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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Doxorubicin plus Olaratumab versus Doxorubicin plus Placebo in Patients with Advanced or Metastatic Soft Tissue Sarcoma

    Summary
    EudraCT number
    		 2015-000134-30
    Trial protocol
    		 DK   HU   DE   ES   AT   FR   SE   FI   BE   NL   PL   GB   IT  
    Global end of trial date
    27 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2025
    First version publication date
    13 Jul 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    I5B-MC-JGDJ
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02451943
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Name: ANNOUNCE
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Clinical Trial Registry Office, Eli Lilly , 1 08772854559, EU_Lilly_Clinical_Trials@lilly.com
    Scientific contact
    Clinical Trial Registry Office, Eli Lilly , 1 877CTLilly, EU_Lilly_Clinical_Trials@lilly.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
    27 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare doxorubicin plus olaratumab versus doxorubicin plus placebo with respect to OS in 2 populations: (1) Patients with advanced or metastatic soft tissue sarcoma (STS) not amenable to treatment with surgery or radiotherapy with curative intent (2) Patients with advanced or metastatic leiomyosarcoma (LMS) not amenable to treatment with surgery or radiotherapy with curative intent
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    United States: 142
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Japan: 45
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Australia: 1
    Worldwide total number of subjects
    509
    EEA total number of subjects
    182
    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)
    360
    From 65 to 84 years
    149
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Completers include participants who died in the study.

    Pre-assignment
    Screening details
    		 NA

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doxorubicin + Olaratumab
    Arm description
    		 75 milligrams per meter squared (mg/m^2) doxorubicin administered intravenously (IV) on day 1 of each 21 day cycle up to 8 cycles plus 20 milligrams per kilogram (mg/kg) dose of olaratumab administered IV on day 1 and day 8 of cycle 1 and 15 mg/kg olaratumab administered IV on day 1 and day 8 of cycles 2-8. 15 mg/kg olaratumab administered IV on day 1 and day 8 of each subsequent 21 day cycle thereafter until documented progressive disease (PD) or discontinuation for any other reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Investigational medicinal product name
    Olaratumab
    Investigational medicinal product code
    Other name
    LY3012207
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Arm title
    		 Doxorubicin + Placebo
    Arm description
    		 75 mg/m^2 doxorubicin administered IV on day 1 of each 21 day cycle up to 8 cycles plus placebo (equivalent volume) administered IV on day 1 and day 8 for 8 cycles. Placebo (equivalent volume) administered on days 1 and 8 of each subsequent 21 day cycle thereafter until PD or discontinuation for any other reason.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Number of subjects in period 1
    		Doxorubicin + Olaratumab Doxorubicin + Placebo
    Started
    258
    251
    Received at Least One Dose of Study Drug
    257
    249
    Completed
    242
    227
    Not completed
    16
    24
         Consent withdrawn by subject
    13
    16
         Sponsor Decision
    -
    4
         Lost to follow-up
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Doxorubicin + Olaratumab
    Reporting group description
    		 75 milligrams per meter squared (mg/m^2) doxorubicin administered intravenously (IV) on day 1 of each 21 day cycle up to 8 cycles plus 20 milligrams per kilogram (mg/kg) dose of olaratumab administered IV on day 1 and day 8 of cycle 1 and 15 mg/kg olaratumab administered IV on day 1 and day 8 of cycles 2-8. 15 mg/kg olaratumab administered IV on day 1 and day 8 of each subsequent 21 day cycle thereafter until documented progressive disease (PD) or discontinuation for any other reason.

    Reporting group title
    Doxorubicin + Placebo
    Reporting group description
    		 75 mg/m^2 doxorubicin administered IV on day 1 of each 21 day cycle up to 8 cycles plus placebo (equivalent volume) administered IV on day 1 and day 8 for 8 cycles. Placebo (equivalent volume) administered on days 1 and 8 of each subsequent 21 day cycle thereafter until PD or discontinuation for any other reason.

    Reporting group values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo Total
    Number of subjects
    		 258 251 509
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.7 ( 12.4 ) 57.1 ( 11.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 144 152 296
        Male
    		 114 99 213
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 26 29 55
        Not Hispanic or Latino
    		 209 199 408
        Unknown or Not Reported
    		 23 23 46
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 3 3 6
        Asian
    		 50 48 98
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 12 2 14
        White
    		 186 193 379
        More than one race
    		 5 4 9
        Unknown or Not Reported
    		 1 1 2
    Region of Enrollment
    Units: Subjects
        United States
    		 69 73 142
        Russia
    		 7 8 15
        Austria
    		 3 0 3
        South Korea
    		 15 13 28
        Netherlands
    		 8 6 14
        Sweden
    		 4 3 7
        Brazil
    		 2 0 2
        Poland
    		 3 2 5
        France
    		 17 18 35
        Argentina
    		 3 4 7
        Hungary
    		 9 11 20
        Japan
    		 23 22 45
        United Kingdom
    		 10 16 26
        Switzerland
    		 4 2 6
        Spain
    		 13 21 34
        Canada
    		 12 6 18
        Belgium
    		 11 10 21
        Finland
    		 4 2 6
        Taiwan
    		 6 7 13
        Denmark
    		 10 2 12
        Italy
    		 5 4 9
        Mexico
    		 7 6 13
        Israel
    		 6 5 11
        Australia
    		 0 1 1
        Germany
    		 7 9 16

    End points

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    End points reporting groups
    Reporting group title
    Doxorubicin + Olaratumab
    Reporting group description
    		 75 milligrams per meter squared (mg/m^2) doxorubicin administered intravenously (IV) on day 1 of each 21 day cycle up to 8 cycles plus 20 milligrams per kilogram (mg/kg) dose of olaratumab administered IV on day 1 and day 8 of cycle 1 and 15 mg/kg olaratumab administered IV on day 1 and day 8 of cycles 2-8. 15 mg/kg olaratumab administered IV on day 1 and day 8 of each subsequent 21 day cycle thereafter until documented progressive disease (PD) or discontinuation for any other reason.

    Reporting group title
    Doxorubicin + Placebo
    Reporting group description
    		 75 mg/m^2 doxorubicin administered IV on day 1 of each 21 day cycle up to 8 cycles plus placebo (equivalent volume) administered IV on day 1 and day 8 for 8 cycles. Placebo (equivalent volume) administered on days 1 and 8 of each subsequent 21 day cycle thereafter until PD or discontinuation for any other reason.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death due to any cause. For each participant, prior to data analysis, a reasonable effort was made to obtain the most up-to-date status (date of death or last date known to be alive). For any participant not known to have died as of the data cutoff date, OS was censored at the date the participant was last known to be alive. For any participant who withdrew consent for survival follow-up, OS was censored at the last date for which the participant provided consent for follow-up contact. The Kaplan-Meier method was used to estimate median parameters. Analysis Population Description (APD): All randomized participants. Censored participants in Doxorubicin + Olaratumab arm = 87 and Doxorubicin + Placebo arm = 91
    End point type
    Primary
    End point timeframe
    Randomization to Date of Death Due to Any Cause (Up to 35.8 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    258
    251
    Units: Months
        median (confidence interval 95%)
    20.37 (17.84 to 22.90)
    19.75 (16.49 to 23.75)
    Statistical analysis title
    		 Outcome Measure No. 1
    Comparison groups
    Doxorubicin + Olaratumab v Doxorubicin + Placebo
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6945
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.841
         upper limit
    		 1.303

    Primary: Overall Survival (OS) Leiomyosarcoma (LMS)

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    End point title
    		 Overall Survival (OS) Leiomyosarcoma (LMS)
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death due to any cause. For each participant, prior to data analysis, a reasonable effort was made to obtain the most up-to-date status (date of death or last date known to be alive). For any participant not known to have died as of the data cutoff date, OS was censored at the date the participant was last known to be alive. For any participant who withdrew consent for survival follow-up, OS was censored at the last date for which the participant provided consent for follow-up contact. The Kaplan-Meier method was used to estimate median parameters. APD: All randomized participants with LMS. Censored participants in Doxorubicin + Olaratumab arm = 42 and Doxorubicin + Placebo arm = 40.
    End point type
    Primary
    End point timeframe
    Randomization to Date of Death Due to Any Cause (Up to 35.8 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    119
    115
    Units: Months
        median (confidence interval 95%)
    21.55 (18.63 to 27.63)
    21.88 (17.54 to 25.07)
    Statistical analysis title
    		 Outcome Measure No.2
    Comparison groups
    Doxorubicin + Olaratumab v Doxorubicin + Placebo
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7618
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.951
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.312

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined by (Response Evaluation Criteria In Solid Tumors RECIST v.1.1) as the time from the date of randomization to the first date of radiologic disease progression or death due to any cause. Progressive Disease (PD) is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 millimeter (mm), or unequivocal progression of non-target lesions, or 1 or more new lesions. Censoring for death or PD due to increase sum of target lesions is defined for each participant as the time from the date of randomization to the first date of radiographic documentation of 1 or more lesions. Censoring for death without progression is defined as the date of death if there is no prior or concurrent radiologic disease progression. APD: All randomized participants. Censored participants in the Doxorubicin + Olaratumab arm = 39 and the Doxorubicin + Placebo arm =34.
    End point type
    Secondary
    End point timeframe
    Randomization to Objective Progression or Death Due to Any Cause (Up to 35.8 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    258
    251
    Units: Months
        median (confidence interval 95%)
    5.42 (4.11 to 6.70)
    6.77 (5.49 to 8.08)
    Statistical analysis title
    		 Outcome Measure No. 3
    Comparison groups
    Doxorubicin + Olaratumab v Doxorubicin + Placebo
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0422
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.231
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.009
         upper limit
    		 1.502

    Secondary: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)

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    End point title
    		 Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants achieving a best overall response of complete response (CR) + partial response (PR). CR is the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to RECIST v1.1. APD: All randomized participants.
    End point type
    Secondary
    End point timeframe
    Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    258
    251
    Units: Percentage of participants
        number (confidence interval 95%)
    14.0 (9.7 to 18.2)
    18.3 (13.5 to 23.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)

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    End point title
    		 Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)
    End point description
    DCR was defined as the percentage of randomized participants achieving a best overall response of CR, PR, or SD per RECIST v.1.1. CR is the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. PD is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
    End point type
    Secondary
    End point timeframe
    Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 35.5 Months) APD: All randomized participants.
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    258
    251
    Units: Percentage of participants
        number (confidence interval 95%)
    67.4 (61.7 to 73.2)
    75.7 (70.4 to 81.0)
    No statistical analyses for this end point

    Secondary: Time to First Worsening on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores

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    End point title
    		 Time to First Worsening on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores
    End point description
    Time to first worsening was calculated as the time from the first study drug dose to the first observation of worsening according to the EORTC QLQ-C30 Scoring Manual (Fayers et al. 2001). The EORTC QLQ-C30 self-reported general cancer instrument consists of 30 total items covered by 1 of 3 dimensions (1 global health status/QoL total score, 5 functional subscales [physical, role, cognitive, emotional, and social]), and 9 symptom subscales [fatigue/nausea/vomiting/pain/dyspnea/insomnia/appetite loss/constipation/diarrhea]). There are 28 questions answered on a 4-point scale where 1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). A linear transformation was used to obtain total score ranging from 0 to 100 where "worsening" was defined as an increase of at least 10 points for the symptom scales or a decrease of at least 10 points for the functional scales and the global health status/QoL scale.
    End point type
    Secondary
    End point timeframe
    Randomization (Cycle 1) through Follow-up (Up to 35.8 Months) APD: All randomized participants who completed at least 1 baseline assessment and at least 1 subsequent assessment during the study period.
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    201
    197
    Units: Months
    median (confidence interval 95%)
        Role Functional Scale (n=202;190)
    1.41 (0.99 to 1.48)
    1.41 (0.954 to 2.00)
        Global Health Status/QoL (n=201;197)
    1.45 (1.41 to 2.10)
    1.84 (1.45 to 2.79)
        Physical Functional Scale (n=205;209)
    1.81 (1.45 to 2.14)
    2.79 (2.07 to 3.48)
        Emotional Functional Scale (n=168;171)
    3.48 (2.50 to 4.37)
    2.83 (2.14 to 4.34)
        Cognitive Functional Scale (n=170;167)
    1.64 (1.41 to 2.14)
    1.45 (1.41 to 2.07)
        Social Functional Scale (n=189;171)
    1.45 (1.38 to 1.64)
    1.41 (1.35 to 1.45)
        Fatigue Symptom Scale (n=210;204)
    0.92 (0.76 to 1.25)
    0.89 (0.76 to 1.38)
        Nausea and Vomiting Symptom Scale (n=182;173)
    1.45 (1.41 to 1.64)
    1.41 (0.95 to 1.45)
        Pain Symptom Scale (n=185;183)
    1.64 (1.41 to 2.10)
    2.10 (1.45 to 2.76)
        Dyspnea Symptom Scale (n= 158;160)
    2.10 (1.45 to 2.76)
    2.07 (1.45 to 2.79)
        Insomnia Symptom Scale (n=151;160)
    2.10 (1.45 to 2.79)
    1.58 (1.41 to 2.33)
        Appetite Loss Symptom Scale (n=182;170)
    1.48 (1.45 to 2.04)
    1.64 (1.41 to 2.14)
        Financial Difficulties Scale (n=132;105)
    1.48 (1.41 to 2.14)
    1.45 (1.41 to 2.10)
        Constipation Symptom Scale (n=169;157)
    1.64 (1.41 to 2.10)
    1.41 (1.41 to 2.10)
        Diarrhea Symptom Scale (n=157;148)
    2.07 (1.45 to 2.79)
    2.79 (2.10 to 3.52)
    No statistical analyses for this end point

    Secondary: Change From Baseline to Maximum Improvement in Health Status Index Score on the EuroQol 5-Dimension 5-Level (EQ-5D-5L)

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    End point title
    		 Change From Baseline to Maximum Improvement in Health Status Index Score on the EuroQol 5-Dimension 5-Level (EQ-5D-5L)
    End point description
    The EQ-5D-5L is a standardized measure of health status used to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists of a descriptive system of the respondent's health which comprises the following 5 dimensions: (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Health status was calculated from a set of item weights to derive a score of 0 to 1, with 1 representing the best health status. United Kingdom (UK) weights were applied. The analysis includes all cycles for which at least 25% of participants in each arm have an assessment. For each participant a change from baseline was calculated for every post-baseline assessment by subtracting the baseline assessment result from the current assessment result. Maximum improvement (over baseline) was determined from the set of all post-baseline change scores. APD: All randomized participants who had a baseline and a post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Randomization through Follow-up (Up to 35.8 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    221
    219
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.163 ( 0.236 )
    -0.171 ( 0.235 )
    No statistical analyses for this end point

    Secondary: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score"

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    End point title
    		 Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score"
    End point description
    Time to first worsening of the brief pain inventory short form modified (mBPI-sf) "worst pain score" was defined as the time from the date of the first study drug dose (baseline date) to the first date of a "worst pain" score increase of greater than or equal to (≥) 2 points from baseline. The mBPI-sf is an 11-item instrument used as a multiple-item measure of cancer pain intensity ranging from 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can imagine or completely interferes). APD: All randomized participants who completed at least 1 baseline assessment and at least 1 subsequent assessment during the study period.
    End point type
    Secondary
    End point timeframe
    Randomization through Follow-up (Up to 34.5 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    211
    206
    Units: Months
        median (confidence interval 95%)
    7.66 (6.01 to 9.63)
    8.08 (6.18 to 11.07)
    No statistical analyses for this end point

    Secondary: Duration of Overall Response (DoR)

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    End point title
    		 Duration of Overall Response (DoR)
    End point description
    The duration of overall response was defined for each participant with a best response of CR or PR and measured from the time measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective disease progression or death due to any cause is observed (taking as reference for PD the smallest measurements recorded on study). APD: All randomized participants who have evaluable DoR data.
    End point type
    Secondary
    End point timeframe
    Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up to 33.4 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    36
    46
    Units: Months
        median (confidence interval 95%)
    8.31 (6.87 to 12.35)
    4.80 (3.65 to 6.83)
    Statistical analysis title
    		 Outcome Measure No. 9
    Comparison groups
    Doxorubicin + Olaratumab v Doxorubicin + Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0934
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.616
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.347
         upper limit
    		 1.093

    Secondary: Duration of Disease Control (DDC)

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    End point title
    		 Duration of Disease Control (DDC)
    End point description
    Duration of disease control was defined for each participant with a best response of CR, PR, or stable disease (SD) as the time from randomization to the first date of disease progression or death due to any cause. APD: All randomized participants who had evaluable DDC data.
    End point type
    Secondary
    End point timeframe
    Date of CR, PR, or SD to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months)
    End point values
    		 Doxorubicin + Olaratumab Doxorubicin + Placebo
    Number of subjects analysed
    174
    190
    Units: Months
        median (confidence interval 95%)
    8.28 (6.93 to 9.72)
    8.34 (8.08 to 9.46)
    Statistical analysis title
    		 Outcome Measure No. 10
    Comparison groups
    Doxorubicin + Olaratumab v Doxorubicin + Placebo
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3347
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.123
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.892
         upper limit
    		 1.413

    Secondary: Pharmacokinetics (PK) Clearance of Olaratumab Mean Parameter Estimate

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    End point title
    		 Pharmacokinetics (PK) Clearance of Olaratumab Mean Parameter Estimate [1]
    End point description
    The PK systemic clearance parameter estimates from the current analysis are listed together with the population PK model estimates. APD: All randomized participants who received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1- 9: Day 1 and 8, Predose, 5 minutes Post dose and then every other cycle and follow-up (30 Days)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All randomized participants who received at least one dose of olaratumab and had evaluable PK data were involved in this analysis.
    End point values
    		 Doxorubicin + Olaratumab
    Number of subjects analysed
    258
    Units: Liter/hour (L/h)
        arithmetic mean (confidence interval 95%)
    0.0195 (0.0189 to 0.0203)
    No statistical analyses for this end point

    Secondary: PK: Volume of Distribution at Steady State (Vss) of Olaratumab: Mean Parameter Estimate

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    End point title
    		 PK: Volume of Distribution at Steady State (Vss) of Olaratumab: Mean Parameter Estimate [2]
    End point description
    The PK parameter estimates from the current analysis are listed together with the population PK model estimates. The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2). APD: All randomized participants who had received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1- 9: Day 1 and 8; Predose, 5 Minutes Post dose and then every other cycle and follow-up (30 Days)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All randomized participants who received at least one dose of olaratumab and had evaluable PK data were involved in this analysis.
    End point values
    		 Doxorubicin + Olaratumab
    Number of subjects analysed
    258
    Units: Liter (L)
        arithmetic mean (confidence interval 95%)
    5.72 (5.28 to 6.17)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline Up To 41 Months
    Adverse event reporting additional description
    All participants who received at least one dose of study drug. Gender specific events occurring only in male or female participants have had the number of participants at risk adjusted accordingly. Based on the planned safety analysis, adverse event analysis was planned as per the treatments the participants received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28.0
    Reporting groups
    Reporting group title
    Doxorubicin + Placebo
    Reporting group description
    		 75 mg/m^2 doxorubicin administered IV on day 1 of each 21 day cycle for 8 cycles plus placebo (equivalent volume) administered IV on day 1 and day 8 for 8 cycles. Beginning with cycle 9, placebo (equivalent volume) administered on days 1 and 8 of each subsequent 21 day cycle until PD or discontinuation for any other reason.

    Reporting group title
    Doxorubicin + Olaratumab
    Reporting group description
    		 75 milligrams per meter squared (mg/m^2) doxorubicin administered intravenously (IV) on day 1 of each 21 day cycle for 8 cycles plus 20 milligrams per kilogram (mg/kg) dose of olaratumab administered IV on day 1 and day 8 of cycle 1 and 15 mg/kg olaratumab administered IV on day 1 and day 8 of cycles 2-8. Beginning with cycle 9, 15 mg/kg olaratumab administered IV on day 1 and day 8 of each subsequent 21 day cycle until documented progressive disease (PD) or discontinuation for any other reason.

    Serious adverse events
    		 Doxorubicin + Placebo Doxorubicin + Olaratumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    89 / 249 (35.74%)
    105 / 257 (40.86%)
         number of deaths (all causes)
    158
    170
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    adenocarcinoma of colon
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    5 / 257 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    embolism
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral arterial occlusive disease
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    superficial vein thrombosis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    extravasation
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malaise
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mucosal inflammation
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    7 / 249 (2.81%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    3 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    anaphylactic reaction
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anaphylactic shock
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypersensitivity
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    vaginal haemorrhage
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed [1]
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    aspiration
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoxia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    3 / 249 (1.20%)
    7 / 257 (2.72%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    pneumothorax
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    3 / 249 (1.20%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ejection fraction decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    electrocardiogram abnormal
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutrophil count decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    4 / 249 (1.61%)
    5 / 257 (1.95%)
         occurrences causally related to treatment / all
    4 / 7
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    platelet count decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    troponin increased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    white blood cell count decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    3 / 249 (1.20%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    femur fracture
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    femoral neck fracture
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rib fracture
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal fracture
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tibia fracture
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    arrhythmia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac failure congestive
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    cardiac failure acute
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    cardiac failure
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    left ventricular dysfunction
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mitral valve disease
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocarditis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pericarditis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    supraventricular tachycardia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    cerebrovascular accident
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    dysarthria
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    migraine
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nervous system disorder
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    paraparesis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sciatic nerve neuropathy
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    somnolence
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vertebrobasilar artery dissection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    4 / 257 (1.56%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile bone marrow aplasia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    33 / 249 (13.25%)
    34 / 257 (13.23%)
         occurrences causally related to treatment / all
    33 / 37
    34 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    8 / 249 (3.21%)
    8 / 257 (3.11%)
         occurrences causally related to treatment / all
    8 / 8
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancytopenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    acute abdomen
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    3 / 257 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    duodenal ulcer
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspepsia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    food poisoning
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric haemorrhage
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intussusception
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    4 / 257 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subileus
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    4 / 257 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    hepatic pain
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nephrolithiasis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         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
    arthralgia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    4 / 257 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intervertebral disc protrusion
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pathological fracture
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    abdominal infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abscess
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bacteraemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cystitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    clostridium difficile colitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gingivitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    herpes zoster
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenic sepsis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenic infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pseudomonal bacteraemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia aspiration
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    4 / 257 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    sepsis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    2 / 249 (0.80%)
    4 / 257 (1.56%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal abscess
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    septic shock
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    3 / 257 (1.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tonsillitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoglycaemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperglycaemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Gender specific events occurring only in male or female participants have had the number of participants at risk adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Doxorubicin + Placebo Doxorubicin + Olaratumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    244 / 249 (97.99%)
    248 / 257 (96.50%)
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    21 / 249 (8.43%)
    20 / 257 (7.78%)
         occurrences all number
    33
    29
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    20 / 249 (8.03%)
    11 / 257 (4.28%)
         occurrences all number
    28
    12
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    19 / 249 (7.63%)
    21 / 257 (8.17%)
         occurrences all number
    25
    25
    lymphocyte count decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    17 / 249 (6.83%)
    17 / 257 (6.61%)
         occurrences all number
    39
    47
    neutrophil count decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    90 / 249 (36.14%)
    92 / 257 (35.80%)
         occurrences all number
    256
    205
    platelet count decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    46 / 249 (18.47%)
    47 / 257 (18.29%)
         occurrences all number
    140
    122
    weight decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    23 / 249 (9.24%)
    25 / 257 (9.73%)
         occurrences all number
    25
    26
    white blood cell count decreased
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    69 / 249 (27.71%)
    68 / 257 (26.46%)
         occurrences all number
    181
    177
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    24 / 249 (9.64%)
    19 / 257 (7.39%)
         occurrences all number
    31
    23
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    35 / 249 (14.06%)
    27 / 257 (10.51%)
         occurrences all number
    49
    44
    dysgeusia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    47 / 249 (18.88%)
    42 / 257 (16.34%)
         occurrences all number
    57
    50
    headache
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    42 / 249 (16.87%)
    43 / 257 (16.73%)
         occurrences all number
    56
    61
    paraesthesia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    16 / 249 (6.43%)
    12 / 257 (4.67%)
         occurrences all number
    17
    15
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    30 / 249 (12.05%)
    24 / 257 (9.34%)
         occurrences all number
    66
    42
    fatigue
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    133 / 249 (53.41%)
    129 / 257 (50.19%)
         occurrences all number
    211
    181
    malaise
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    15 / 249 (6.02%)
    11 / 257 (4.28%)
         occurrences all number
    20
    13
    oedema peripheral
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    25 / 249 (10.04%)
    37 / 257 (14.40%)
         occurrences all number
    39
    44
    pyrexia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    42 / 249 (16.87%)
    50 / 257 (19.46%)
         occurrences all number
    61
    65
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    121 / 249 (48.59%)
    115 / 257 (44.75%)
         occurrences all number
    230
    169
    febrile neutropenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    9 / 249 (3.61%)
    13 / 257 (5.06%)
         occurrences all number
    12
    13
    leukopenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    11 / 249 (4.42%)
    14 / 257 (5.45%)
         occurrences all number
    23
    36
    neutropenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    59 / 249 (23.69%)
    59 / 257 (22.96%)
         occurrences all number
    121
    131
    thrombocytopenia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    19 / 249 (7.63%)
    14 / 257 (5.45%)
         occurrences all number
    35
    29
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    44 / 249 (17.67%)
    31 / 257 (12.06%)
         occurrences all number
    55
    43
    abdominal pain upper
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    20 / 249 (8.03%)
    17 / 257 (6.61%)
         occurrences all number
    23
    23
    constipation
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    94 / 249 (37.75%)
    86 / 257 (33.46%)
         occurrences all number
    144
    122
    diarrhoea
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    76 / 249 (30.52%)
    79 / 257 (30.74%)
         occurrences all number
    118
    123
    dry mouth
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    19 / 249 (7.63%)
    22 / 257 (8.56%)
         occurrences all number
    21
    23
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    18 / 249 (7.23%)
    16 / 257 (6.23%)
         occurrences all number
    19
    17
    dyspepsia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    29 / 249 (11.65%)
    28 / 257 (10.89%)
         occurrences all number
    34
    33
    nausea
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    171 / 249 (68.67%)
    154 / 257 (59.92%)
         occurrences all number
    369
    293
    stomatitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    93 / 249 (37.35%)
    79 / 257 (30.74%)
         occurrences all number
    167
    134
    vomiting
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    70 / 249 (28.11%)
    62 / 257 (24.12%)
         occurrences all number
    128
    78
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    66 / 249 (26.51%)
    46 / 257 (17.90%)
         occurrences all number
    81
    54
    epistaxis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    13 / 249 (5.22%)
    7 / 257 (2.72%)
         occurrences all number
    19
    7
    dyspnoea
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    39 / 249 (15.66%)
    46 / 257 (17.90%)
         occurrences all number
    48
    53
    oropharyngeal pain
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    19 / 249 (7.63%)
    16 / 257 (6.23%)
         occurrences all number
    25
    20
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    127 / 249 (51.00%)
    113 / 257 (43.97%)
         occurrences all number
    132
    116
    dry skin
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    11 / 249 (4.42%)
    15 / 257 (5.84%)
         occurrences all number
    11
    15
    pruritus
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    23 / 249 (9.24%)
    15 / 257 (5.84%)
         occurrences all number
    26
    16
    rash
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    18 / 249 (7.23%)
    13 / 257 (5.06%)
         occurrences all number
    20
    16
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    16 / 249 (6.43%)
    17 / 257 (6.61%)
         occurrences all number
    17
    21
    insomnia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    34 / 249 (13.65%)
    25 / 257 (9.73%)
         occurrences all number
    39
    29
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    31 / 249 (12.45%)
    35 / 257 (13.62%)
         occurrences all number
    38
    48
    arthralgia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    22 / 249 (8.84%)
    32 / 257 (12.45%)
         occurrences all number
    27
    40
    myalgia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    12 / 249 (4.82%)
    13 / 257 (5.06%)
         occurrences all number
    13
    20
    muscle spasms
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    8 / 249 (3.21%)
    18 / 257 (7.00%)
         occurrences all number
    9
    25
    pain in extremity
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    27 / 249 (10.84%)
    29 / 257 (11.28%)
         occurrences all number
    40
    37
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    16 / 249 (6.43%)
    10 / 257 (3.89%)
         occurrences all number
    17
    12
    rhinitis
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    13 / 249 (5.22%)
    6 / 257 (2.33%)
         occurrences all number
    16
    6
    upper respiratory tract infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    25 / 249 (10.04%)
    25 / 257 (9.73%)
         occurrences all number
    30
    31
    urinary tract infection
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    23 / 249 (9.24%)
    20 / 257 (7.78%)
         occurrences all number
    28
    29
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    93 / 249 (37.35%)
    74 / 257 (28.79%)
         occurrences all number
    131
    108
    dehydration
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    9 / 249 (3.61%)
    18 / 257 (7.00%)
         occurrences all number
    13
    24
    hyperglycaemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    10 / 249 (4.02%)
    13 / 257 (5.06%)
         occurrences all number
    14
    21
    hypokalaemia
    alternative dictionary used: MedDRA 28.0
         subjects affected / exposed
    14 / 249 (5.62%)
    14 / 257 (5.45%)
         occurrences all number
    18
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2015
    • Leiomyosarcoma (LMS) was added as a specific population to be tested within the primary objective, and is now co-primary with the STS (ITT) population. • Pleomorphic was added to the stratifications factors • Due to regional/institutional differences dexrazoxane dosing was modified • PFS2 was added to the efficacy endpoints • Cardiovascular monitoring was increased • Gatekeeping methods have been included for OS, PFS, ORR, and DoR • Grade 1 liposarcoma patients are now included under certain conditions • The olaratumab dosing regimen was modified • Management of infusion-related reactions was modified • Single interim analysis will be performed based on 60% of overall OS events (194) in the ITT population and 72 events from the LMS • Analysis of OS will be based on the stratified log-rank test analyzed by the randomization strata, excluding region.
    04 Jan 2016
    • Some exclusion criteria were deleted • Grade 4 nonhematologic toxicity as related to study therapy is now considered a basis for study drug discontinuation • Duration of Response was deleted from secondary objectives. • O’Brien-Fleming alpha spending will now be used for all efficacy boundaries • bisphosphonate osteoclast inhibitors are now allowed, denosumab is still not permitted.
    22 Jan 2016
    • Germany was directed to refer to Addendum (7)
    12 Jan 2017
    • Patients receiving anticoagulants are now eligible to participate • Long-term follow-up for survival and patient reported outcome collection were updated so that these events are concurrent with the collection of ECG data • Efficacy interim stopping rules were removed from the protocol plan, as the intention is to continue the study until the final analysis with the sponsor remaining blinded to aggregate data by study arm until the final analysis. • Urine protein creatinine ratio of spot urine can now be used in place of 24-hour urine protein excretion.

    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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