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    Clinical Trial Results:
    Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Multiple Dose Regimens of MT-3724 for the Treatment of Patients with Relapsed non-Hodgkin’s B-Cell Lymphoma and B-Cell Chronic Lymphocytic Leukemia (title of protocol for Part 1 and 2); Safety, Pharmacodynamics and Efficacy of MT-3724 for the Treatment of Patients with Relapsed or Refractory DLBCL (Part 3)

    Summary
    EudraCT number
    		 2019-001073-86
    Trial protocol
    		 ES   PL   GB  
    Global end of trial date
    19 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Nov 2022
    First version publication date
    01 Nov 2022
    Other versions
    Summary report(s)
    		 MT-3724-NHL_001 FDA Premature Closure of Study
    MT-3724-NHL_001 Abbreviated Study Report
    MT-3724-NHL_001 Study Report Synopsis - 22 January 2021

    Trial information

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    Trial identification
    Sponsor protocol code
    200MT-3724_NHL_0010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02361346
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND number: 121918
    Sponsors
    Sponsor organisation name
    Molecular Templates, Inc.
    Sponsor organisation address
    9301 Amberglen Blvd., Suite 100, Austin, TX, United States, 78729
    Public contact
    Corporate Headquarters, Molecular Templates, Inc., info@MTEM.com
    Scientific contact
    Corporate Headquarters, Molecular Templates, Inc., info@MTEM.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
    11 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives in Part 1 of the study were to: • Define the maximum tolerated dose (MTD) of a single cycle of MT-3724 given on Days 1, 3, 5, 8, 10 and 12 at which there are negligible side effects and/or at which maximum pharmacokinetic (PK)/pharmacodynamic (PD) parameter changes are observed. • Determine PK and PD profiles of MT-3724 in escalating dose cohorts. In Part 2 of the study, up to 40 additional subjects with relapsed/refractory DLBCL were to be treated with MTD of MT-3724 determined in Part 1 in the MTD expansion cohort. The primary objectives in Part 2 were to: • Identify the frequency and nature of clinical and laboratory adverse events (AEs), both reported and observed, as a measure of safety and tolerability over repeated cycles of MT-3724 at the MTD. • Define the PK and PD profiles of MT-3724 at the MTD in this subpopulation.
    Protection of trial subjects
    The study was conducted in full compliance with the principles of the "Declaration of Helsinki" (as amended in Tokyo, Venice, Hong Kong, and South Africa), International Council on Harmonisation (ICH) guidelines, and all of the applicable United States (US) Code of Federal Regulations (CFR), 21 CFR Part 50 & 312. Before undertaking any study-related procedures, the purpose and nature of the study, as well as possible adverse effects, were explained to subjects in understandable terms and written informed consent was obtained from each individual. Each informed consent was to be appropriately signed and dated by the subject and the person obtaining consent. An independent Data Monitoring Committee (DMC) was established to protect the safety of participants and assure the integrity of the study. The DMC Chair (or designee) reviewed all available safety data for all enrolled subjects on a weekly basis and reviewed causally related severe and/or serious AEs, AESI, or other identified safety trends on a monthly basis. Full DMC meetings were convened as needed. The full DMC met at each end-of-cohort and upon completion/termination of the study to review safety data. The DMC made the recommendation in Part 2 of the study to adjust the MTD from 75 μg/kg to 50 μg/kg/dose with a maximum of 6000 μg/dose based on 2 cases of Grade 2 capillary leak syndrome.
    Background therapy
    		 None.
    Evidence for comparator
    		 None.
    Actual start date of recruitment
    24 Feb 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Georgia: 2
    Country: Number of subjects enrolled
    Moldova, Republic of: 1
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    27
    EEA total number of subjects
    0
    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)
    12
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Conducted in the United States (5 sites), Moldova (1 site), and Georgia (1 site). Part 1: first subject enrolled 24 Feb 2015; last subject completed 29 Nov 2016. Part 2: first subject enrolled 09 Oct 2017; last subject completed 11 Oct 2019.

    Pre-assignment
    Screening details
    		 A total of 27 subjects were enrolled and treated at 7 sites in Parts 1 and 2 (1 site did not enroll any subjects). 18 subjects were screen failures due to: inclusion/exclusion criteria not met (17) and consent withdrawn (1).

    Period 1
    Period 1 title
    Part 1 and Part 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (MT-3724 5 µg/kg)
    Arm description
    		 Part 1: MT-3724 5 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-3724
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vial containing 2.0 ml of MT-3724 (0.5 mg/ml) diluted in 5% dextrose in water or normal saline for IV infusion. For Part 1, the infusion time was 2 to 4 hours and for Part 2 the infusion time was 2 hours (± 15 minutes). Subjects received doses of MT-3724 on Days 1, 3, 5, 8, 10, and 12 (within protocol specified time windows).

    Arm title
    		 Cohort 2 (MT-3724 10 µg/kg)
    Arm description
    		 Part 1: MT-3724 10 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-3724
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vial containing 2.0 ml of MT-3724 (0.5 mg/ml) diluted in 5% dextrose in water or normal saline for IV infusion. For Part 1, the infusion time was 2 to 4 hours and for Part 2 the infusion time was 2 hours (± 15 minutes). Subjects received doses of MT-3724 on Days 1, 3, 5, 8, 10, and 12 (within protocol specified time windows).

    Arm title
    		 Cohort 3 (MT-3724 20 µg/kg)
    Arm description
    		 Part 1: MT-3724 20 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-3724
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vial containing 2.0 ml of MT-3724 (0.5 mg/ml) diluted in 5% dextrose in water or normal saline for IV infusion. For Part 1, the infusion time was 2 to 4 hours and for Part 2 the infusion time was 2 hours (± 15 minutes). Subjects received doses of MT-3724 on Days 1, 3, 5, 8, 10, and 12 (within protocol specified time windows).

    Arm title
    		 Cohort 4 (MT-3724 50 µg/kg)
    Arm description
    		 Part 1: MT-3724 50 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses. There was 1 subject in Cohort 4 with a TEAE (PT: cardiac arrest) leading to death; this TEAE was considered to be unrelated to treatment and secondary to disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-3724
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vial containing 2.0 ml of MT-3724 (0.5 mg/ml) diluted in 5% dextrose in water or normal saline for IV infusion. For Part 1, the infusion time was 2 to 4 hours and for Part 2 the infusion time was 2 hours (± 15 minutes). Subjects received doses of MT-3724 on Days 1, 3, 5, 8, 10, and 12 (within protocol specified time windows).

    Arm title
    		 Cohort 5 (MT-3724 100 µg/kg)
    Arm description
    		 Part 1: MT-3724 100 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-3724
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vial containing 2.0 ml of MT-3724 (0.5 mg/ml) diluted in 5% dextrose in water or normal saline for IV infusion. For Part 1, the infusion time was 2 to 4 hours and for Part 2 the infusion time was 2 hours (± 15 minutes). Subjects received doses of MT-3724 on Days 1, 3, 5, 8, 10, and 12 (within protocol specified time windows).

    Arm title
    		 Cohort 6 (MT-3724 75 µg/kg)
    Arm description
    		 Part 1: MT-3724 75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The planned dose for cohort 6 was 150 µg/kg. As the maximum tolerated dose (MTD) was exceeded in Cohort 5, an additional dose cohort of 75 μg/kg/dose was added to more narrowly identify the MTD (Cohort 6). The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-3724
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vial containing 2.0 ml of MT-3724 (0.5 mg/ml) diluted in 5% dextrose in water or normal saline for IV infusion. For Part 1, the infusion time was 2 to 4 hours and for Part 2 the infusion time was 2 hours (± 15 minutes). Subjects received doses of MT-3724 on Days 1, 3, 5, 8, 10, and 12 (within protocol specified time windows).

    Arm title
    		 Cohort 7 (MT-3724 50/75 µg/kg)
    Arm description
    		 Part 2: MT-3724 50/75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The first 3 of 6 subjects enrolled in Cohort 7 were treated at 75 μg/kg/dose. The last 3 of 6 subjects were treated with the adjusted MTD (50 μg/kg/dose) following the emergence of Grade 2 capillary leak syndrome (CLS) in 2 subjects in Cohort 7 treated with 75 μg/kg/dose. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-3724
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vial containing 2.0 ml of MT-3724 (0.5 mg/ml) diluted in 5% dextrose in water or normal saline for IV infusion. For Part 1, the infusion time was 2 to 4 hours and for Part 2 the infusion time was 2 hours (± 15 minutes). Subjects received doses of MT-3724 on Days 1, 3, 5, 8, 10, and 12 (within protocol specified time windows).

    Number of subjects in period 1
    		Cohort 1 (MT-3724 5 µg/kg) Cohort 2 (MT-3724 10 µg/kg) Cohort 3 (MT-3724 20 µg/kg) Cohort 4 (MT-3724 50 µg/kg) Cohort 5 (MT-3724 100 µg/kg) Cohort 6 (MT-3724 75 µg/kg) Cohort 7 (MT-3724 50/75 µg/kg)
    Started
    3
    3
    3
    4
    2
    6
    6
    Completed
    1
    2
    0
    0
    0
    1
    1
    Not completed
    2
    1
    3
    4
    2
    5
    5
         Adverse event, serious fatal
    -
    -
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    1
         Physician decision
    -
    -
    -
    -
    -
    -
    1
         Disease progression
    2
    1
    3
    1
    -
    4
    3
         Adverse event, non-fatal
    -
    -
    -
    2
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (MT-3724 5 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 5 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 2 (MT-3724 10 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 10 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 3 (MT-3724 20 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 20 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 4 (MT-3724 50 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 50 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses. There was 1 subject in Cohort 4 with a TEAE (PT: cardiac arrest) leading to death; this TEAE was considered to be unrelated to treatment and secondary to disease progression.

    Reporting group title
    Cohort 5 (MT-3724 100 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 100 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 6 (MT-3724 75 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The planned dose for cohort 6 was 150 µg/kg. As the maximum tolerated dose (MTD) was exceeded in Cohort 5, an additional dose cohort of 75 μg/kg/dose was added to more narrowly identify the MTD (Cohort 6). The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 7 (MT-3724 50/75 µg/kg)
    Reporting group description
    		 Part 2: MT-3724 50/75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The first 3 of 6 subjects enrolled in Cohort 7 were treated at 75 μg/kg/dose. The last 3 of 6 subjects were treated with the adjusted MTD (50 μg/kg/dose) following the emergence of Grade 2 capillary leak syndrome (CLS) in 2 subjects in Cohort 7 treated with 75 μg/kg/dose. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group values
    		 Cohort 1 (MT-3724 5 µg/kg) Cohort 2 (MT-3724 10 µg/kg) Cohort 3 (MT-3724 20 µg/kg) Cohort 4 (MT-3724 50 µg/kg) Cohort 5 (MT-3724 100 µg/kg) Cohort 6 (MT-3724 75 µg/kg) Cohort 7 (MT-3724 50/75 µg/kg) Total
    Number of subjects
    		 3 3 3 4 2 6 6 27
    Age categorical
    Units: Subjects
    Age continuous
    Demographic and baseline characteristics were generally well matched between the cohorts, and no notable differences in age, sex, race, ethnicity, and medical/disease history were observed. Overall, the mean (SD) age was 64.6 (10.50) years (Parts 1 and 2) and 64.0 (x) years (Part 3).
    Units: years
        arithmetic mean (standard deviation)
    		 73.3 ( 6.43 ) 70.7 ( 8.74 ) 64.3 ( 14.01 ) 57.8 ( 16.66 ) 65.0 ( 4.24 ) 67.2 ( 4.40 ) 59.3 ( 10.58 ) -
    Gender categorical
    The majority of subjects were female (63%) in Parts 1 and 2. The majority of subjects were male (72.7%) in Part 3.
    Units: Subjects
        Female
    		 0 2 2 3 1 4 5 17
        Male
    		 3 1 1 1 1 2 1 10
    Race
    The majority of subjects were White (85.2%) in Parts 1 and 2. All subjects were White (100%) in Part 3.
    Units: Subjects
        White
    		 2 3 3 2 2 5 6 23
        Black
    		 0 0 0 0 0 0 0 0
        Asian
    		 1 0 0 0 0 1 0 2
        Other
    		 0 0 0 2 0 0 0 2
    Ethnicity
    The majority of subjects were of Non-Hispanic origin (88.9% in Parts 1 and 2; 90.9% in Part 3).
    Units: Subjects
        Hispanic
    		 0 0 0 2 0 0 0 2
        Non-Hispanic
    		 3 3 3 2 2 6 5 24
        Unknown
    		 0 0 0 0 0 0 1 1
    Height
    The subjects' height was measured at Screening. The overall mean (SD) height was 164.00 (8.33) cm (Parts 1 and 2) and 173.1 cm (Part 3).
    Units: cm
        arithmetic mean (standard deviation)
    		 165.17 ( 8.31 ) 164.73 ( 3.95 ) 172.33 ( 9.07 ) 157.20 ( 6.39 ) 168.10 ( 2.97 ) 162.73 ( 6.32 ) 163.30 ( 11.77 ) -
    Weight
    Body weight measured before the start of treatment on C1D1 was used to calculate the MT-3724 dose in all subsequent cycles. The dose was re-calculated when the body weight changed by >10% from the baseline value; or according to institutional policies should they require adjustment for any change in body weight. The overall mean (SD) weight was 80.61 (22.17) kg.
    Units: kg
        arithmetic mean (standard deviation)
    		 74.83 ( 17.79 ) 81.20 ( 14.37 ) 65.70 ( 11.14 ) 70.58 ( 6.99 ) 96.55 ( 17.04 ) 72.82 ( 20.36 ) 99.83 ( 30.73 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (MT-3724 5 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 5 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 2 (MT-3724 10 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 10 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 3 (MT-3724 20 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 20 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 4 (MT-3724 50 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 50 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses. There was 1 subject in Cohort 4 with a TEAE (PT: cardiac arrest) leading to death; this TEAE was considered to be unrelated to treatment and secondary to disease progression.

    Reporting group title
    Cohort 5 (MT-3724 100 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 100 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 6 (MT-3724 75 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The planned dose for cohort 6 was 150 µg/kg. As the maximum tolerated dose (MTD) was exceeded in Cohort 5, an additional dose cohort of 75 μg/kg/dose was added to more narrowly identify the MTD (Cohort 6). The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Reporting group title
    Cohort 7 (MT-3724 50/75 µg/kg)
    Reporting group description
    		 Part 2: MT-3724 50/75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The first 3 of 6 subjects enrolled in Cohort 7 were treated at 75 μg/kg/dose. The last 3 of 6 subjects were treated with the adjusted MTD (50 μg/kg/dose) following the emergence of Grade 2 capillary leak syndrome (CLS) in 2 subjects in Cohort 7 treated with 75 μg/kg/dose. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for demographic/baseline characteristics and safety analyses. The Full Analysis set (FAS) population included all subjects from the Safety Set (SS) who had a least 1 tumor re-evaluation performed (scheduled or unscheduled). The FAS was the primary population for all exploratory efficacy analyses.

    Subject analysis set title
    Combined 50 μg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Combined (50 μg/kg/dose) analysis set includes all subjects with a starting dose of 50 μg/kg in Part 1 or Part 2.

    Subject analysis set title
    All Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Subject analysis set title
    5 μg/kg (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Subject analysis set title
    10 μg/kg (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Subject analysis set title
    20 μg/kg (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Subject analysis set title
    37.5 μg/kg (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Subject analysis set title
    50 μg/kg (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Subject analysis set title
    75 μg/kg (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Subject analysis set title
    100 μg/kg (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic Analysis Set (PAS) included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.

    Primary: Adverse Events (Safety Set)

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    End point title
    		 Adverse Events (Safety Set) [1]
    End point description
    Safety assessments of all AEs included DLTs. Cumulative AE data were reviewed periodically by the DMC as well as ad hoc review of SAEs and/or severe AEs as they were reported. AEs were assessed using the CTCAE, version 4.03. Parts 1 and 2: All 27 subjects had at least 1 TEAE and 26 subjects (96.3%) had at least 1 treatment-related TEAE. 14 subjects (51.9%) had at least 1 serious TEAE, and 6 subjects (22.2%) had at least 1 treatment-related serious TEAE. There were no differences in incidences of the most common TEAEs between the cohorts. There was 1 subject (Subject 01005 in Cohort 4) with a TEAE (PT: cardiac arrest) leading to death; this TEAE was considered to be unrelated to treatment and secondary to disease progression.
    End point type
    Primary
    End point timeframe
    Safety was monitored throughout the study.
    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: This study was primarily descriptive in nature; therefore, there were no formal statistical hypothesis tests were planned.
    End point values
    		 Cohort 1 (MT-3724 5 µg/kg) Cohort 2 (MT-3724 10 µg/kg) Cohort 3 (MT-3724 20 µg/kg) Cohort 4 (MT-3724 50 µg/kg) Cohort 5 (MT-3724 100 µg/kg) Cohort 6 (MT-3724 75 µg/kg) Cohort 7 (MT-3724 50/75 µg/kg)
    Number of subjects analysed
    3 [2]
    3
    3 [3]
    4 [4]
    2
    6 [5]
    6 [6]
    Units: subjects
        At least 1 TEAE
    3
    3
    3
    4
    2
    6
    6
        At least 1 treatment-related (TR) TEAE
    3
    3
    2
    4
    2
    6
    6
        At least 1 TEAE with severity ≥Grade 3
    3
    0
    2
    4
    2
    3
    6
        At least 1 TR TEAE with severity ≥Grade 3
    1
    0
    0
    2
    2
    2
    6
        At least 1 non-serious TEAE
    3
    3
    3
    4
    2
    6
    6
        At least 1 non-serious TR TEAE
    3
    3
    2
    4
    2
    6
    6
        At least 1 serious TEAE
    1
    0
    2
    4
    2
    3
    2
        At least 1 serious TR TEAE
    0
    0
    0
    1
    2
    2
    1
        At least 1 TEAE leading to early study withdrawal
    0
    0
    0
    2
    2
    1
    0
        At least 1 DLT
    0
    0
    0
    0
    2
    0
    0
        At least 1 TEAE leading to death
    0
    0
    0
    1
    0
    0
    0
        A TR TEAE leading to death
    0
    0
    0
    0
    0
    0
    0
    Notes
    [2] - TR TEAE ≥ Grade 3 = 33.3%; serious TEAE = 33.3%
    [3] - TR TEAE = 66.7%; TEAE ≥ Grade 3 = 66.7%; non-serious TR TEAE = 66.7%; serious TEAE = 66.7%
    [4] - TR TEAE ≥Gr 3 =50%; serious TR TEAE =25%; TEAE early withdrawal =50%;TEAE leading to death =25%.
    [5] - TEAE ≥Gr3 =50%; TR TEAE ≥Gr3 = 33.3%; serious TEAE=50%; serious TR TEAE =33.3%; TEAE early w/d 16.7%
    [6] - Serious TEAE = 33.3%; serious TR TEAE = 16.7%
    No statistical analyses for this end point

    Other pre-specified: Maximum Observed Serum Concentration (Cmax) (PAS)

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) (PAS)
    End point description
    PK serum samples were analyzed for concentrations of free MT-3724. PK analyses were conducted using the PAS, which included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters. Overall, Day 1 maximum observed serum concentration (Cmax) increased with increasing dose level but were variable, with geometric coefficient of variation (CV%) (where calculable) ranging from 42.7% to 77.8%. '99999' indicates the value was not reported (NR) or not calculated for the timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Blood samples were collected prior to, during, and at specified times following the MT-3724 infusion for determination of free MT-3724 concentrations in serum (Cycle 1 on Days 1, 3, and 12). Serum PK parameters on Cycle 1 Day 1 are presented.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    1 [7]
    3
    3
    7
    9
    2 [8]
    Units: nanogram(s)/millilitre
        geometric mean (geometric coefficient of variation)
    57.5 ( 99999 )
    70.4 ( 61.9 )
    132 ( 46.6 )
    445 ( 42.7 )
    486 ( 77.8 )
    828 ( 99999 )
    Notes
    [7] - Geometric coefficient of variation was not calculated.
    [8] - Geometric coefficient of variation was not calculated.
    No statistical analyses for this end point

    Other pre-specified: Time to Maximum Plasma Concentration (Tmax) (PAS)

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax) (PAS)
    End point description
    PK serum samples were analyzed for concentrations of free MT-3724. PK analyses were conducted using the PAS, which included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters. Time to maximum plasma concentration (Tmax) was similar across dose levels with medians ranging from 1.85 to 3.29 hours post-start of infusion, which was largely due to variability in infusion duration.
    End point type
    Other pre-specified
    End point timeframe
    Blood samples were collected prior to, during, and at specified times following the MT-3724 infusion for determination of free MT-3724 concentrations in serum (Cycle 1 on Days 1, 3, and 12). Serum PK parameters on Cycle 1 Day 1 are presented.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    1
    3
    3
    7
    9
    2
    Units: hour
        median (full range (min-max))
    2.10 (2.10 to 2.10)
    2.08 (1.97 to 3.00)
    2.08 (2.08 to 2.08)
    2.32 (2.08 to 2.58)
    1.85 (1.70 to 4.42)
    3.29 (2.50 to 4.08)
    No statistical analyses for this end point

    Other pre-specified: Time to last measurable plasma concentration (Tlast) (PAS)

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    End point title
    		 Time to last measurable plasma concentration (Tlast) (PAS)
    End point description
    PK serum samples were analyzed for concentrations of free MT-3724. PK analyses were conducted using the PAS, which included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters.
    End point type
    Other pre-specified
    End point timeframe
    Blood samples were collected prior to, during, and at specified times following the MT-3724 infusion for determination of free MT-3724 concentrations in serum (Cycle 1 on Days 1, 3, and 12). Serum PK parameters on Cycle 1 Day 1 are presented.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    1
    3
    3
    7
    9
    2
    Units: hour
        median (full range (min-max))
    5.00 (5.00 to 5.00)
    3.00 (2.82 to 6.00)
    5.92 (4.08 to 6.00)
    6.00 (5.92 to 6.82)
    5.92 (3.00 to 8.00)
    7.24 (6.48 to 8.00)
    No statistical analyses for this end point

    Other pre-specified: Area under concentration-time curve from time 0 to the last quantifiable concentration (AUClast) (PAS)

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    End point title
    		 Area under concentration-time curve from time 0 to the last quantifiable concentration (AUClast) (PAS)
    End point description
    PK serum samples were analyzed for concentrations of free MT-3724. PK analyses were conducted using the PAS, which included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters. '99999' indicates the value was not reported (NR) or not calculated for the timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Blood samples were collected prior to, during, and at specified times following the MT-3724 infusion for determination of free MT-3724 concentrations in serum (Cycle 1 on Days 1, 3, and 12). Serum PK parameters on Cycle 1 Day 1 are presented.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    1 [9]
    3
    3
    7
    9
    2 [10]
    Units: hour*nanogram/millilitre
        geometric mean (geometric coefficient of variation)
    170 ( 99999 )
    155 ( 155 )
    333 ( 73.2 )
    1370 ( 32.1 )
    1410 ( 102 )
    2980 ( 99999 )
    Notes
    [9] - Geometric coefficient of variation was not calculated.
    [10] - Geometric coefficient of variation was not calculated.
    No statistical analyses for this end point

    Other pre-specified: Area Under Concentration-time Curve from Time 0 to 4 hours (AUC0-4) (PAS)

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    End point title
    		 Area Under Concentration-time Curve from Time 0 to 4 hours (AUC0-4) (PAS)
    End point description
    PK serum samples were analyzed for concentrations of free MT-3724. PK analyses were conducted using the PAS, which included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters. The area under concentration-time curve from time 0 to 4 hours (AUC0-4) increased with increasing dose in an approximately dose-proportional manner from 5 to 100 μg/kg. Compared to Day 1, there were fewer PK samples collected on Days 5 and 12, resulting in fewer evaluable PK profiles. '99999' indicates the value was not reported (NR) or not calculated for the timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Blood samples were collected prior to, during, and at specified times following the MT-3724 infusion for determination of free MT-3724 concentrations in serum (Cycle 1 on Days 1, 3, and 12). Serum PK parameters on Cycle 1 Day 1 are presented.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    1 [11]
    1 [12]
    3
    7
    9
    2 [13]
    Units: h*nanogram(s)/millilitre
        geometric mean (geometric coefficient of variation)
    140 ( 99999 )
    365 ( 99999 )
    278 ( 56.2 )
    1040 ( 35.1 )
    1060 ( 95.2 )
    1650 ( 99999 )
    Notes
    [11] - Geometric coefficient of variation was not calculated.
    [12] - Geometric coefficient of variation was not calculated.
    [13] - Geometric coefficient of variation was not calculated.
    No statistical analyses for this end point

    Other pre-specified: Area under concentration-time curve from time 0 to infinity (AUCinf) (PAS)

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    End point title
    		 Area under concentration-time curve from time 0 to infinity (AUCinf) (PAS)
    End point description
    PK serum samples were analyzed for concentrations of free MT-3724. PK analyses were conducted using the PAS, which included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters. '99999' indicates the value was not reported (NR) or not calculated for the timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Blood samples were collected prior to, during, and at specified times following the MT-3724 infusion for determination of free MT-3724 concentrations in serum (Cycle 1 on Days 1, 3, and 12). Serum PK parameters on Cycle 1 Day 1 are presented.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    0 [14]
    0 [15]
    3
    7
    9
    2 [16]
    Units: h*nanogram(s)/millilitre
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    451 ( 87.5 )
    1680 ( 28.3 )
    1680 ( 114 )
    3970 ( 99999 )
    Notes
    [14] - The AUCinf was not reportable for the 5 and 10 μg/kg cohorts.
    [15] - The AUCinf was not reportable for the 5 and 10 μg/kg cohorts.
    [16] - Geometric coefficient of variation was not calculated.
    No statistical analyses for this end point

    Other pre-specified: Half-life (t1/2) (PAS)

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    End point title
    		 Half-life (t1/2) (PAS)
    End point description
    PK serum samples were analyzed for concentrations of free MT-3724. PK analyses were conducted using the PAS, which included all subjects from the SS with sufficient serum concentration data to determine the primary PK parameters. The t½ was not reportable for the 5 and 10 μg/kg cohorts, but geometric means were similar for the 20 to 100 μg/kg cohorts, ranging from 1.50 to 2.83 hours. '99999' indicates the value was not reported (NR) or not calculated for the timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Blood samples were collected prior to, during, and at specified times following the MT-3724 infusion for determination of free MT-3724 concentrations in serum (Cycle 1 on Days 1, 3, and 12). Serum PK parameters on Cycle 1 Day 1 are presented.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    0 [17]
    0 [18]
    3
    7
    9
    2 [19]
    Units: hour
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    2.07 ( 58.6 )
    1.92 ( 32.1 )
    1.50 ( 59.0 )
    2.78 ( 99999 )
    Notes
    [17] - The t½ was not reportable for the 5 and 10 μg/kg cohorts.
    [18] - The t½ was not reportable for the 5 and 10 μg/kg cohorts.
    [19] - Geometric coefficient of variation was not calculated.
    No statistical analyses for this end point

    Other pre-specified: CD19+ Change (%) (PAS)

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    End point title
    		 CD19+ Change (%) (PAS)
    End point description
    The number of subjects in each dose group with CD19+ flow cytometry data was generally low, leading to high variability and mean changes in CD19+ values that were sensitive to a single subject’s data. Generally, mean percentage of CD19+ cells from the peripheral blood decreased after treatment. On Cycle 1 Day 23 and Cycle 2 Day 1, 7 of 9 subjects demonstrated decreased percentage of CD19+ cells compared to baseline. At the End of Study, 9 of 10 subjects demonstrated decreased CD19+ compared to baseline. '99999' indicates the value was not reported (NR) or not calculated (<3 evaluable subjects) for the timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Serial blood samples for PD assessment were collected at Screening, Cycle 1 Day 8, Cycle 1 Day 23, Cycle 3 Day 1, Cycle 5 Day 1, and EOT. Unscheduled assessments could be performed at any time at the investigator’s discretion.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 37.5 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS)
    Number of subjects analysed
    1
    2
    1
    1
    4 [20]
    1
    Units: percent
    geometric mean (geometric coefficient of variation)
        Screening
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1 Day 8
    0 ( 99999 )
    34.2 ( 99999 )
    0 ( 99999 )
    167 ( 99999 )
    -49.1 ( -87.8 )
    -57.4 ( 99999 )
        Cycle 1 Day 23
    25.4 ( 99999 )
    -60.2 ( 99999 )
    -46.3 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    -77.4 ( 99999 )
        Cycle 3 Day 1
    -41.2 ( 99999 )
    -50.9 ( 99999 )
    -75.4 ( 99999 )
    99999 ( 99999 )
    -48.2 ( -54.1 )
    -88.5 ( 99999 )
        Cycle 5 Day 1
    15.8 ( 99999 )
    -35.4 ( 99999 )
    -78.3 ( 99999 )
    99999 ( 99999 )
    -72.1 ( 99999 )
    -86.8 ( 99999 )
        End of Study
    -30.7 ( 99999 )
    -23.7 ( 99999 )
    -79.9 ( 99999 )
    -63.0 ( 99999 )
    -63.3 ( -45.9 )
    -85.1 ( 99999 )
    Notes
    [20] - Sample size: Screening: NR; C1D8: n=3; C1D23: NR; C3D1: n=3; C5D1: n=2; EOS: n=4
    No statistical analyses for this end point

    Other pre-specified: CD19+ Absolute (PAS)

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    End point title
    		 CD19+ Absolute (PAS)
    End point description
    Flow cytometry: Individual lymphocyte subset analyses were presented graphically by dose and time based on 2 types of cell quantification; percent of baseline and absolute cell count. At the EOT, 9 of 10 subjects demonstrated decreased CD19+ compared to baseline. Due to high variability in the data, small sample size, and inconsistent sampling, PK-PD relationships were difficult to discern. '99999' indicates the value was not reported (NR) or not calculated (<3 evaluable subjects) for the timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Serial blood samples for PD assessment were collected at Screening, Cycle 1 Day 8, Cycle 1 Day 23, Cycle 3 Day 1, Cycle 5 Day 1, and EOT. Unscheduled assessments could be performed at any time at the investigator’s discretion.
    End point values
    		 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 37.5 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS)
    Number of subjects analysed
    1
    2
    1
    1
    4 [21]
    3 [22]
    Units: cells/microlitre
    geometric mean (geometric coefficient of variation)
        Screening
    99999 ( 99999 )
    286 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    84.0 ( 133 )
    1180 ( 172 )
        Cycle 1 Day 8
    114 ( 99999 )
    325 ( 99999 )
    244 ( 99999 )
    72.0 ( 99999 )
    57.7 ( 158 )
    126 ( 99999 )
        Cycle 1 Day 23
    143 ( 99999 )
    104 ( 99999 )
    131 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    67.0 ( 99999 )
        Cycle 3 Day 1
    67.0 ( 99999 )
    134 ( 99999 )
    60.0 ( 99999 )
    99999 ( 99999 )
    1170 ( 168 )
    34.0 ( 99999 )
        Cycle 5 Day 1
    132 ( 99999 )
    180 ( 99999 )
    53.0 ( 99999 )
    99999 ( 99999 )
    26.0 ( 99999 )
    39.0 ( 99999 )
        End of Study
    79.0 ( 99999 )
    184 ( 99999 )
    49.0 ( 99999 )
    10.0 ( 99999 )
    340 ( 177 )
    44.0 ( 99999 )
    Notes
    [21] - Sample size: Screening: n=3; C1D8: n=3; C1D23: NR; C3D1: n=3; C5D1: n=2; EOS: n=4
    [22] - Sample size: Screening: n=3; C1D8: n=1; C1D23: n=1; C3D1: n=1; C5D1: n=1; EOS: n=1
    No statistical analyses for this end point

    Other pre-specified: Anti-Drug Antibody Incidence by Actual Dose

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    End point title
    		 Anti-Drug Antibody Incidence by Actual Dose
    End point description
    Anti-drug antibodies (ADAs) in serum of subjects with NHL or CLL at baseline and following exposure to MT-3724 were assessed. Overall, the presence of ADAs increased with the duration of treatment, and there was no apparent relationship between MT-3724 dose level and ADA incidence. Safety events observed in the trial did not seem to correlate with presence of ADAs. Also based on data available clinical response was not observed to be confounded by presence of ADAs.
    End point type
    Other pre-specified
    End point timeframe
    During Parts 1 and 2, blood samples for immunogenicity assessments of ADAs were collected at Screening, Day 23, pre-dose for Cycles 2 through 5, and EOT. Additional samples were taken if clinically indicated.
    End point values
    		 All Subjects 5 μg/kg (PAS) 10 μg/kg (PAS) 20 μg/kg (PAS) 37.5 μg/kg (PAS) 50 μg/kg (PAS) 75 μg/kg (PAS) 100 μg/kg (PAS)
    Number of subjects analysed
    27 [23]
    3 [24]
    3 [25]
    3 [26]
    1 [27]
    7 [28]
    9 [29]
    2 [30]
    Units: subjects
        Screening
    5
    2
    0
    0
    0
    2
    0
    1
        Cycle 1 Day 23
    6
    0
    3
    1
    0
    1
    1
    0
        Cycle 2 Day 1
    11
    0
    3
    1
    1
    4
    2
    0
        Cycle 3 Day 1
    6
    0
    2
    1
    0
    2
    1
    0
        Cycle 4 Day 1
    7
    1
    2
    1
    0
    2
    1
    0
        Cycle 5 Day 1
    6
    1
    2
    1
    0
    1
    1
    0
        End of Study
    13
    2
    2
    1
    1
    4
    3
    0
    Notes
    [23] - Sample size: Screening: n=27; C1D23: n=15; C2D1: n=20; C3D1: n=8; C4D1: n=8; C5D1: n=7; EOS: n=20
    [24] - Sample size: Screening: n=3; C1D23: n=1; C2D1: n=1; C3D1: n=1; C4D1: n=1; C5D1: n=1; EOS: n=3
    [25] - Sample size: Screening: n=3; C1D23: n=3; C2D1: n=3; C3D1: n=2; C4D1: n=2; C5D1: n=2; EOS: n=2
    [26] - Sample size: Screening: n=3; C1D23: n=2; C2D1: n=2; C3D1: n=1; C4D1: n=1; C5D1: n=1; EOS: n=2
    [27] - Sample size: Screening: n=0; C1D23: n=0; C2D1: n=1; C3D1: n=0; C4D1: n=0; C5D1: n=0; EOS: n=1
    [28] - Sample size: Screening: n=7; C1D23: n=3; C2D1: n=6; C3D1: n=3; C4D1: n=3; C5D1: n=2; EOS: n=6
    [29] - Sample size: Screening: n=9; C1D23: n=5; C2D1: n=7; C3D1: n=1; C4D1: n=1; C5D1: n=1; EOS: n=5
    [30] - Sample size: Screening: n=2; C1D23: n=1; C2D1: n=0; C3D1: n=0; C4D1: n=0; C5D1: n=0; EOS: n=1
    No statistical analyses for this end point

    Other pre-specified: Best Overall Response (FAS)

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    End point title
    		 Best Overall Response (FAS)
    End point description
    The MTD was identified as 50 μg/kg/dose. The first 2 subjects in Part 1 treated at 100 μg/kg had 1 dose limiting toxicity (DLT) each (Grade 3 pneumonia and Grade 2 ileus). Therefore, 75 μg/kg was initially declared to be the MTD. In Part 2 of the study, 2 of 3 subjects treated at 75 μg/kg had DLTs of Grade 2 CLS. Because these events led to dose reduction in both subjects, MTD was adjusted to 50 μg/kg. Best overall response (BOR) at any time during the study, as determined by the Cheson criteria on at least 1 post-baseline tumor assessment. This included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).
    End point type
    Other pre-specified
    End point timeframe
    Disease response was assessed following completion of even numbered (e.g., 2, 4) cycles of MT-3724 and at the final safety assessment (optional) following termination of MT-3724 using standard disease response criteria.
    End point values
    		 Cohort 1 (MT-3724 5 µg/kg) Cohort 2 (MT-3724 10 µg/kg) Cohort 3 (MT-3724 20 µg/kg) Cohort 4 (MT-3724 50 µg/kg) Cohort 5 (MT-3724 100 µg/kg) Cohort 6 (MT-3724 75 µg/kg) Cohort 7 (MT-3724 50/75 µg/kg) Combined 50 μg/kg
    Number of subjects analysed
    3 [31]
    3 [32]
    3 [33]
    4 [34]
    2 [35]
    6 [36]
    6 [37]
    6 [38]
    Units: subjects
        Complete Remission
    0
    0
    0
    0
    0
    0
    2
    2
        Unconfirmed/Uncertain Complete Remission
    0
    0
    0
    0
    0
    0
    0
    0
        Partial Remission
    1
    0
    1
    0
    0
    0
    1
    0
        Stable Disease
    0
    2
    0
    0
    1
    1
    1
    0
        Progressive Disease
    2
    1
    2
    3
    0
    3
    2
    4
        Not Evaluable
    0
    0
    0
    0
    0
    0
    0
    0
    Notes
    [31] - PR: 33.3%; PD: 66.7%
    [32] - SD: 66.7%; PD: 33.3%
    [33] - PR: 33.3%; PD: 66.7%
    [34] - PD: 100.0%
    [35] - SD: 100.0%
    [36] - SD: 25.0%; PD: 75.0%
    [37] - CR: 33.3%; PR: 16.7%; SD: 16.7%; PD: 33.3%
    [38] - CR: 33.3%; PD: 66.7%
    No statistical analyses for this end point

    Other pre-specified: Objective Response Rate (FAS)

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    End point title
    		 Objective Response Rate (FAS)
    End point description
    The MTD was identified as 50 μg/kg/dose. The first 2 subjects in Part 1 treated at 100 μg/kg had 1 DLT each (Grade 3 pneumonia and Grade 2 ileus). Therefore, 75 μg/kg was initially declared to be the MTD. In Part 2 of the study, 2 of 3 subjects treated at 75 μg/kg had DLTs of Grade 2 CLS. Because these events led to dose reduction in both subjects, MTD was adjusted to 50 μg/kg. Objective Response Rate (ORR), defined as the proportion of subjects with either CR or PR as determined by the Cheson criteria. As this was a dose finding study designed to assess the safety and tolerability of MT-3724, all efficacy analyses were exploratory in nature and based on documented tumor responses. Due to the limited treatment period following responses, no interpretation of the results could be made.
    End point type
    Other pre-specified
    End point timeframe
    Disease response was assessed following completion of even numbered (e.g., 2, 4) cycles of MT-3724 and at the final safety assessment (optional) following termination of MT-3724 using standard disease response criteria.
    End point values
    		 Cohort 1 (MT-3724 5 µg/kg) Cohort 2 (MT-3724 10 µg/kg) Cohort 3 (MT-3724 20 µg/kg) Cohort 4 (MT-3724 50 µg/kg) Cohort 5 (MT-3724 100 µg/kg) Cohort 6 (MT-3724 75 µg/kg) Cohort 7 (MT-3724 50/75 µg/kg) Combined 50 μg/kg
    Number of subjects analysed
    3 [39]
    3
    3 [40]
    4
    2
    6
    6 [41]
    6 [42]
    Units: percent
    number (confidence interval 95%)
        Objective Response Rate (ORR)
    33.3 (0.8 to 90.6)
    0 (0 to 0)
    33.3 (0.8 to 90.6)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    50.0 (11.8 to 88.2)
    33.3 (4.3 to 77.7)
    Notes
    [39] - ORR: n=1
    [40] - ORR: n=1
    [41] - ORR: n=3
    [42] - ORR: n=2
    No statistical analyses for this end point

    Other pre-specified: Disease Control Rate (FAS)

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    End point title
    		 Disease Control Rate (FAS)
    End point description
    The MTD was identified as 50 μg/kg/dose. The first 2 subjects in Part 1 treated at 100 μg/kg had 1 DLT each (Grade 3 pneumonia and Grade 2 ileus). Therefore, 75 μg/kg was initially declared to be the MTD. In Part 2 of the study, 2 of 3 subjects treated at 75 μg/kg had DLTs of Grade 2 CLS. Because these events led to dose reduction in both subjects, MTD was adjusted to 50 μg/kg. Disease control rate (DCR), defined as the proportion of subjects with either CR, PR, or SD as determined by the Cheson criteria. As this was a dose finding study designed to assess the safety and tolerability of MT-3724, all efficacy analyses were exploratory in nature and based on documented tumor responses. Due to the limited treatment period following responses, no interpretation of the results could be made.
    End point type
    Other pre-specified
    End point timeframe
    Disease response was assessed following completion of even numbered (e.g., 2, 4) cycles of MT-3724 and at the final safety assessment (optional) following termination of MT-3724 using standard disease response criteria.
    End point values
    		 Cohort 1 (MT-3724 5 µg/kg) Cohort 2 (MT-3724 10 µg/kg) Cohort 3 (MT-3724 20 µg/kg) Cohort 4 (MT-3724 50 µg/kg) Cohort 5 (MT-3724 100 µg/kg) Cohort 6 (MT-3724 75 µg/kg) Cohort 7 (MT-3724 50/75 µg/kg) Combined 50 μg/kg
    Number of subjects analysed
    3 [43]
    3 [44]
    3 [45]
    4
    2 [46]
    6 [47]
    6 [48]
    6 [49]
    Units: percent
    number (confidence interval 95%)
        Disease Control Rate
    33.3 (0.8 to 90.6)
    66.7 (9.4 to 99.2)
    33.3 (0.8 to 90.6)
    0 (0 to 0)
    100.0 (2.5 to 100.0)
    25.0 (0.6 to 80.6)
    66.7 (22.3 to 95.7)
    33.3 (4.3 to 77.7)
    Notes
    [43] - DCR: n=1
    [44] - DCR: n=2
    [45] - DCR: n=3
    [46] - DCR: n=1
    [47] - DCR: n=1
    [48] - DCR: n=4
    [49] - DCR: n=2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reporting began on the day of the first dose of study drug after signing informed consent until the STFU Visit or phone call, or until the start of new cancer therapy, whichever occurred first.
    Adverse event reporting additional description
    TEAEs were all AEs that started or worsened after the first administration of MT-3724 up until the last study visit. Safety results are presented for the SS, which included all subjects who received any amount of MT-3724. If a subject experienced more than 1 event with a given SOC or PT, that subject was counted only once for that SOC or PT.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Cohort 1 (5 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 5 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for the analysis of safety.

    Reporting group title
    Cohort 2 (10 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 10 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for the analysis of safety.

    Reporting group title
    Cohort 3 (20 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 20 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for the analysis of safety.

    Reporting group title
    Cohort 4 (50µg/kg)
    Reporting group description
    		 Part 1: MT-3724 50 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for the analysis of safety. There was 1 subject in Cohort 4 with a TEAE (PT: cardiac arrest) leading to death; this TEAE was considered to be unrelated to treatment and secondary to disease progression.

    Reporting group title
    Cohort 5 (100 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 100 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for the analysis of safety.

    Reporting group title
    Cohort 6 (75 µg/kg)
    Reporting group description
    		 Part 1: MT-3724 75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. Planned dose for cohort 6 was 150 µg/kg. As the MTD was exceeded in Cohort 5, an additional dose cohort of 75 μg/kg/dose was added to more narrowly identify the MTD (Cohort 6). The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for the analysis of safety.

    Reporting group title
    Cohort 7 (50/75 µg/kg)
    Reporting group description
    		 Part 2: MT-3724 50/75 µg/kg administered as an initial 12-day course followed by at least a 2-week observation period providing a study period of 28 days in total. The first 3 of 6 subjects enrolled in Cohort 7 were treated at 75 μg/kg/dose. The last 3 of 6 subjects were treated with the adjusted MTD (50 μg/kg/dose) following the emergence of grade 2 CLS in 2 subjects in Cohort 7 treated with 75 μg/kg/dose. The Safety Set (SS) included all subjects who received any amount of MT-3724. The SS was the primary population for the analysis of safety.

    Serious adverse events
    		 Cohort 1 (5 µg/kg) Cohort 2 (10 µg/kg) Cohort 3 (20 µg/kg) Cohort 4 (50µg/kg) Cohort 5 (100 µg/kg) Cohort 6 (75 µg/kg) Cohort 7 (50/75 µg/kg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    4 / 4 (100.00%)
    2 / 2 (100.00%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
    Additional description: There was 1 subject in Cohort 4 with a TEAE (PT: cardiac arrest) leading to death; this TEAE was considered to be unrelated to treatment and secondary to disease progression.
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    Additional description: Renal failure acute
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 (5 µg/kg) Cohort 2 (10 µg/kg) Cohort 3 (20 µg/kg) Cohort 4 (50µg/kg) Cohort 5 (100 µg/kg) Cohort 6 (75 µg/kg) Cohort 7 (50/75 µg/kg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    4 / 4 (100.00%)
    2 / 2 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    3
    Lymphoedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Venous thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    1
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 2 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    Face oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    3
    1
    2
    1
    0
    2
    2
    Infusion site irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Injection site extravasation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Injection site reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    Swelling
    Additional description: Local swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    0 / 3 (0.00%)
    4 / 4 (100.00%)
    1 / 2 (50.00%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
         occurrences all number
    1
    3
    0
    4
    1
    4
    3
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    1 / 2 (50.00%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    1
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    1
    1
    0
    2
    0
    Dysphonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypocapnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    4 / 6 (66.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Throat irritation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Dysphoria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    1
    0
    0
    3
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Scratch
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood lactic acid increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Heart rate increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cardiomyopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 4 (50.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    Headache
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 4 (50.00%)
    1 / 2 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Lymph node pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    0
    Pancytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Retinal exudates
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    1
    0
    Gastrointestinal disorders
    Anal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 4 (50.00%)
    1 / 2 (50.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
         occurrences all number
    2
    0
    0
    2
    1
    3
    3
    Dyspepsia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    1
    Gastric ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Melaena
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    3
    0
    0
    0
    2
    1
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    Reflux gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    1
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Blister
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cold sweat
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    2
    Rash maculo-papular
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    3
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Groin pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    2 / 2 (100.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
         occurrences all number
    1
    2
    1
    0
    2
    2
    3
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Pyoderma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Troponin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 4 (50.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    Failure to thrive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Gout
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 2 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 4 (50.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    2 / 2 (100.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jan 2015
    Version 2.0 • This amendment corrected that the Medical Monitor would review all available safety data bi-weekly, rather than the DMC. • This amendment corrected the dilution of MT-3724, indicating it could also be diluted in normal saline prior to infusion. • This amendment added that serum from blood samples could also be analyzed for any other anti-CD20 biologic agent which the subject may have received prior to enrolment. • A correction was made to the anticipated start of enrollment, and the addition of dose cohorts if (1) less than 2 DLTs were observed at the completion of that cohort’s first cycle and (2) maximum PK/PD parameter changes had not yet been observed. • Text was added and amended to clarify the PK assessment and parameters. • Amendments were made to indicate appropriate documentation of AEs and SAEs in CRFs.
    15 May 2015
    Version 3.0 • This amendment changed the minimum platelet count to > 50,000/μL, because potential subjects with CTCAE v. 4.03 Grade III thrombocytopenia solely due to tumor infiltration of bone marrow and who were free of clinically significant signs/symptoms of bleeding may have experienced an increase in platelet count if the tumor cell infiltration was reduced or eliminated by MT-3724. • This amendment corrected the pre-infusion treatment for study investigators to more clearly document that they may have adjusted the recommended pre-infusion treatments (anti-pyretic, anti-histamine and glucocorticosteroids) for each subject as often as necessary based on that subject’s past medical history, current medical status and/or the subject’s response to one or more of the pretreatment medications.
    08 Jul 2015
    Version 4.0 • This protocol amendment enabled Investigators to enroll subjects with an expanded range of B cell hematologic malignancies (CLL/SLL) under the same investigational new drug (IND) application in one uniform clinical trial (IND#121918). • This amendment defined how further dose escalation would occur (increments of 50 μg/kg/dose), and once the maximum administered dose was identified, how dose de-escalation would occur (decrements of 25 μg/kg/dose) until the MTD was identified. The protocol retained the caveat that dose escalations was confirmed or modified by the DMC at each end-of-cohort review as the DMC reviewed the cumulative safety data across all subjects, all cohorts. • This amendment added inclusion criteria for subjects with CLL. Subjects were also required to have at least a 84 day washout (~3 half-lives for rituximab) of any prior anti-CD20 MAb therapy. • This amendment clarified the reporting requirements for SAEs. Regardless of suspected causality, SAEs were to be reported from the initiation of screening through 30 days after a subject’s last dose. • This amendment updated central laboratory requirements for flow cytometry samples (a separate tube for complete blood count no longer required).
    07 Jan 2016
    Version 5.0 • This protocol amendment enabled Investigators to enroll subjects with an expanded range of B cell hematologic malignancies (CLL/SLL) under the same IND in one uniform clinical trial (IND#121918). • This amendment defined how further dose escalation would occur (increments of 50 μg/kg/dose), and once the maximum administered dose was identified, how dose de-escalation would occur (decrements of 25 μg/kg/dose) until the MTD was identified. The protocol retained the caveat that dose escalations was confirmed or modified by the DMC at each end-of-cohort review as the DMC reviewed the cumulative safety data across all subjects, all cohorts.
    05 Jan 2017
    Version 6.0 • Limited enrollment to subject with relapsed/refractory DLBCL, including those with mixed histology. • Inclusion criteria for the requirement of a rituximab sample for subjects who received rituximab within 256 days was implemented. • Added required washout for obinutuzumab, ofatumumab and ibritumomab tiuxetan • Added option for dose reduction by 25% to 33% in response to adverse event.
    08 Feb 2018
    Version 7.0 • Text was added and amended to clarify the PK assessment and parameters. • Amendments were made to indicate appropriate documentation of AEs and SAEs in CRFs.
    15 Apr 2019
    Version 7.1 • The purpose of this amendment was to add MT-3724 to be administered until disease progression, unacceptable toxicity, death, withdrawal of consent or other reason for withdrawal. The continued dosing was allowed beyond cycle 5, so subjects did not have to enroll in a separate protocol for continued dosing.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Mar 2021
    On 19 March 2021, the US Food and Drug Administration (FDA) placed all MT-3724 IND clinical study protocols on a full hold and requested additional information. Due to the significant time needed to address the FDA requests, Molecular Templates, Inc., closed the conduct of study MT-3724_NHL_001 in all countries. Parts 1 and 2 (considered to be a Phase 1/1b of the study) were completed at the time of study closure and a full clinical study report (CSR) was prepared. Part 3 was ongoing at the time of study closure (aborted study) and only an abbreviated CSR will be prepared, and results will be added to this posting at a later date.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The phase 1 parts of this study were not designed to optimize follow-up for response, and thus there are few data points to permit definitive conclusions for efficacy.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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