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    Clinical Trial Results:
    A Randomized Multicenter Phase 3 Study of Milademetan Versus Trabectedin in Patients with Dedifferentiated Liposarcoma

    Summary
    EudraCT number
    		 2021-001394-23
    Trial protocol
    		 FR   AT   PL   DE   BE   IE   IT  
    Global end of trial date
    01 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2024
    First version publication date
    03 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RAIN-3201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rain Oncology Inc.
    Sponsor organisation address
    8000 Jarvis Avenue, Suite 204, Newark, United States, 94560
    Public contact
    Clinical Trial information, Rain Oncology Inc., 1 5109535559, info@rainoncology.com
    Scientific contact
    Clinical Trial information, Rain Oncology Inc., 1 5109535559, info@rainoncology.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
    01 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to compare progression-free survival (PFS) between the milademetan treatment arm and trabectedin control arm, as determined by blinded independent central review (BICR), in patients with unresectable or metastatic dedifferentiated (DD) liposarcoma, with or without a well-differentiated (WD) component, who progressed on 1 or more prior systemic therapies including at least 1 anthracycline-based therapy.
    Protection of trial subjects
    This study was to be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), with the Declaration of Helsinki and with other applicable regulatory requirements. Before the start of the study, the study protocol and/or other relevant documents were approved by the IECs/IRBs/Competent Authorities, in accordance with local legal requirements. Before each patient was admitted to the study, written informed consent was obtained from the patient according to the regulatory and legal requirements of the participating country. The consent form was signed, dated, and retained by the Investigator or designee (as listed on the Delegation of Authority Log) as part of the study records. An Independent Data Monitoring Committee (IDMC) reviewed unblinded safety data during the course of the study and made recommendations to the Sponsor as applicable and outlined in the IDMC charter.
    Background therapy
    		 -
    Evidence for comparator
    		 Trabectedin was the chosen active control treatment because it has been approved as a second-line therapy by the FDA for patients with liposarcoma (LPS) or leiomyosarcoma who received a prior anthracycline-containing regimen. Trabectedin was approved for LPS based on improved PFS. In this study, the primary endpoint was to compare PFS, as determined by BICR, between patients receiving milademetan versus trabectedin.
    Actual start date of recruitment
    07 Jul 2021
    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
    Canada: 3
    Country: Number of subjects enrolled
    Georgia: 7
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Italy: 20
    Worldwide total number of subjects
    175
    EEA total number of subjects
    73
    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)
    98
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 200 patients were screened and 175 were randomized across 58 study sites in Austria, Belgium, Canada, France, Georgia, Germany, Hong Kong, Italy, Poland, South Korea, Spain, Taiwan, UK and the US. First patient signed informed consent form: 07 July 2021. First patient randomized/enrolled: 13 July 2021.

    Pre-assignment
    Screening details
    		 Male and female patients at least 18 years of age with histologically confirmed DDLPS, with or without a well-differentiated (WD) component, by local pathologic review. They must have received 1 or more systemic cancer therapy regimens, including at least 1 anthracycline-based regimen, and had radiographic progressive disease (per RECIST v1.1).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Milademetan
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Milademetan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered 260 mg QD orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle

    Arm title
    		 Trabectedin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trabectedin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 1.5 mg/m2 BSA as a 24-hour IV infusion, every 3 weeks (ie, 21-day cycles) through a central venous line

    Number of subjects in period 1
    		Milademetan Trabectedin
    Started
    86
    89
    Completed
    0
    0
    Not completed
    86
    89
         Adverse event, serious fatal
    43
    30
         Consent withdrawn by subject
    8
    13
         Physician decision
    1
    1
         1 d/c study w/reason "progression disease"
    -
    1
         Lost to follow-up
    -
    2
         Ongoing on study when study stopped
    34
    42

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Milademetan
    Reporting group description
    		 -

    Reporting group title
    Trabectedin
    Reporting group description
    		 -

    Reporting group values
    		 Milademetan Trabectedin Total
    Number of subjects
    		 86 89 175
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 51 47 98
        From 65-84 years
    		 35 42 77
    Gender categorical
    Units: Subjects
        Female
    		 40 36 76
        Male
    		 46 53 99
    Tumor status
    Units: Subjects
        Locally advanced
    		 23 13 36
        Metastatic
    		 63 76 139
    Number of lines of therapy in metastatic setting
    Units: Subjects
        Zero
    		 21 26 47
        One
    		 38 32 70
        Two
    		 14 15 29
        Three
    		 7 9 16
        Three plus
    		 6 7 13
    ECOG PS
    Units: Subjects
        Zero
    		 45 47 92
        One
    		 41 42 83
    Number of prior treatments
    Units: Subjects
        ≤ 2
    		 65 65 130
        > 2
    		 21 24 45
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 15 12 27
        Black or African American
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        White
    		 59 63 122
        Unknown
    		 11 12 23
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 6 9
        Not Hispanic or Latino
    		 71 72 143
        Not reported
    		 12 11 23
    Time from initial diagnosis
    Units: year
        arithmetic mean (standard deviation)
    		 4.27 ± 4.301 4.83 ± 4.102 -
    Time from metastatic diagnosis
    Units: year
        arithmetic mean (standard deviation)
    		 1.54 ± 1.523 1.75 ± 2.112 -

    End points

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    End points reporting groups
    Reporting group title
    Milademetan
    Reporting group description
    		 -

    Reporting group title
    Trabectedin
    Reporting group description
    		 -

    Primary: Progression Free Survival (PFS) as determined by BICR

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    End point title
    		 Progression Free Survival (PFS) as determined by BICR
    End point description
    The primary efficacy endpoint was to demonstrate whether there was an increase in PFS in patients treated with milademetan versus trabectedin in the ITT population. Tumor response was to be assessed in accordance with RECIST version 1.1 by BICR. The study did not meet its primary endpoint, PFS by BICR.
    End point type
    Primary
    End point timeframe
    PFS=the time from randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause. When 105 BICR assessed PFS events had occurred, the primary PFS analysis was to be performed.
    End point values
    		 Milademetan Trabectedin
    Number of subjects analysed
    86 [1]
    89 [2]
    Units: month
        median (confidence interval 95%)
    3.6 (2.1 to 4.1)
    2.2 (1.9 to 4.2)
    Notes
    [1] - a. Pts with PFS events: 61 b. Pts censored: 25 c. Kaplan-Meier estimate of PFS rate 6 month: 25.7%
    [2] - a. Pts with PFS events: 54 b. Pts censored: 35 c. Kaplan-Meier estimate of PFS rate 6 month: 26.5%
    Statistical analysis title
    		 Statistical analysis for PFS
    Statistical analysis description
    2-sided, log-rank test was used to compare milademetan vs trabectedin at a significance value of 0.05. PFS was summarized using Kaplan-Meier. Median event times & corresponding 2-sided 95% CIs were provided. A log-rank test stratified by ECOG (0 versus 1) & number of prior lines of therapy (≤2 vs >2) were used to test the null hypothesis of no difference in the PFS between the 2 treatment groups at a significance level of 0.05.
    Comparison groups
    Milademetan v Trabectedin
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.53 [4]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.29
    Notes
    [3] - The p-value from the stratified log-rank test was 0.53, which indicates there was no statistical difference in BICR PFS between 2 treatment arms. A stratified Cox proportional hazard model was used to estimate the hazard ratio. Unstratified analysis was also provided as a sensitivity analysis.
    [4] - Stratified log-rank test, p-value = 0.53 Stratified Cox proportional hazards model p-value = 0.533

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    To compare the milademetan treatment arm versus the trabectedin control arm for the OS. In the ITT Population, survival data was to be collected throughout the study treatment phase and long-term follow-up. Survival follow-up after patient discontinuation of investigational product was to be conducted approximately every 12 weeks to assess for survival until subject’s loss to follow-up or death, or for 24 months following the final dose of study drug, whichever came first. The study was not powered to address OS as of the cutoff date and the results presented in this report should be understood in this context. There were no statistically significant differences between the study arms in OS. OS was to be followed after the primary PFS analysis, and the final analysis of OS was to be performed 24 months after the last dose; however, the study was prematurely discontinued.
    End point type
    Secondary
    End point timeframe
    OS measured from randomized date to death date by any cause, censored at last date known alive on or prior to the data cutoff date.
    End point values
    		 Milademetan Trabectedin
    Number of subjects analysed
    86 [5]
    89 [6]
    Units: month
        median (confidence interval 95%)
    9.5 (6.5 to 12.8)
    10.2 (8.6 to 99999)
    Notes
    [5] - a. Pts. with death: 44 b. Reason censored: i. ended study not due to death=13 ii. data cut-off=29
    [6] - 1.Pt w/death: 31; 2.Reason censored: a.ended study not due to death=21 b.data cut-off=37; "99999"=NE
    Statistical analysis title
    		 Statistical analysis for OS
    Statistical analysis description
    OS was summarized using the Kaplan-Meier method and displayed graphically when appropriate. Median event times and the corresponding 2-sided 95% CIs were provided. The OS rate (proportion of patients surviving) at various time points (e.g., 3, 6, and 12 months) was calculated using Kaplan-Meier methods.
    Comparison groups
    Trabectedin v Milademetan
    Number of subjects included in analysis
    175
    Analysis specification
    Post-hoc
    Analysis type
    		 other [7]
    P-value
    		 = 0.308 [8]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 2.04
    Notes
    [7] - The Kaplan-Meier estimate of OS rate at 6 months was 64.7% (95% CI: 53.3, 73.9) for the Milademetan Arm, and was 71.1% (95% CI: 59.4, 80.0) for the Trabectedin Arm. The OS results using the unstratified Kaplan-Meier and Cox models, the CCDD Population, or the Per Protocol Population reflect those results found in the ITT Population.
    [8] - Stratified log-rank test, p-value = 0.308 Stratified Cox proportional hazards model p-value = 0.310

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    To compare the milademetan treatment arm versus the trabectedin control arm for the DCR (ITT Population) by BICR and Investigator assessment. The DCR for each treatment group was estimated by dividing the number of patients with CR, PR, or SD for at least 16 weeks by the number of patients enrolled in the respective treatment group. Similar analysis as for ORR was to be performed for DCR. There were no statistically significant differences between the study arms in Investigator-assessed DCR.
    End point type
    Secondary
    End point timeframe
    The DCR was to be measured as the percentage of patients who have achieved CR, PR, or SD for at least 16 weeks according to RECIST version 1.1 recorded in the period between first study drug dose and disease progression or death to any cause.
    End point values
    		 Milademetan Trabectedin
    Number of subjects analysed
    86 [9]
    89 [10]
    Units: percent
    number (confidence interval 95%)
        By BICR, Patients with disease control
    33.7 (23.9 to 44.7)
    27.0 (18.1 to 37.4)
        Investigator-assessed, Patients with disease contr
    40.7 (30.2 to 51.8)
    29.2 (20.1 to 39.8)
    Notes
    [9] - By BICR, Exact 95% CI of DCR (%): 23.9, 44.7 Invgtor-assessed, Exact 95% CI of DCR (%): 30.2, 51.8
    [10] - By BICR, Exact 95% CI of DCR (%): 18.1, 37.4 Invgtor-assessed, Exact 95% CI of DCR (%): 20.1, 39.8
    Statistical analysis title
    		 Difference in DCR By BICR
    Comparison groups
    Milademetan v Trabectedin
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.332
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR
    Point estimate
    6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 20.4
    Statistical analysis title
    		 Difference in DCR for Investigator-assessed
    Comparison groups
    Milademetan v Trabectedin
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.112
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR
    Point estimate
    11.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 25.5

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    To compare the milademetan treatment arm versus the trabectedin control arm for the ORR (ITT Population) by BICR and Investigator assessment. The ORR for each treatment group was estimated by dividing the number of patients with confirmed CR or PR by the number of patients enrolled in the respective treatment group. There were no statistically significant differences between the study arms in Investigator-assessed ORR.
    End point type
    Secondary
    End point timeframe
    The ORR was defined as the percentage of patients who achieve a confirmed CR or PR according to RECIST version 1.1 that must be confirmed by a subsequent tumor assessment at least 4 weeks after the initial observed response.
    End point values
    		 Milademetan Trabectedin
    Number of subjects analysed
    86 [11]
    89 [12]
    Units: percent
    number (confidence interval 95%)
        By BICR, Patients with an OR
    4.7 (1.3 to 11.5)
    3.4 (0.7 to 9.5)
        Investigator-assessed, Patients with an OR
    10.5 (4.9 to 18.9)
    2.2 (0.3 to 7.9)
    Notes
    [11] - By BICR, Exact 95% CI of ORR (%): 1.3, 11.5 Invgtor-assessed, Exact 95% CI of ORR (%): 4.9, 18.9
    [12] - By BICR, Exact 95% CI of ORR (%): 0.7, 9.5 Invgtor-assessed, Exact 95% CI of ORR (%): 0.3, 7.9
    Statistical analysis title
    		 Difference in ORR By BICR
    Comparison groups
    Trabectedin v Milademetan
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.667
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 7.1
    Statistical analysis title
    		 Difference in ORR Investigator-assessed
    Comparison groups
    Milademetan v Trabectedin
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.026
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR
    Point estimate
    8.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 15.4

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    To compare the milademetan treatment arm versus the trabectedin control arm for the DOR (ITT Population) by BICR and Investigator assessment. The DOR was not evaluable (NE) in either arm.
    End point type
    Secondary
    End point timeframe
    The time from date of first response to date of disease progression or death.DOR was to be summarized by treatment group for the patients who had an ORR.If there were patients that continued to respond, they would be censored at their last tumor assessmen
    End point values
    		 Milademetan Trabectedin
    Number of subjects analysed
    86 [13]
    89 [14]
    Units: month
    median (confidence interval 95%)
        DOR By BICR
    99999 (99999 to 99999)
    99999 (3.5 to 99999)
        DOR By Investigator
    5.7 (3.5 to 99999)
    6.3 (6.3 to 99999)
    Notes
    [13] - "99999" equals not evaluable (NE)
    [14] - "99999" equals NE
    Statistical analysis title
    		 DOR By BICR
    Comparison groups
    Milademetan v Trabectedin
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.317 [15]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 5.83
    Notes
    [15] - Unstratified log-rank test, p-value = 0.317 Unstratified Cox proportional hazards model p-value = 0.999 "0" for lower limit equals NE
    Statistical analysis title
    		 DOR By Investigator
    Comparison groups
    Trabectedin v Milademetan
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.484 [16]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 50.51
    Notes
    [16] - Unstratified log-rank test, p-value = 0.484 Unstratified Cox proportional hazards model p-value = 0.492

    Secondary: Progression Free Survival (PFS) as determined by Investigator

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    End point title
    		 Progression Free Survival (PFS) as determined by Investigator
    End point description
    To compare the milademetan treatment arm versus the trabectedin control arm for the PFS (ITT Population) by Investigator assessment. There were no statistically significant differences between the study arms in Investigator-assessed PFS.
    End point type
    Secondary
    End point timeframe
    PFS was defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause.
    End point values
    		 Milademetan Trabectedin
    Number of subjects analysed
    86 [17]
    89 [18]
    Units: month
        median (confidence interval 95%)
    3.7 (2.1 to 5.4)
    2.1 (1.9 to 3.9)
    Notes
    [17] - a. Pts with PFS events: 62 b. Pts censored: 24 c. Kaplan-Meier estimate of PFS rate 6 month: 30.7%
    [18] - a. Pts with PFS events: 58 b. Pts censored: 31 c. Kaplan-Meier estimate of PFS rate 6 month: 29.3%
    Statistical analysis title
    		 Statistical analysis for PFS by Investigator
    Statistical analysis description
    The treatment difference in the investigator assessed (IA) PFS was to be assessed w/the product limit estimate of median time to event w/95% CI. Differences between treatment groups were to be examined using a stratified log rank test statistic. A stratified Cox Proportional hazard model was to be used to estimate the hazard ratio. Unstratified log-rank test and Cox model was to be performed as sensitivity analysis. IA PFS was to be displayed using a Kaplan-Meier survival plot.
    Comparison groups
    Trabectedin v Milademetan
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.219 [20]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.15
    Notes
    [19] - Interpretation of the PFS by Investigator results was unchanged using the unstratified Kaplan-Meier and Cox models, all observed events, the CCDD Population, or the Per Protocol Population and reflect those found in the ITT Population.
    [20] - Stratified Log-rank Test, p-value = 0.219 Stratified Cox Proportional Hazards Model p-value = 0.224

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After signing informed consent but before initiation of study drug, an event was to be entered on the AE CRF if related to protocol-required procedures.After 1st study drug dose, all AEs were to be entered on AE CRF until 30days after last study drug dose
    Adverse event reporting additional description
    All AEs were to be followed until resolution or until stable, if possible.The Sponsor may have requested certain AEs be followed beyond the protocol-defined f/u period. Investigator must have reported all SAEs regardless of causality within 24hrs of learning of event.Incidence of SAEs occurring in >1 Patient reported in SAE table. Safety Population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Milademetan
    Reporting group description
    		 -

    Reporting group title
    Trabectedin
    Reporting group description
    		 -

    Serious adverse events
    		 Milademetan Trabectedin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 86 (36.05%)
    38 / 79 (48.10%)
         number of deaths (all causes)
    44
    29
         number of deaths resulting from adverse events
    1
    5
    Investigations
    Platelet count decreased
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 86 (16.28%)
    15 / 79 (18.99%)
         occurrences causally related to treatment / all
    8 / 16
    30 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    8 / 86 (9.30%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    8 / 13
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 79 (6.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Milademetan Trabectedin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 86 (100.00%)
    77 / 79 (97.47%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    5 / 86 (5.81%)
    3 / 79 (3.80%)
         occurrences all number
    7
    5
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 86 (2.33%)
    3 / 79 (3.80%)
         occurrences all number
    2
    3
    Hypertension
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 79 (2.53%)
         occurrences all number
    3
    2
    Haematoma
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 79 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 86 (34.88%)
    24 / 79 (30.38%)
         occurrences all number
    47
    42
    Asthenia
         subjects affected / exposed
    28 / 86 (32.56%)
    18 / 79 (22.78%)
         occurrences all number
    63
    32
    Oedema peripheral
         subjects affected / exposed
    4 / 86 (4.65%)
    9 / 79 (11.39%)
         occurrences all number
    6
    11
    Pyrexia
         subjects affected / exposed
    3 / 86 (3.49%)
    6 / 79 (7.59%)
         occurrences all number
    4
    7
    Chills
         subjects affected / exposed
    2 / 86 (2.33%)
    4 / 79 (5.06%)
         occurrences all number
    2
    4
    Mucosal inflammation
         subjects affected / exposed
    2 / 86 (2.33%)
    4 / 79 (5.06%)
         occurrences all number
    2
    4
    Device related thrombosis
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Localised oedema
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    3
    Pain
         subjects affected / exposed
    0 / 86 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 86 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    4
    Pleural effusion
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Hiccups
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Dyspnoea exertional
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 79 (3.80%)
         occurrences all number
    1
    3
    Productive cough
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    2
    3
    Acute respiratory failure
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 79 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    5 / 86 (5.81%)
    9 / 79 (11.39%)
         occurrences all number
    6
    11
    Cough
         subjects affected / exposed
    5 / 86 (5.81%)
    11 / 79 (13.92%)
         occurrences all number
    5
    12
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Anxiety
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Insomnia
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 79 (2.53%)
         occurrences all number
    3
    2
    Investigations
    Platelet count decreased
         subjects affected / exposed
    21 / 86 (24.42%)
    9 / 79 (11.39%)
         occurrences all number
    58
    42
    Blood creatinine increased
         subjects affected / exposed
    8 / 86 (9.30%)
    7 / 79 (8.86%)
         occurrences all number
    8
    11
    White blood cell count decreased
         subjects affected / exposed
    12 / 86 (13.95%)
    8 / 79 (10.13%)
         occurrences all number
    19
    40
    Neutrophil count decreased
         subjects affected / exposed
    20 / 86 (23.26%)
    15 / 79 (18.99%)
         occurrences all number
    51
    58
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 86 (4.65%)
    12 / 79 (15.19%)
         occurrences all number
    5
    20
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 86 (3.49%)
    5 / 79 (6.33%)
         occurrences all number
    11
    12
    Weight decreased
         subjects affected / exposed
    3 / 86 (3.49%)
    4 / 79 (5.06%)
         occurrences all number
    3
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 86 (4.65%)
    19 / 79 (24.05%)
         occurrences all number
    8
    42
    Blood bilirubin increased
         subjects affected / exposed
    4 / 86 (4.65%)
    2 / 79 (2.53%)
         occurrences all number
    6
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 86 (2.33%)
    12 / 79 (15.19%)
         occurrences all number
    3
    25
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    3
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    4
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    7 / 79 (8.86%)
         occurrences all number
    0
    12
    International normalised ratio increased
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Transaminases increased
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    5
    Troponin T increased
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 79 (2.53%)
         occurrences all number
    2
    2
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Tremor
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 79 (0.00%)
         occurrences all number
    4
    0
    Taste disorder
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 79 (0.00%)
         occurrences all number
    3
    0
    Syncope
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 79 (0.00%)
         occurrences all number
    2
    0
    Sciatica
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 79 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    2
    1
    Neuropathy peripheral
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    2
    1
    Dizziness
         subjects affected / exposed
    2 / 86 (2.33%)
    3 / 79 (3.80%)
         occurrences all number
    2
    3
    Headache
         subjects affected / exposed
    7 / 86 (8.14%)
    3 / 79 (3.80%)
         occurrences all number
    7
    4
    Dysgeusia
         subjects affected / exposed
    9 / 86 (10.47%)
    6 / 79 (7.59%)
         occurrences all number
    12
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    35 / 86 (40.70%)
    28 / 79 (35.44%)
         occurrences all number
    71
    96
    Thrombocytopenia
         subjects affected / exposed
    31 / 86 (36.05%)
    11 / 79 (13.92%)
         occurrences all number
    137
    30
    Neutropenia
         subjects affected / exposed
    15 / 86 (17.44%)
    13 / 79 (16.46%)
         occurrences all number
    42
    28
    Leukopenia
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 79 (3.80%)
         occurrences all number
    3
    12
    Lymphopenia
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 79 (2.53%)
         occurrences all number
    6
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 79 (0.00%)
         occurrences all number
    4
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    61 / 86 (70.93%)
    45 / 79 (56.96%)
         occurrences all number
    118
    81
    Vomiting
         subjects affected / exposed
    38 / 86 (44.19%)
    14 / 79 (17.72%)
         occurrences all number
    64
    15
    Diarrhoea
         subjects affected / exposed
    24 / 86 (27.91%)
    21 / 79 (26.58%)
         occurrences all number
    46
    28
    Abdominal pain
         subjects affected / exposed
    16 / 86 (18.60%)
    9 / 79 (11.39%)
         occurrences all number
    21
    15
    Constipation
         subjects affected / exposed
    10 / 86 (11.63%)
    20 / 79 (25.32%)
         occurrences all number
    15
    25
    Dyspepsia
         subjects affected / exposed
    6 / 86 (6.98%)
    5 / 79 (6.33%)
         occurrences all number
    6
    6
    Abdominal distension
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 79 (3.80%)
         occurrences all number
    3
    3
    Dry mouth
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 79 (3.80%)
         occurrences all number
    4
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 79 (2.53%)
         occurrences all number
    4
    2
    Dysphagia
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    2
    3
    Flatulence
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 79 (2.53%)
         occurrences all number
    3
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 79 (3.80%)
         occurrences all number
    1
    4
    Stomatitis
         subjects affected / exposed
    1 / 86 (1.16%)
    4 / 79 (5.06%)
         occurrences all number
    1
    4
    Abdominal discomfort
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Proctalgia
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    3
    Cholestasis
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Alopecia
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    3
    1
    Nail disorder
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 79 (0.00%)
         occurrences all number
    3
    0
    Hyperhidrosis
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 79 (0.00%)
         occurrences all number
    4
    0
    Dry skin
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 79 (1.27%)
         occurrences all number
    3
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Haematuria
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    3
    Chronic kidney disease
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Acute kidney injury
         subjects affected / exposed
    1 / 86 (1.16%)
    5 / 79 (6.33%)
         occurrences all number
    1
    5
    Dysuria
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 79 (2.53%)
         occurrences all number
    2
    3
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    3
    Neck pain
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    5
    Musculoskeletal pain
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    3
    Arthralgia
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 79 (6.33%)
         occurrences all number
    0
    6
    Myalgia
         subjects affected / exposed
    2 / 86 (2.33%)
    5 / 79 (6.33%)
         occurrences all number
    2
    8
    Muscular weakness
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    2
    1
    Flank pain
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 79 (1.27%)
         occurrences all number
    2
    1
    Pain in extremity
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 79 (3.80%)
         occurrences all number
    3
    3
    Back pain
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 79 (2.53%)
         occurrences all number
    6
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Device related infection
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 86 (2.33%)
    4 / 79 (5.06%)
         occurrences all number
    3
    4
    Oral candidiasis
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 79 (0.00%)
         occurrences all number
    4
    0
    COVID-19
         subjects affected / exposed
    7 / 86 (8.14%)
    5 / 79 (6.33%)
         occurrences all number
    7
    5
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 79 (3.80%)
         occurrences all number
    1
    4
    Hyponatraemia
         subjects affected / exposed
    2 / 86 (2.33%)
    5 / 79 (6.33%)
         occurrences all number
    2
    7
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 86 (2.33%)
    6 / 79 (7.59%)
         occurrences all number
    2
    8
    Hyperkalaemia
         subjects affected / exposed
    2 / 86 (2.33%)
    4 / 79 (5.06%)
         occurrences all number
    2
    4
    Dehydration
         subjects affected / exposed
    2 / 86 (2.33%)
    4 / 79 (5.06%)
         occurrences all number
    3
    5
    Vitamin B12 deficiency
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 79 (1.27%)
         occurrences all number
    3
    1
    Hypomagnesaemia
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 79 (3.80%)
         occurrences all number
    3
    3
    Hypokalaemia
         subjects affected / exposed
    4 / 86 (4.65%)
    5 / 79 (6.33%)
         occurrences all number
    6
    6
    Hypophosphataemia
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 79 (2.53%)
         occurrences all number
    6
    2
    Decreased appetite
         subjects affected / exposed
    25 / 86 (29.07%)
    17 / 79 (21.52%)
         occurrences all number
    32
    22
    Hypocalcaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    4 / 79 (5.06%)
         occurrences all number
    1
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2021
    • Made the following updates to the patient selection criteria: o Required documentation of advanced unresectable and/or metastatic disease o Added requirements for anticoagulation medication and antihypertensive medication o Revised the systolic and diastolic parameters • Added criteria for treatment beyond progression
    20 May 2021
    • Updated milademetan dose modification guidelines to recommend discontinuation for Grade 3 and 4 AEs that do not resolve to Grade 1 within 4 weeks; resumption after Grade 4 nonhematologic AEs must be discussed with the Medical Monitor; required discontinuation for a recurrent Grade 4 event.
    18 Mar 2022
    • Changed the definition of DCR from patients who achieve complete response, partial response, or stable disease for at least 8 weeks to patients who achieve this for at least 16 weeks • Changed the definition of TEAEs to account for the possibility of new anticancer therapy starting before 30 days after a patient’s last dose of study drug

    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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