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    Clinical Trial Results:
    A Phase 4, Open-Label, Randomized Study of two Inotuzumab Ozogamicin Dose Levels In Adult Participants With Relapsed Or Refractory B-Cell Acute Lymphoblastic Leukemia Eligible for Hematopoietic Stem Cell Transplantation and who Have Risk Factor(S) for Veno-Occlusive Disease

    Summary
    EudraCT number
    2018-001557-27
    Trial protocol
    PL   BE   HU   ES  
    Global end of trial date
    26 May 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Jun 2024
    First version publication date
    08 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B1931030
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03677596
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the rates of veno-occlusive disease (VOD) and hematologic remission (complete remission/complete remission with incomplete hematologic recovery [CR/Cri]) for 2 Inotuzumab Ozogamicin dose levels in adult subjects with relapsed or refractory B-cell Acute lymphocytic leukemia (ALL) who are eligible for hematopoietic stem cell transplant (HSCT) and who are at higher risk for developing VOD post-HSCT.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    India: 14
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Singapore: 5
    Country: Number of subjects enrolled
    Türkiye: 43
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    102
    EEA total number of subjects
    31
    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)
    95
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 102 were enrolled and treated. In Run-in Phase, 22 subjects were enrolled and treated. In Randomised Phase, 80 subjects were enrolled and treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized)
    Arm description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15). The maximum treatment duration was approximately 26 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Inotuzumab Ozogamicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.2 mg/m²/cycle administered in 3 divided doses (0.6 mg/m² on Day 1, 0.3 mg/m² on Days 8 and 15) intravenously.

    Arm title
    1.8 mg/m²/cycle (Dose Level 1 Randomized Phase)
    Arm description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle administrated in 3 divided doses (0.8 mg/m² on Day 1, 0.5 mg/m² on Days 8 and 15) intravenously. After CR/CRi was achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Days 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Inotuzumab Ozogamicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8 mg/m²/cycle administrated in 3 divided doses (0.8 mg/m² on Day 1, 0.5 mg/m² on Days 8 and 15) intravenously.

    Number of subjects in period 1
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.8 mg/m²/cycle (Dose Level 1 Randomized Phase)
    Started
    64
    38
    Completed
    41
    19
    Not completed
    23
    19
         Adverse event, serious fatal
    10
    6
         Consent withdrawn by subject
    3
    -
         Disease Relapse
    2
    2
         Adverse event, non-fatal
    -
    1
         Progressive Disease
    8
    8
         Unspecified
    -
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15). The maximum treatment duration was approximately 26 weeks.

    Reporting group title
    1.8 mg/m²/cycle (Dose Level 1 Randomized Phase)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle administrated in 3 divided doses (0.8 mg/m² on Day 1, 0.5 mg/m² on Days 8 and 15) intravenously. After CR/CRi was achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Days 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Reporting group values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.8 mg/m²/cycle (Dose Level 1 Randomized Phase) Total
    Number of subjects
    64 38 102
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0
        Between 18 and 65 years
    59 36 95
        >=65 years
    5 2 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.27 ( 14.85 ) 39.47 ( 15.26 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    28 18 46
        Male
    36 20 56
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    11 11 22
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    51 25 76
        More than one race
    0 0 0
        Unknown or Not Reported
    2 2 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    7 3 10
        Not Hispanic or Latino
    56 35 91
        Unknown or Not Reported
    1 0 1
    ECOG Performance Status
    Eastern Cooperative Oncology Group (ECOG) Performance Status is defined as: ECOG=0: Fully active, able to carry on all predisease performance without restriction; ECOG=1: Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, ie, light house work, office work; ECOG=2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
    Units: Subjects
        ECOG = 0
    28 20 48
        ECOG = 1
    33 13 46
        ECOG = 2
    3 5 8
    Body Mass Index (BMI)
    BMI (kg/m^2) was computed as Height (cm)/Weight (kg) x 100.
    Units: kg/m^2
        median (full range (min-max))
    25.26 (16 to 39) 24.78 (16 to 41) -
    Body Surface Area (BSA)
    BSA (m^2) will be computed using Du Bois Formula: 0.007184 x Weight (kg)^0.425 x Height (cm)^0.725.
    Units: m^2
        median (full range (min-max))
    1.84 (1 to 3) 1.79 (1 to 3) -
    Subject analysis sets

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised Phase)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day 1, 0.3 mg/m² on Days 8 and 15) intravenously. After CR/CRi was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomized)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomized)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis sets values
    1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomized) 1.8 mg/m²/cycle (Dose Level 1 Randomised) 1.2 mg/m²/cycle (Dose Level 2 Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects
    22
    42
    42
    38
    10
    21
    12
    22
    11
    35
    26
    41
    2
    3
    3
    Age Categorical
    Units: Subjects
        <=18 years
        Between 18 and 65 years
        >=65 years
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    ECOG Performance Status
    Eastern Cooperative Oncology Group (ECOG) Performance Status is defined as: ECOG=0: Fully active, able to carry on all predisease performance without restriction; ECOG=1: Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, ie, light house work, office work; ECOG=2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
    Units: Subjects
        ECOG = 0
        ECOG = 1
        ECOG = 2
    Body Mass Index (BMI)
    BMI (kg/m^2) was computed as Height (cm)/Weight (kg) x 100.
    Units: kg/m^2
        median (full range (min-max))
    Body Surface Area (BSA)
    BSA (m^2) will be computed using Du Bois Formula: 0.007184 x Weight (kg)^0.425 x Height (cm)^0.725.
    Units: m^2
        median (full range (min-max))
    18 ( to )

    End points

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    End points reporting groups
    Reporting group title
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15). The maximum treatment duration was approximately 26 weeks.

    Reporting group title
    1.8 mg/m²/cycle (Dose Level 1 Randomized Phase)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle administrated in 3 divided doses (0.8 mg/m² on Day 1, 0.5 mg/m² on Days 8 and 15) intravenously. After CR/CRi was achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Days 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised Phase)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day 1, 0.3 mg/m² on Days 8 and 15) intravenously. After CR/CRi was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomized)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomized)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Run-in)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle (0.6 mg/m² on Day 1, 0.3 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Subject analysis set title
    1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 26 weeks.

    Primary: Percentage of Subjects With Veno-occlusive Disease (VOD)

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    End point title
    Percentage of Subjects With Veno-occlusive Disease (VOD) [1] [2]
    End point description
    VOD happened when the small blood vessels that lead into the liver and were inside the liver become blocked. VOD is defined as: a. Classical VOD (first 21 days after HSCT): Bilirubin>=2 mg/dL and 2 (or more) of the following criteria must also be present: 1. Painful hepatomegaly; 2. Weight gain >5%; 3. Ascites. b. Late onset VOD (>21 days after HSCT): Classical VOD beyond Day 21; or Histologically proven VOD; or Two or more of the following criteria must be present: 1. Bilirubin >2 mg/dL; 2. Painful hepatomegaly; 3. Weight gain >5%; 4. Ascites. and hemodynamical and/or ultrasound evidence of VOD. All randomised subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    From consent up to follow-up (up to 2 years)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    [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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Percentage of subjects
        number (not applicable)
    12.5
    9.1
    14.3
    5.3
    No statistical analyses for this end point

    Primary: Rate of Hematologic Remission (Complete Response [CR] / Complete Response with Incomplete Hematologic Recovery[CRi])

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    End point title
    Rate of Hematologic Remission (Complete Response [CR] / Complete Response with Incomplete Hematologic Recovery[CRi]) [3] [4]
    End point description
    CR=disappearance of leukemia indicated by <5% marrow blasts, absence of peripheral blood leukemic blasts,recovery of hematopoiesis defined by absolute neutrophil count (ANC)>=1000/µL and platelets>=100000/µL. C1 extramedullary disease status is required. CRi = CR except with ANC <1000/µL and/or platelets <100000/µL. Subjects randomised into study with study drug assignment based on randomisation.
    End point type
    Primary
    End point timeframe
    From first dose of study treatment till follow-up of up to 2 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    [4] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Percentage of subjects
        number (not applicable)
    71.9
    50.0
    83.3
    68.4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (Treatment-related)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (Treatment-related) [5]
    End point description
    Adverse event (AE) = any untoward medical occurrence in subject who received study treatment without regard to possibility of causal relationship. Treatment emergent AEs (TEAEs) were defined as AEs that reported the period starting with the first dose of study treatment drug through 63 days after last dose or 1 day before start day of new anticancer therapy, whichever occurred first. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Grades of severity were defined by CTCAE v3.0. Grade 3 = severe adverse event; Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE. Causality of TEAEs were assessed by the Investigator. All randomised subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks)
    Notes
    [5] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Subjects
        Participants with AEs
    31
    13
    18
    22
        Participants with SAEs
    15
    7
    8
    10
        Participants with Maximum Grade 3 or 4 AEs
    20
    9
    11
    11
        Participants with Maximum Grade 5 AEs
    2
    1
    1
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (All Causalities)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (All Causalities) [6]
    End point description
    Adverse event (AE) = any untoward medical occurrence in subject who received study treatment without regard to possibility of causal relationship. On-treatment period was defined as the period starting with the 1st dose of study treatment through 63 days after last dose or 1 day before start day of new anticancer therapy, whichever occurred first. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All VOD cases were reported as SAE. Grades of severity were defined by Common terminology criteria for adverse events (CTCAE) v3.0. Grade 3=severe adverse event; Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. All randomised subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks)
    Notes
    [6] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Subjects
        Subjects with AE
    60
    21
    39
    35
        Subjects with SAEs
    43
    15
    28
    21
        Subjects with Maximum Grade 3 or 4 AE
    30
    9
    21
    18
        Subjects with Maximum Grade 5 adverse events
    19
    7
    12
    10
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift Summary of Hematology Laboratory Test Results from Grade Less Than or Equal to (<=) 2 at Baseline to Grade 3 or 4 Post-Baseline

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    End point title
    Number of Subjects With Shift Summary of Hematology Laboratory Test Results from Grade Less Than or Equal to (<=) 2 at Baseline to Grade 3 or 4 Post-Baseline [7]
    End point description
    Baseline assessment was defined as the last assessment performed on or prior to the date of the first dose of study treatment. Following Parameters were analyzed for laboratory assessment: Hematology (Activated partial thromboplastin time prolonged, Anemia, Hemoglobin increased, International normalization rate (INR) increased, Leukocytosis, Lymphocyte count decreased, Lymphocyte count increased, Neutrophil count decreased, Platelet count decreased, White blood cell decreased). Grades of severity were defined by CTCAE v3.0. Grade 2 = moderate adverse event; Grade 3= severe adverse event; Grade 4 = life-threatening consequences; urgent intervention indicated. All randomised subjects who received at least 1 dose of study drug and with at least 1 postbaseline assessment in each treatment group. ‘Number analysed’ = subjects evaluable for this endpoint for each specified row. ’99999’=Grade4 was not applicable for the test.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks)
    Notes
    [7] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Subjects
        APT time prolonged - Grade 3 (n=51,19,32,27)
    0
    0
    0
    0
        APT time prolonged - Grade 4 (n=51,19,32,27)
    99999
    99999
    99999
    99999
        Anemia - Grade 3 (n=37,15,22,20)
    21
    8
    13
    11
        Anemia - Grade 4 (n=37,15,22,20)
    99999
    99999
    99999
    99999
        Hemoglobin increased - Grade 3(n=18,6,12,13)
    0
    0
    0
    0
        Hemoglobin increased - Grade 4(n=18,6,12,13)
    99999
    99999
    99999
    99999
        INR increased - Grade 3(n=27,11,16,12)
    0
    0
    0
    0
        INR increased - Grade 4(n=27,11,16,12)
    99999
    99999
    99999
    99999
        Leukocytosis - Grade 3(n=18,7,11,13)
    1
    1
    0
    0
        Leukocytosis - Grade 4(n=18,7,11,13)
    99999
    99999
    99999
    99999
        Lymphocyte count decreased-Grade 3(n=51,16,35,28)
    16
    1
    15
    7
        Lymphocyte count decreased-Grade 4(n=51,16,35,28)
    6
    4
    2
    4
        Lymphocyte count increased-Grade 3(n=27,13,14,17)
    3
    2
    1
    3
        Lymphocyte count increased-Grade 4(n=27,13,14,17)
    99999
    99999
    99999
    99999
        Neutrophil count decreased-Grade 3(n=51,17,34,27)
    8
    2
    6
    7
        Neutrophil count decreased-Grade 4(n=51,17,34,27)
    21
    11
    10
    9
        Platelet count decreased-Grade 3(n=41,13,28,28)
    7
    1
    6
    5
        Platelet count decreased - Grade 4(n=41,13,28,28)
    7
    4
    3
    7
        White blood cell decreased-Grade 3(n=56,18,38,29)
    18
    5
    13
    9
        White blood cell decreased-Grade 4(n=56,18,38,29)
    17
    7
    10
    11
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Serious Adverse Events (Post-HSCT)

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    End point title
    Number of Subjects With Treatment-Emergent Serious Adverse Events (Post-HSCT) [8]
    End point description
    A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All SAEs occurred after HSCT were reported in this endpoint. All randomised subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Starting from the first transplant after inotuzumab ozogamicin treatment and including the entire duration of subsequent follow up (approximately 52 weeks)
    Notes
    [8] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Subjects
    14
    6
    8
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift Summary of Chemistry Laboratory Test Results from Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline

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    End point title
    Number of Subjects With Shift Summary of Chemistry Laboratory Test Results from Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline [9]
    End point description
    Baseline assessment=last assessment performed on or prior to date of first dose of study treatment. Parameters analysed for laboratory assessment:Chemistry(Alanine aminotransferase[ALT] increased,Alkaline phosphatase[ALP] increased,Aspartate aminotransferase[AST] increased,Blood bilirubin increased,Chronic kidney disease,Creatinine increased,Gamma glutamyl transpeptidase[GGT] increased,Hypercalcemia,Hyperglycemia,Hyperkalemia, Hypermagnesemia,Hypernatremia,Hypoalbuminemia,Hypocalcemia,Hypoglycemia,Hypokalemia,Hypomagnesemia, Hyponatremia,Hypophosphatemia,Lipase increased,Serum amylase increased).Grades of severity defined by CTCAE v3.0.Grade 2=moderate AE ;Grade 3=severe AE ;Grade 4= life-threatening consequences; urgent intervention indicated. All randomised subjects who received at least 1 dose of study drug with at least 1 postbaseline assessment in each treatment group.‘Number analysed’= subjects evaluable for each specified row.’99999’=Grade4 was not applicable for the test.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks)
    Notes
    [9] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Subjects
        ALT increased - Grade 3 (n=29,14,15,23)
    1
    1
    0
    0
        ALT increased - Grade 4(n=29,14,15,23)
    0
    0
    0
    0
        ALP increased - Grade 3 (n=42,14,28,22)
    1
    1
    0
    1
        ALP increased - Grade 4 (n=42,14,28,22)
    0
    0
    0
    0
        AST increased - Grade 3(n=42,16,26,26)
    4
    1
    3
    0
        AST increased - Grade 4(n=42,16,26,26)
    0
    0
    0
    0
        Blood bilirubin increased - Grade 3(n=31,14,17,20)
    2
    1
    1
    0
        Blood bilirubin increased - Grade 4(n=31,14,17,20)
    0
    0
    0
    0
        Chronic kidney disease - Grade 3(n=9,2,7,7)
    0
    0
    0
    0
        Chronic kidney disease - Grade 4(n=9,2,7,7)
    0
    0
    0
    0
        Creatinine increased - Grade 3(n=50,19,31,26)
    0
    0
    0
    0
        Creatinine increased - Grade 4(n=50,19,31,26)
    0
    0
    0
    0
        GGT increased - Grade 3(n=37,15,22,26)
    3
    1
    2
    3
        GGT increased - Grade 4(n=37,15,22,26)
    0
    0
    0
    0
        Hypercalcemia - Grade 3(n=22,10,12,15)
    0
    0
    0
    0
        Hypercalcemia - Grade 4(n=22,10,12,15)
    0
    0
    0
    0
        Hyperglycemia - Grade 3(n=37,13,24,21)
    4
    2
    2
    2
        Hyperglycemia - Grade 4(n=37,13,24,21)
    0
    0
    0
    0
        Hyperkalemia - Grade 3(n=21,10,11,14)
    0
    0
    0
    0
        Hyperkalemia - Grade 4(n=21,10,11,14)
    1
    1
    0
    0
        Hypermagnesemia - Grade 3(n=21,11,10,15)
    1
    1
    0
    1
        Hypermagnesemia - Grade 4(n=21,11,10,15)
    0
    0
    0
    0
        Hypernatremia - Grade 3(n=19,9,10,15)
    0
    0
    0
    0
        Hypernatremia - Grade 4(n=19,9,10,15)
    1
    0
    1
    0
        Hypoalbuminemia - Grade 3 (n=31,16,15,21)
    4
    1
    3
    3
        Hypoalbuminemia - Grade 4(n=31,16,15,21)
    99999
    99999
    99999
    99999
        Hypocalcemia - Grade 3(n=28,12,16,15)
    1
    1
    0
    0
        Hypocalcemia - Grade 4(n=28,12,16,15)
    0
    0
    0
    0
        Hypoglycemia - Grade 3(n=22,10,12,16)
    0
    0
    0
    0
        Hypoglycemia - Grade 4(n=22,10,12,16)
    0
    0
    0
    0
        Hypokalemia - Grade 3(n=32,13,19,24)
    3
    1
    2
    1
        Hypokalemia - Grade 4(n=32,13,19,24)
    1
    1
    0
    0
        Hypomagnesemia - Grade 3(n=30,14,16,18)
    1
    1
    0
    1
        Hypomagnesemia - Grade 4(n=30,14,16,18)
    0
    0
    0
    1
        Hyponatremia - Grade 3(n=27,13,14,19)
    1
    1
    0
    0
        Hyponatremia - Grade 4(n=27,13,14,19)
    0
    0
    0
    0
        Hypophosphatemia- Grade 3(n=26,13,13,18)
    2
    2
    0
    1
        Hypophosphatemia - Grade 4(n=26,13,13,18)
    0
    0
    0
    1
        Lipase increased - Grade 3(n=38,15,23,24)
    6
    3
    3
    2
        Lipase increased - Grade 4(n=38,15,23,24)
    2
    0
    2
    0
        Serum amylase increased - Grade 3(n=32,14,18,22)
    2
    1
    1
    0
        Serum amylase increased - Grade 4(n=32,14,18,22)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Duration of Remission (DoR) in Subjects who Achieved CR/CRi

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    End point title
    Duration of Remission (DoR) in Subjects who Achieved CR/CRi [10]
    End point description
    DoR was defined as time from date of first response in responders (CR/CRi) to the date of disease progression (i.e., objective progression, relapse from CR/CRi, including post-study treatment follow-up disease assessments) or death due to any cause, whichever occurs first. DoR was estimated using Kaplan-Meier methods. 99999 indicates upper limit was not estimated due to fewer number of subjects with event. Subjects who were randomised into the study and with a remission (CR/CRi).
    End point type
    Secondary
    End point timeframe
    From date of first response (subjects who achieved CR/CRi) to the date of disease progression or death due to any cause
    Notes
    [10] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    46
    11
    35
    26
    Units: Months
        median (confidence interval 95%)
    5.5 (4.7 to 13.4)
    5.2 (1.9 to 99999)
    6.5 (4.6 to 20.9)
    6.8 (4.7 to 8.7)
    No statistical analyses for this end point

    Secondary: Number of Subjects Achieving a CR/CRi with Minimal Residual Disease (MRD) Negativity

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    End point title
    Number of Subjects Achieving a CR/CRi with Minimal Residual Disease (MRD) Negativity [11]
    End point description
    Subjects who achieved CR/CRi, a patient was considered to be MRD negative if the minimum MRD (%) between the date of achieving CR/CRi and end of treatment test is <0.01%. All subjects who were randomised into the study and achieved CR/CRi.
    End point type
    Secondary
    End point timeframe
    At screening, once at Day 16-28 of Cycles 1 and 2, or until CR/CRi and MRD negativity were achieved, then after every 1-2 cycles as clinically indicated, and at EOT visit
    Notes
    [11] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    46
    11
    35
    26
    Units: Subjects
    33
    8
    25
    18
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS) [12]
    End point description
    PFS was defined as time from date of randomisation to the date of disease progression (i.e., objective progression, relapse from CR/CRi, including post-study treatment follow-up disease assessments), death due to any cause, or starting new induction therapy/post-therapy HSCT without achieving CR/CRi, whichever occurred first. PFS was estimated using Kaplan-Meier methods. Results were reported as of the data cutoff date on 21 Sep 2022.All subjects who were randomised into the study with study drug assignment based on randomisation.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to date of disease progression, death, or starting new induction therapy/post-therapy HSCT without achieving CR/Cri
    Notes
    [12] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Months
        median (confidence interval 95%)
    5.3 (3.4 to 7.2)
    2.9 (1.7 to 5.8)
    6.4 (4.8 to 16.0)
    6.3 (2.8 to 8.0)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival [13]
    End point description
    Overall survival was defined as the time from date of first dose of study treatment to death due to any cause. Subjects without confirmation of death were censored at the date that the subject was last known to be alive. 99999 indicates upper limit was not estimable due to fewer number of subjects with event. All subjects who were randomised into the study with study drug assignment based on randomisation.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to death due to any cause
    Notes
    [13] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Months
        median (confidence interval 95%)
    7.6 (5.8 to 10.0)
    4.5 (3.2 to 8.6)
    9.6 (6.4 to 99999)
    8.1 (5.4 to 10.4)
    No statistical analyses for this end point

    Secondary: Number of Subjects who Received HSCT Post Inotuzumab Ozogamicin Treatment

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    End point title
    Number of Subjects who Received HSCT Post Inotuzumab Ozogamicin Treatment [14]
    End point description
    Subjects who underwent HSCT after inotuzumab ozogamicin treatment. All subjects who were randomised into the study with study drug assignment based on randomisation.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment till follow-up of up to 2 years
    Notes
    [14] - 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: No statistical analysis was planned for this endpoint
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Subjects
    31
    10
    21
    12
    No statistical analyses for this end point

    Secondary: Number of Subjects With Post-HSCT Mortality

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    End point title
    Number of Subjects With Post-HSCT Mortality [15]
    End point description
    Post-HSCT Mortality was defined as the time from date of first HSCT after inotuzumab ozogamicin treatment to death due to any cause. All subjects who were randomised into the study with study drug assignment based on randomisation and who were post HSCT.
    End point type
    Secondary
    End point timeframe
    From date of HSCT to the date of death due to any cause (approximately 4 years)
    Notes
    [15] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    31
    10
    21
    12
    Units: Subjects
    14
    6
    8
    6
    No statistical analyses for this end point

    Secondary: Cumulative Incidence Rate of Post-HSCT Relapse at Month 12

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    End point title
    Cumulative Incidence Rate of Post-HSCT Relapse at Month 12 [16]
    End point description
    Post-HSCT relapse is defined as the time from date of first HSCT after inotuzumab ozogamicin treatment to the date of first relapse post-HSCT. Cumulative incidence rates of an event at a particular timepoint were estimated with the CI calculated based on the cumulative incidence function using the method described by Kalbfleisch RL and Prentice JD. All subjects who were randomised into the study with study drug assignment based on randomisation and who were post HSCT.
    End point type
    Secondary
    End point timeframe
    From date of HSCT to the date of first relapse post-HSCT to Month 12
    Notes
    [16] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    31
    10
    21
    12
    Units: Percentages of subjects
        number (confidence interval 95%)
    17.58 (6.17 to 33.79)
    11.11 (0.40 to 41.66)
    20.51 (6.00 to 40.97)
    16.67 (2.26 to 42.89)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Post HSCT Relapse-Related Mortality

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    End point title
    Number of Subjects with Post HSCT Relapse-Related Mortality [17]
    End point description
    Post HSCT Relapse-Related Mortality was defined as time from date of first HSCT after inotuzumab ozogamicin treatment to death due to any cause with prior relapse. All subjects who were randomised into the study with study drug assignment based on randomisation and who underwent HSCT after inotuzumab ozogamicin treatment.
    End point type
    Secondary
    End point timeframe
    From date of HSCT to the date of death due to any cause with prior relapse/progression post-HSCT (approximately 4 years)
    Notes
    [17] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Number of subjects analysed
    31
    10
    21
    12
    Units: Subjects
    4
    1
    3
    2
    No statistical analyses for this end point

    Secondary: Mean Predose Concentrations (Ctrough) of Inotuzumab Ozogamicin

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    End point title
    Mean Predose Concentrations (Ctrough) of Inotuzumab Ozogamicin [18]
    End point description
    Ctrough was defined as the mean Predose concentration of study treatment. All treated subjects who received at least 1 dose of study drug and had at least one PK sample collected and analysed. ‘Number analysed’ = Subjects evaluable for this endpoint for each specified row.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Cycle 1 Day 1, 8 and 15, and on Day1 and 8 of Cycle 2, 3 and 4.
    Notes
    [18] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    64
    22
    42
    38
    Units: Nanogram per milliliter
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (C1D1) n=61,22,39,37
    0.8 ( 5.56 )
    1.9 ( 9.10 )
    0.2 ( 1.38 )
    0.1 ( 0.35 )
        C1D8 (n=60,22,38,36)
    8.1 ( 21.24 )
    7.7 ( 20.53 )
    8.3 ( 21.91 )
    4.3 ( 6.05 )
        C1D15 (n=60,21,39,33)
    15.8 ( 31.34 )
    8.9 ( 11.14 )
    19.5 ( 37.67 )
    25.8 ( 32.89 )
        C2D1 (n=54,17,37,24)
    15.6 ( 24.95 )
    16.4 ( 21.43 )
    15.2 ( 26.67 )
    22.0 ( 47.15 )
        C2D8 (n=51,18,33,22)
    42.7 ( 46.93 )
    42.6 ( 56.57 )
    42.8 ( 41.73 )
    48.6 ( 24.99 )
        C3D1 (n=17,5,12,11)
    30.2 ( 43.39 )
    21.4 ( 18.46 )
    33.9 ( 50.64 )
    37.1 ( 34.03 )
        C3D8 (n=19,5,14,9)
    36.2 ( 18.20 )
    31.9 ( 25.43 )
    37.8 ( 15.82 )
    68.8 ( 39.22 )
        C4D1 (n=6,2,4,0)
    29.4 ( 18.12 )
    50.0 ( 14.64 )
    19.2 ( 7.42 )
    99999 ( 99999 )
        C4D8 (n=6,2,4,1
    47.7 ( 10.63 )
    48.7 ( 7.99 )
    47.2 ( 12.88 )
    90.4 ( 99999 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Post HSCT non-Relapse Mortality

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    End point title
    Number of Subjects With Post HSCT non-Relapse Mortality [19]
    End point description
    Post HSCT non-relapse mortality was defined as time from date of first HSCT after inotuzumab ozogamicin treatment to death due to any cause without prior relapse. All subjects who were randomised into the study with study drug assignment based on randomisation and who underwent HSCT after inotuzumab ozogamicin treatment.
    End point type
    Secondary
    End point timeframe
    From date of HSCT to the date of death due to any cause without prior relapse/progression post-HSCT (approximately 4 years)
    Notes
    [19] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.2 mg/m²/cycle (Dose Level 2 Randomised)
    Number of subjects analysed
    31
    10
    21
    12
    Units: Subjects
    10
    5
    5
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-Drug Antibody (ADA)

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    End point title
    Number of Subjects With Positive Anti-Drug Antibody (ADA) [20]
    End point description
    ADA incidence is defined as combined results of treatment-boosted and treatment-induced ADA-positive subjects. The immunogenicity of inotuzumab ozogamicin was evaluated using a validated electrochemiluminescence (ECL)-based immunoassay. Subjects who received at least 1 dose of study drug and had at least 1 ADA sample collected and analysed for immunogenicity.
    End point type
    Secondary
    End point timeframe
    At Day 1 of every cycle prior to the beginning of inotuzumab ozogamicin infusion and at the EOT visit, up to approximately 4 years
    Notes
    [20] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.8 mg/m²/cycle (Dose Level 1 Randomised) 1.2 mg/m²/cycle (Dose Level 2 Randomized)
    Number of subjects analysed
    63
    22
    38
    41
    Units: Subjects
        Positive Predose ADA
    4
    1
    2
    3
        Treatment-induced ADA
    1
    1
    1
    0
        Treatment-boosted ADA
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Neutralizing Antibody (NAb)

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    End point title
    Number of Subjects With Positive Neutralizing Antibody (NAb) [21]
    End point description
    NAb incidence is defined as combined results of treatment-boosted and treatment-induced NAb-positive subjects. The immunogenicity of inotuzumab ozogamicin was evaluated using a validated electrochemiluminescence (ECL)-based immunoassay. Subjects who received at least 1 dose of study drug and had at least 1 Nab sample collected and analysed for immunogenicity.
    End point type
    Secondary
    End point timeframe
    At Day 1 of every cycle prior to the beginning of inotuzumab ozogamicin infusion and at the EOT visit, up to approximately 4 years.
    Notes
    [21] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    1.2 mg/m²/cycle (Dose Level 2 Run-in + Randomized) 1.2 mg/m²/cycle (Dose Level 2 Run-in) 1.2 mg/m²/cycle (Dose Level 2 Randomised Phase) 1.8 mg/m²/cycle (Dose Level 1 Randomised)
    Number of subjects analysed
    5
    2
    3
    3
    Units: Subjects
        Positive Predose NAb
    0
    0
    0
    0
        Treatment-induced NAb
    0
    0
    0
    0
        Treatment-boosted NAb
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of consent including a minimum of 9 weeks after the last dose
    Adverse event reporting additional description
    Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis performed on safety set.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    1.2 mg/m2/cycle (Run-in)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day1, 0.3 mg/m² on Days 8 and 15) intravenously. After complete response (CR)/complete remission with incomplete hematologic recovery (CRi) was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15). The cycle length was 21-28 days. The maximum treatment duration was approximately 4 years.

    Reporting group title
    1.8 mg/m2/cycle (Randomized)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.8 mg/m²/cycle (0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 15) intravenously. After CR/CRi is achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Day 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 4 years.

    Reporting group title
    1.2 mg/m2/cycle (Run-in + Randomized)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.8 mg/m² on Day 1, 0.5 mg/m² on Days 8 and 15) intravenously. After CR/CRi was achieved, the dose was reduced to 1.5 mg/m²/cycle (0.5 mg/m² on Days 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 4 years.

    Reporting group title
    1.2 mg/m2/cycle (Randomized)
    Reporting group description
    Subjects received a starting dose of inotuzumab ozogamicin 1.2 mg/m²/cycle administrated in 3 divided doses (0.6 mg/m² on Day 1, 0.3 mg/m² on Days 8 and 15) intravenously. After CR/CRi was achieved, the dose was reduced to 0.9 mg/m²/cycle (0.3 mg/m² on Days 1, 8 and 15) for 2-3 cycles. The cycle length was 21-28 days. The maximum treatment duration was approximately 4 years.

    Serious adverse events
    1.2 mg/m2/cycle (Run-in) 1.8 mg/m2/cycle (Randomized) 1.2 mg/m2/cycle (Run-in + Randomized) 1.2 mg/m2/cycle (Randomized)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 22 (68.18%)
    21 / 38 (55.26%)
    43 / 64 (67.19%)
    28 / 42 (66.67%)
         number of deaths (all causes)
    16
    26
    40
    24
         number of deaths resulting from adverse events
    7
    10
    19
    12
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm recurrence
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 38 (5.26%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 38 (5.26%)
    4 / 64 (6.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 4
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    0 / 3
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 38 (7.89%)
    3 / 64 (4.69%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 1
    Immune system disorders
    Graft versus host disease in liver
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sinus polyp
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella test positive
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery thrombosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system lesion
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 38 (5.26%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia megaloblastic
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 38 (10.53%)
    7 / 64 (10.94%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 6
    7 / 8
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    2 / 64 (3.13%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venoocclusive liver disease
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 38 (5.26%)
    8 / 64 (12.50%)
    6 / 42 (14.29%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 2
    6 / 12
    1 / 7
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    COVID-19
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    2 / 64 (3.13%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    3 / 64 (4.69%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    Hepatosplenic candidiasis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 38 (0.00%)
    2 / 64 (3.13%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    Septic shock
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    4 / 64 (6.25%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 2
    Sepsis
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 38 (2.63%)
    6 / 64 (9.38%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 4
    0 / 3
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    2 / 64 (3.13%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    1 / 1
    Pneumonia fungal
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 38 (0.00%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    0 / 64 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 38 (7.89%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    1.2 mg/m2/cycle (Run-in) 1.8 mg/m2/cycle (Randomized) 1.2 mg/m2/cycle (Run-in + Randomized) 1.2 mg/m2/cycle (Randomized)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 22 (81.82%)
    29 / 38 (76.32%)
    50 / 64 (78.13%)
    32 / 42 (76.19%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 38 (7.89%)
    3 / 64 (4.69%)
    0 / 42 (0.00%)
         occurrences all number
    3
    12
    3
    0
    Neutrophil count decreased
         subjects affected / exposed
    4 / 22 (18.18%)
    4 / 38 (10.53%)
    5 / 64 (7.81%)
    1 / 42 (2.38%)
         occurrences all number
    9
    17
    15
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    6 / 38 (15.79%)
    5 / 64 (7.81%)
    4 / 42 (9.52%)
         occurrences all number
    1
    6
    6
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 38 (10.53%)
    5 / 64 (7.81%)
    3 / 42 (7.14%)
         occurrences all number
    2
    4
    5
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 38 (7.89%)
    3 / 64 (4.69%)
    2 / 42 (4.76%)
         occurrences all number
    2
    3
    5
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 22 (18.18%)
    8 / 38 (21.05%)
    7 / 64 (10.94%)
    3 / 42 (7.14%)
         occurrences all number
    7
    10
    11
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 38 (7.89%)
    10 / 64 (15.63%)
    5 / 42 (11.90%)
         occurrences all number
    8
    6
    14
    6
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 38 (5.26%)
    2 / 64 (3.13%)
    2 / 42 (4.76%)
         occurrences all number
    0
    2
    2
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 38 (0.00%)
    2 / 64 (3.13%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 22 (0.00%)
    4 / 38 (10.53%)
    4 / 64 (6.25%)
    4 / 42 (9.52%)
         occurrences all number
    0
    4
    4
    4
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    5 / 22 (22.73%)
    13 / 38 (34.21%)
    19 / 64 (29.69%)
    14 / 42 (33.33%)
         occurrences all number
    10
    29
    40
    30
    Leukopenia
         subjects affected / exposed
    2 / 22 (9.09%)
    6 / 38 (15.79%)
    8 / 64 (12.50%)
    6 / 42 (14.29%)
         occurrences all number
    3
    10
    9
    6
    Febrile neutropenia
         subjects affected / exposed
    1 / 22 (4.55%)
    4 / 38 (10.53%)
    3 / 64 (4.69%)
    2 / 42 (4.76%)
         occurrences all number
    1
    5
    4
    3
    Anaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    6 / 38 (15.79%)
    11 / 64 (17.19%)
    9 / 42 (21.43%)
         occurrences all number
    6
    9
    23
    17
    Neutropenia
         subjects affected / exposed
    4 / 22 (18.18%)
    10 / 38 (26.32%)
    20 / 64 (31.25%)
    16 / 42 (38.10%)
         occurrences all number
    6
    26
    43
    37
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 22 (22.73%)
    1 / 38 (2.63%)
    10 / 64 (15.63%)
    5 / 42 (11.90%)
         occurrences all number
    13
    1
    22
    9
    Fatigue
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 38 (2.63%)
    4 / 64 (6.25%)
    2 / 42 (4.76%)
         occurrences all number
    2
    1
    4
    2
    Asthenia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 38 (5.26%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences all number
    0
    3
    1
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 22 (4.55%)
    4 / 38 (10.53%)
    3 / 64 (4.69%)
    2 / 42 (4.76%)
         occurrences all number
    2
    4
    4
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 38 (7.89%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences all number
    0
    3
    1
    1
    Abdominal pain
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 38 (2.63%)
    7 / 64 (10.94%)
    5 / 42 (11.90%)
         occurrences all number
    3
    1
    8
    5
    Diarrhoea
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 38 (2.63%)
    3 / 64 (4.69%)
    3 / 42 (7.14%)
         occurrences all number
    0
    1
    4
    4
    Vomiting
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 38 (7.89%)
    6 / 64 (9.38%)
    5 / 42 (11.90%)
         occurrences all number
    2
    5
    9
    7
    Stomatitis
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 38 (5.26%)
    2 / 64 (3.13%)
    1 / 42 (2.38%)
         occurrences all number
    1
    4
    2
    1
    Nausea
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 38 (7.89%)
    5 / 64 (7.81%)
    5 / 42 (11.90%)
         occurrences all number
    0
    4
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 38 (10.53%)
    5 / 64 (7.81%)
    2 / 42 (4.76%)
         occurrences all number
    4
    4
    7
    3
    Skin and subcutaneous tissue disorders
    Rash papular
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 38 (5.26%)
    1 / 64 (1.56%)
    0 / 42 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 38 (0.00%)
    3 / 64 (4.69%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    3
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 38 (5.26%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences all number
    0
    2
    1
    1
    Bone pain
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 38 (7.89%)
    1 / 64 (1.56%)
    1 / 42 (2.38%)
         occurrences all number
    0
    4
    1
    1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 38 (0.00%)
    4 / 64 (6.25%)
    1 / 42 (2.38%)
         occurrences all number
    3
    0
    4
    1
    Influenza
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 38 (0.00%)
    2 / 64 (3.13%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 38 (5.26%)
    2 / 64 (3.13%)
    2 / 42 (4.76%)
         occurrences all number
    0
    2
    2
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 38 (2.63%)
    4 / 64 (6.25%)
    2 / 42 (4.76%)
         occurrences all number
    2
    1
    6
    4
    Hypomagnesaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 38 (2.63%)
    4 / 64 (6.25%)
    3 / 42 (7.14%)
         occurrences all number
    1
    1
    5
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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