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    Clinical Trial Results:
    A Phase II Randomized Trial of the Combination of Ridaforolimus and Exemestane, Compared to Ridaforolimus, Dalotuzumab and Exemestane in High Proliferation, Estrogen Receptor Positive

    Summary
    EudraCT number
    2012-000335-11
    Trial protocol
    ES   SE   CZ   BE   PT   DE   DK   IT  
    Global end of trial date
    15 Mar 2018

    Results information
    Results version number
    v1
    This version publication date
    07 Mar 2019
    First version publication date
    07 Mar 2019
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    8669-064
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01605396
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    MK-8669-064: Merck Registration Number
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    15 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study is to evaluate the efficacy of the triplet of ridaforolimus, dalotuzumab and exemestane compared to the combination of ridaforolimus and exemestane in post-menopausal participants with breast cancer. The primary hypothesis of the study is that the triplet of ridaforolimus, dalotuzumab and exemestane will improve progression free survival (PFS) compared to ridaforolimus and exemestane.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Portugal: 5
    Worldwide total number of subjects
    80
    EEA total number of subjects
    36
    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)
    54
    From 65 to 84 years
    25
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Of 196 screened participants, 80 were randomized to either ridaforolimus plus dalotuzumab plus exemestane or ridaforolimus plus exemestane.

    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
    Ridaforolimus + Dalotuzumab + Exemestane
    Arm description
    Participants receive ridaforolimus 10 mg orally (PO) every 5 days (QD x 5) plus dalotuzumab 10 mg/kg intravenously (IV) every week (QW) plus exemestane 25 mg PO every day (QD) in 28-day cycles until documented disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Ridaforolimus
    Investigational medicinal product code
    Other name
    MK-8669
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ridaforolimus 10 mg tablet, administered PO at a dose of 10 mg (triplet) or 30 mg (doublet) depending upon randomization, on Days 1-5, 8-12, 15-19, & 22-26 of 28-day cycle.

    Investigational medicinal product name
    Dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab 10 mg/kg administered IV weekly on Days 1, 8, 15, and 22 of 28-day cycle.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg tablet administered PO QD.

    Arm title
    Ridaforolimus + Exemestane
    Arm description
    Participants receive ridaforolimus 30 mg PO QD x 5 plus exemestane 25 mg PO QD treatment in 28-day cycles until documented disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Ridaforolimus
    Investigational medicinal product code
    Other name
    MK-8669
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ridaforolimus 10 mg tablet, administered PO at a dose of 10 mg (triplet) or 30 mg (doublet) depending upon randomization, on Days 1-5, 8-12, 15-19, & 22-26 of 28-day cycle.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg tablet administered PO QD.

    Number of subjects in period 1
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane
    Started
    40
    40
    Treated
    39
    40
    Completed
    0
    0
    Not completed
    40
    40
         Physician decision
    2
    2
         Transfer Off Study
    4
    5
         Non-Compliance With Study Drug
    1
    1
         Adverse event, non-fatal
    5
    3
         Progressive Disease
    23
    27
         Consent withdrawn by subject
    4
    2
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ridaforolimus + Dalotuzumab + Exemestane
    Reporting group description
    Participants receive ridaforolimus 10 mg orally (PO) every 5 days (QD x 5) plus dalotuzumab 10 mg/kg intravenously (IV) every week (QW) plus exemestane 25 mg PO every day (QD) in 28-day cycles until documented disease progression or unacceptable toxicity.

    Reporting group title
    Ridaforolimus + Exemestane
    Reporting group description
    Participants receive ridaforolimus 30 mg PO QD x 5 plus exemestane 25 mg PO QD treatment in 28-day cycles until documented disease progression or unacceptable toxicity.

    Reporting group values
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane Total
    Number of subjects
    40 40 80
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    60.7 ± 9.0 57.7 ± 11.8 -
    Sex: Female, Male
    Units: Subjects
        Female
    40 40 80
        Male
    0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    9 14 23
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    2 1 3
        White
    26 24 50
        More than one race
    3 1 4
        Unknown or Not Reported
    0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    4 4 8
        Not Hispanic or Latino
    35 34 69
        Unknown or Not Reported
    1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Ridaforolimus + Dalotuzumab + Exemestane
    Reporting group description
    Participants receive ridaforolimus 10 mg orally (PO) every 5 days (QD x 5) plus dalotuzumab 10 mg/kg intravenously (IV) every week (QW) plus exemestane 25 mg PO every day (QD) in 28-day cycles until documented disease progression or unacceptable toxicity.

    Reporting group title
    Ridaforolimus + Exemestane
    Reporting group description
    Participants receive ridaforolimus 30 mg PO QD x 5 plus exemestane 25 mg PO QD treatment in 28-day cycles until documented disease progression or unacceptable toxicity.

    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 randomization to progressive disease, or death, whichever occurs first. Response was assessed according to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by a blinded independent central review (BICR). According to RECIST 1.1, progressive disease (PD) was defined as a 20% relative increase in the sum of diameters (SOD) of target lesions, taking as reference the nadir SOD and an absolute increase of >5 mm in the SOD, or the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and median PFS (95% confidence interval [CI]) in weeks was reported for each treatment arm. All randomized participants were analyzed.
    End point type
    Primary
    End point timeframe
    From Day 1 through post-study follow-up visit (up to ~19 months)
    End point values
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane
    Number of subjects analysed
    40
    40
    Units: Weeks
        median (confidence interval 95%)
    23.29 (8.71 to 38.43)
    31.86 (16.00 to 39.29)
    Statistical analysis title
    PFS: HR Comparison of Treatment
    Statistical analysis description
    Hazard ratio (HR) and p-value for treatment difference based on Cox regression model with Efron tie handling for treatment comparison (Ridaforolimus + Dalotuzumab + Exemestane arm versus Ridaforolimus + Exemestane arm).
    Comparison groups
    Ridaforolimus + Dalotuzumab + Exemestane v Ridaforolimus + Exemestane
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.565
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.72

    Secondary: Percent Change from Baseline in Sum of Target Lesion Diameters at Week 16

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    End point title
    Percent Change from Baseline in Sum of Target Lesion Diameters at Week 16
    End point description
    The percent change from baseline to Week 16 in the sum of target lesion diameters as determined by anatomic imaging was defined as the line length (i.e., diameter) for each target lesion identified at baseline summed across all lesions at baseline, and separately at each post-baseline time point. The primary analysis was conducted using a constrained longitudinal data analysis (cLDA) method and target lesion measurements according to the BICR. Percent change from baseline in sum of target lesion diameters at Week 16 was reported for each treatment arm. All randomized participants with available Week 16 target lesion measurements were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane
    Number of subjects analysed
    15
    32
    Units: percent change
        arithmetic mean (standard deviation)
    -19.3 ± 20.4
    -10.7 ± 28.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Objective Response (Objective Response Rate [ORR])

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    End point title
    Percentage of Participants with Objective Response (Objective Response Rate [ORR])
    End point description
    ORR was defined as the percentage of participants whose best response was complete response (CR; disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal) or partial response (PR; at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 and based on BICR. ORR was reported for each treatment arm. All randomized participants were analyzed.
    End point type
    Secondary
    End point timeframe
    From Day 1 through post-study follow-up visit (up to ~19 months)
    End point values
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane
    Number of subjects analysed
    40
    40
    Units: Percentage of Participants
        number (confidence interval 95%)
    15.0 (5.7 to 29.8)
    25.0 (12.7 to 41.2)
    Statistical analysis title
    ORR: Difference in Response Rates
    Statistical analysis description
    Miettinen and Nurminen’s method was used to compare ORR between the two treatment arms (Ridaforolimus + Dalotuzumab + Exemestane arm versus Ridaforolimus + Exemestane arm), and to calculate a p-value and 95% confidence interval (CI) for the difference in response rates.
    Comparison groups
    Ridaforolimus + Dalotuzumab + Exemestane v Ridaforolimus + Exemestane
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.267
    Method
    Miettinen and Nurminen’s Method
    Parameter type
    Difference of Percentages
    Point estimate
    -10
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.8
         upper limit
    8

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date last known to be alive. OS was analyzed using the Kaplan-Meier method and median OS (95% confidence interval [CI]) in months was reported for each treatment arm. All randomized participants were analyzed. A value of 9999 indicates that median OS (95% CI) could not be calculated due to an insufficient number of deaths on study (i.e. median OS was not reached).
    End point type
    Secondary
    End point timeframe
    From Day 1 through post-study follow-up visit (up to ~19 months)
    End point values
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane
    Number of subjects analysed
    40
    40
    Units: Weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (60.6 to 9999)
    Statistical analysis title
    OS: HR Comparison of Treatment
    Statistical analysis description
    HR and p-value for treatment difference based on Cox regression model with Efron tie handling for treatment comparison (Ridaforolimus + Dalotuzumab + Exemestane arm versus Ridaforolimus + Exemestane arm).
    Comparison groups
    Ridaforolimus + Dalotuzumab + Exemestane v Ridaforolimus + Exemestane
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.562
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    4.13

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days after last dose of treatment (up to 15.83 months)
    Adverse event reporting additional description
    All randomized participants who received at least one dose of study treatment and had data up to the 29-April-2014 database lock. For nine participants who continued to receive treatment under compassionate use after database lock, safety data was not included in any study database but was reported to global safety.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ridaforolimus + Dalotuzumab + Exemestane
    Reporting group description
    Participants receive ridaforolimus 10 mg orally (PO) every 5 days (QD x 5) plus dalotuzumab 10 mg/kg intravenously (IV) every week (QW) plus exemestane 25 mg PO every day (QD) in 28-day cycles until documented disease progression or unacceptable toxicity.

    Reporting group title
    Ridaforolimus + Exemestane
    Reporting group description
    Participants received ridaforolimus 30 mg PO QD x 5 plus exemestane 25 mg PO QD treatment in 28-day cycles until documented disease progression or unacceptable toxicity.

    Serious adverse events
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 39 (20.51%)
    17 / 40 (42.50%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Oesophagitis chemical
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sinus tachycardia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hydropneumothorax
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondrocalcinosis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ridaforolimus + Dalotuzumab + Exemestane Ridaforolimus + Exemestane
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    40 / 40 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 40 (10.00%)
         occurrences all number
    2
    5
    Lymphoedema
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 40 (10.00%)
         occurrences all number
    1
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 39 (25.64%)
    14 / 40 (35.00%)
         occurrences all number
    13
    15
    Chest pain
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    4
    Chills
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Local swelling
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Fatigue
         subjects affected / exposed
    11 / 39 (28.21%)
    7 / 40 (17.50%)
         occurrences all number
    13
    9
    Oedema peripheral
         subjects affected / exposed
    3 / 39 (7.69%)
    10 / 40 (25.00%)
         occurrences all number
    6
    12
    Pyrexia
         subjects affected / exposed
    4 / 39 (10.26%)
    5 / 40 (12.50%)
         occurrences all number
    7
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Insomnia
         subjects affected / exposed
    0 / 39 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    4
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 39 (15.38%)
    3 / 40 (7.50%)
         occurrences all number
    9
    3
    Blood cholesterol increased
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 40 (10.00%)
         occurrences all number
    2
    5
    Neutrophil count decreased
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Platelet count decreased
         subjects affected / exposed
    1 / 39 (2.56%)
    5 / 40 (12.50%)
         occurrences all number
    1
    5
    Weight decreased
         subjects affected / exposed
    3 / 39 (7.69%)
    6 / 40 (15.00%)
         occurrences all number
    3
    6
    White blood cell count decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 39 (15.38%)
    9 / 40 (22.50%)
         occurrences all number
    8
    11
    Leukopenia
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    5
    Neutropenia
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 40 (7.50%)
         occurrences all number
    4
    6
    Thrombocytopenia
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 39 (20.51%)
    10 / 40 (25.00%)
         occurrences all number
    10
    13
    Dyspnoea
         subjects affected / exposed
    4 / 39 (10.26%)
    8 / 40 (20.00%)
         occurrences all number
    4
    10
    Epistaxis
         subjects affected / exposed
    10 / 39 (25.64%)
    4 / 40 (10.00%)
         occurrences all number
    15
    7
    Interstitial lung disease
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Pneumonitis
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 40 (15.00%)
         occurrences all number
    1
    7
    Dysgeusia
         subjects affected / exposed
    14 / 39 (35.90%)
    6 / 40 (15.00%)
         occurrences all number
    16
    6
    Headache
         subjects affected / exposed
    6 / 39 (15.38%)
    13 / 40 (32.50%)
         occurrences all number
    6
    18
    Neuropathy peripheral
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Tremor
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 39 (15.38%)
    4 / 40 (10.00%)
         occurrences all number
    7
    7
    Abdominal pain upper
         subjects affected / exposed
    4 / 39 (10.26%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    Constipation
         subjects affected / exposed
    7 / 39 (17.95%)
    8 / 40 (20.00%)
         occurrences all number
    7
    11
    Diarrhoea
         subjects affected / exposed
    14 / 39 (35.90%)
    15 / 40 (37.50%)
         occurrences all number
    31
    28
    Dry mouth
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Dyspepsia
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Nausea
         subjects affected / exposed
    9 / 39 (23.08%)
    9 / 40 (22.50%)
         occurrences all number
    18
    11
    Oral pain
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Stomatitis
         subjects affected / exposed
    30 / 39 (76.92%)
    36 / 40 (90.00%)
         occurrences all number
    54
    88
    Toothache
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    4
    Vomiting
         subjects affected / exposed
    8 / 39 (20.51%)
    8 / 40 (20.00%)
         occurrences all number
    20
    8
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Dermatitis acneiform
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 40 (7.50%)
         occurrences all number
    2
    4
    Dry skin
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Nail disorder
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    4
    Erythema
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Onycholysis
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Pruritus
         subjects affected / exposed
    1 / 39 (2.56%)
    5 / 40 (12.50%)
         occurrences all number
    2
    7
    Rash
         subjects affected / exposed
    8 / 39 (20.51%)
    8 / 40 (20.00%)
         occurrences all number
    12
    13
    Skin lesion
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 39 (12.82%)
    5 / 40 (12.50%)
         occurrences all number
    6
    6
    Back pain
         subjects affected / exposed
    2 / 39 (5.13%)
    6 / 40 (15.00%)
         occurrences all number
    2
    7
    Bone pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Joint swelling
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Muscle spasms
         subjects affected / exposed
    7 / 39 (17.95%)
    1 / 40 (2.50%)
         occurrences all number
    7
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Myalgia
         subjects affected / exposed
    4 / 39 (10.26%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    Pain in extremity
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 40 (15.00%)
         occurrences all number
    1
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 39 (38.46%)
    11 / 40 (27.50%)
         occurrences all number
    16
    13
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Hyperglycaemia
         subjects affected / exposed
    11 / 39 (28.21%)
    10 / 40 (25.00%)
         occurrences all number
    14
    20
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Gingivitis
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 40 (5.00%)
         occurrences all number
    2
    3
    Cystitis
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Herpes zoster
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 40 (7.50%)
         occurrences all number
    4
    5
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 40 (15.00%)
         occurrences all number
    2
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2013
    Global Amendment 3 (AM3) reduced the sample size of the protocol from 150 participants to approximately 84 participants, updated the safety analysis, and removed the interim efficacy analysis.
    05 Aug 2014
    Global Amendment 4 (AM4) ended further efficacy measurements on study, revised safety monitoring to include only serious adverse events, and ended survival follow-up on study as a result of study objectives having been met. Participants receiving study medication could continue to be treated at the discretion of the investigator until disease progression or unacceptable toxicity, subject to availability of study medications and not to exceed 2-3 years.

    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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