrences all number
    16
    7
    3
    Abdominal pain
         subjects affected / exposed
    5 / 32 (15.63%)
    5 / 32 (15.63%)
    6 / 31 (19.35%)
         occurrences all number
    5
    5
    7
    Dyspepsia
         subjects affected / exposed
    4 / 32 (12.50%)
    4 / 32 (12.50%)
    3 / 31 (9.68%)
         occurrences all number
    5
    5
    4
    Dry mouth
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    5 / 31 (16.13%)
         occurrences all number
    1
    3
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 32 (3.13%)
    3 / 31 (9.68%)
         occurrences all number
    3
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         occurrences all number
    2
    2
    2
    Mouth ulceration
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    6
    0
    1
    Dysphagia
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 32 (9.38%)
    12 / 32 (37.50%)
    6 / 31 (19.35%)
         occurrences all number
    3
    21
    6
    Rash
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 32 (9.38%)
    5 / 31 (16.13%)
         occurrences all number
    3
    6
    5
    Dermatitis acneiform
         subjects affected / exposed
    6 / 32 (18.75%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    7
    2
    0
    Dry skin
         subjects affected / exposed
    4 / 32 (12.50%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    5
    0
    3
    Rash maculo-papular
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    3 / 31 (9.68%)
         occurrences all number
    2
    1
    3
    Erythema
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    1
    Dysuria
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    2
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 32 (15.63%)
    7 / 32 (21.88%)
    2 / 31 (6.45%)
         occurrences all number
    6
    7
    2
    Pain in extremity
         subjects affected / exposed
    6 / 32 (18.75%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
         occurrences all number
    13
    2
    2
    Arthralgia
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 32 (3.13%)
    3 / 31 (9.68%)
         occurrences all number
    5
    1
    4
    Musculoskeletal pain
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    3
    3
    0
    Bone pain
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    4
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
         occurrences all number
    5
    2
    2
    Influenza
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    2
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    2
    Pneumonia
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    3
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 32 (46.88%)
    10 / 32 (31.25%)
    11 / 31 (35.48%)
         occurrences all number
    19
    15
    14
    Hyperglycaemia
         subjects affected / exposed
    4 / 32 (12.50%)
    4 / 32 (12.50%)
    8 / 31 (25.81%)
         occurrences all number
    5
    6
    13
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 32 (15.63%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    6
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    5 / 32 (15.63%)
    2 / 31 (6.45%)
         occurrences all number
    0
    7
    3
    Dehydration
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    1
    2
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
         occurrences all number
    0
    3
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    3
    Hyperuricaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
         occurrences all number
    0
    3
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Iron deficiency
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2017
    The primary purpose of Amendment 4 was to make following changes. Change the dosing conditions for participants receiving weekly MLN0128 in Arm B, such that participants take their doses with a light meal.Add a PK sample collection at 3 to 6 hours post-dose on Cycle 1 Day 1 for participants receiving weekly MLN0128 in Arm B.Clarify that disease assessment images will be collected and reviewed by a sponsor-specified central imaging vendor.Update the description of investigator responsibilities.Clarify the procedures for fasting serum glucose monitoring.Clarify that study drugs should be taken with approximately 240 mL of water.Clarify the instructions for dose modification due to adverse events of alanine aminotransferase or aspartate aminotransferase elevation.
    03 Oct 2017
    The primary purpose of Amendment 6 was to make following changes.Remove the exclusion criterion relating to treatment with strong cytochrome P450 (CYP) inhibitors or inducers.Update the list of concomitant medications prohibited during the study.Update the description of potential drug-drug interactions.Update the list of relevant CYP inhibitors and inducers.Remove dietary restrictions related to CYP inhibitors and inducers.Clarify language surrounding the use of contrast with magnetic resonance imaging (MRI).
    03 Dec 2018
    The primary purpose of Amendment 9 was to make following changes. Removed long-term follow-up, the option for cross-over treatment from Arm A to Arm B or Arm C and added the option for participants to transfer to a Post-Trial Access (PTA) program.Study closure was defined as when the last participant discontinues treatment.A new section was added detailing the PTA program.Modified the exclusion criterion relating to proton-pump inhibitors (PPIs).Revised the restrictions on concomitant use of proton-pump inhibitors (PPIs).Physical examinations after Screening were changed to symptom-directed physical examinations. The requirement for a confirmatory scan 4 weeks from the previous scan for participants with a complete response (CR) or partial response (PR) was removed. A recommendation was added for radiographic assessment every 6 months after 12 cycles of treatment.The requirement for weight to be measured at Day 15 of Cycles 1 and 2 was removed.

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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