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    Clinical Trial Results:
    A Phase 2, Multicenter Study to Assess the Efficacy and Safety of Autologous Tumor Infiltrating Lymphocytes (LN 144) for Treatment of Patients with Metastatic Melanoma

    Summary
    EudraCT number
    		 2017-000760-15
    Trial protocol
    		 GB   HU   DE   ES   FR   IT  
    Global end of trial date
    24 Oct 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Nov 2025
    First version publication date
    12 Nov 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C-144-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02360579
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Iovance Biotherapeutics, Inc.
    Sponsor organisation address
    825 Industrial Rd Suite 100, San Carlos, United States, 94070
    Public contact
    Rana Fiaz, Executive Medical Director, Iovance Biotherapeutics, Inc., +1 844-845-4682, Clinical.Inquiries@iovance.com
    Scientific contact
    Rana Fiaz, Executive Medical Director, Iovance Biotherapeutics, Inc., +1 844-845-4682, Clinical.Inquiries@iovance.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
    05 Mar 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Oct 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the efficacy of LN-144 in patients with unresectable or metastatic melanoma using the ORR, as assessed by the IRC per RECIST v1.1
    Protection of trial subjects
    This study was conducted in compliance with the Good Clinical Practice (GCP) guidelines and adhered to applicable national and/or local statutes and regulations concerning ethical committee review, informed consent, and the protection of human subjects involved in clinical trials.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    United States: 163
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    220
    EEA total number of subjects
    46
    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)
    175
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Cohort 3 patients had progressed following initial treatment in Cohorts 1, 2, 4 and then were retreated with a second TIL regimen. For sections below where no results are presented for this cohort, these patients are accounted for in their original cohort.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Cohort 1
    Arm description
    		 Non-cryopreserved TIL (LN-144, Gen 1) A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with TIL followed by IL-2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Non-cryopreserved TIL (Gen 1)
    Investigational medicinal product code
    LN-144
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Infusion
    Dosage and administration details
    Non-cryopreserved TIL (Gen 1) is a preparation of TIL derived from an individual patient's tumor for patient-directed immunotherapy. Non-cryopreserved TIL is provided as a single dose for infusion containing 1 × 10^9 to 150 × 10^9 viable cells. Patients were to receive the full dose of product that was manufactured. Lot numbers are patient-specific.

    Arm title
    		 Cohort 2
    Arm description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product). Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lifileucel (Gen 2)
    Investigational medicinal product code
    LN-144
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Infusion
    Dosage and administration details
    Lifileucel is a preparation of TIL derived from an individual patient's tumor for patient-directed immunotherapy. Lifileucel is provided as a single dose for infusion containing 1 × 10^9 to 150 × 10^9 viable cells suspended in a cryopreservation medium. Patients were to receive the full dose of product that was manufactured. Lot numbers are patient-specific.

    Arm title
    		 Cohort 3 (Retreatment Cohort)
    Arm description
    		 Retreatment cohort: patients from Cohort 1, Cohort 2 or Cohort 4 may rescreen for a second TIL regimen therapy if they meet all Inclusion and Exclusion Criteria (except exclusion criterion b). Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lifileucel (Gen 2)
    Investigational medicinal product code
    LN-144
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Infusion
    Dosage and administration details
    Lifileucel is a preparation of TIL derived from an individual patient's tumor for patient-directed immunotherapy. Lifileucel is provided as a single dose for infusion containing 1 × 10^9 to 150 × 10^9 viable cells suspended in a cryopreservation medium. Patients were to receive the full dose of product that was manufactured. Lot numbers are patient-specific.

    Arm title
    		 Cohort 4
    Arm description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product) Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lifileucel (Gen 2)
    Investigational medicinal product code
    LN-144
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Infusion
    Dosage and administration details
    Lifileucel is a preparation of TIL derived from an individual patient's tumor for patient-directed immunotherapy. Lifileucel is provided as a single dose for infusion containing 1 × 10^9 to 150 × 10^9 viable cells suspended in a cryopreservation medium. Patients were to receive the full dose of product that was manufactured. Lot numbers are patient-specific.

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 (Retreatment Cohort) Cohort 4
    Started
    31
    78
    12
    111
    Completed
    0
    14
    1
    14
    Not completed
    31
    64
    11
    97
         Consent withdrawn by subject
    -
    -
    -
    3
         Death
    16
    49
    11
    71
         Unknown
    7
    -
    -
    -
         Did not receive TIL
    8
    11
    -
    22
         Lost to follow-up
    -
    4
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Non-cryopreserved TIL (LN-144, Gen 1) A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with TIL followed by IL-2.

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product). Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.

    Reporting group title
    Cohort 3 (Retreatment Cohort)
    Reporting group description
    		 Retreatment cohort: patients from Cohort 1, Cohort 2 or Cohort 4 may rescreen for a second TIL regimen therapy if they meet all Inclusion and Exclusion Criteria (except exclusion criterion b). Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product) Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 (Retreatment Cohort) Cohort 4 Total
    Number of subjects
    		 31 78 12 111 220
    Age categorical
    Total Number of 220 includes Cohort 1, 2, and 4. Cohort 3 is a retreatment cohort.
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 29 62 11 84 175
        From 65-84 years
    		 2 16 1 27 45
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 52 (28 to 72) 55 (20 to 79) 52 (29 to 66) 55 (25 to 74) -
    Gender categorical
    Total Number of 220 includes Cohort 1, 2, and 4. Cohort 3 is a retreatment cohort.
    Units: Subjects
        Female
    		 14 37 3 51 102
        Male
    		 17 41 9 60 118

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Non-cryopreserved TIL (LN-144, Gen 1) A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with TIL followed by IL-2.

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product). Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.

    Reporting group title
    Cohort 3 (Retreatment Cohort)
    Reporting group description
    		 Retreatment cohort: patients from Cohort 1, Cohort 2 or Cohort 4 may rescreen for a second TIL regimen therapy if they meet all Inclusion and Exclusion Criteria (except exclusion criterion b). Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product) Lifileucel: A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with lifileucel followed by IL-2.

    Subject analysis set title
    Pooled Cohorts 2 & 4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set is defined as participants who received the lifileucel infusion that met product manufacturing specifications. Data from Cohorts 2 and 4 participants in full analysis set are pooled to evaluate efficacy of cryopreserved TIL product.

    Primary: Disease Assessment for Objective Response Rate

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    End point title
    		 Disease Assessment for Objective Response Rate [1] [2]
    End point description
    The Full Analysis Set is defined as patients who received the lifileucel infusion that met product manufacturing specifications. Evaluate the efficacy of LN-144 in patients with unresectable or metastatic melanoma using the objective response rate (ORR), as assessed by the Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
    End point type
    Primary
    End point timeframe
    Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analysis has been performed for this primary endpoint due to single arm study design.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analyses of efficacy and safety data were performed for Cohort 2, Cohort 4, and pooled Cohorts 2 and 4 in order to evaluate cryopreserved TIL product. Cohort 3 patients had progressed following initial treatment in Cohorts 1, 2, 4 and then were retreated with a second TIL regimen. These patients are accounted for below in their original cohorts. Tumor assessments for Cohort 1 patients were not assessed by the IRC.
    End point values
    		 Cohort 2 Cohort 4 Pooled Cohorts 2 & 4
    Number of subjects analysed
    66
    87
    153
    Units: %
        number (confidence interval 95%)
    34.8 (23.5 to 47.6)
    28.7 (19.5 to 39.4)
    31.4 (24.1 to 39.4)
    No statistical analyses for this end point

    Secondary: Disease Assessment for Duration of Response

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    End point title
    		 Disease Assessment for Duration of Response [3]
    End point description
    Evaluate the efficacy endpoints of duration of response (DOR) by the IRC and by the investigator per RECIST v1.1. Due to the high concordance between the objective response as assessed by the Investigator and the IRC (89.4% in Cohort 2 and 92.0% in Cohort 4), the efficacy results as assessed by the IRC are presented.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analyses of efficacy and safety data were performed for Cohort 2, Cohort 4, and pooled Cohorts 2 and 4 in order to evaluate cryopreserved TIL product. Cohort 3 patients had progressed following initial treatment in Cohorts 1, 2, 4 and then were retreated with a second TIL regimen. These patients are accounted for in their original cohorts. Tumor assessments for Cohort 1 patients were not assessed by the IRC.
    End point values
    		 Cohort 2 Cohort 4 Pooled Cohorts 2 & 4
    Number of subjects analysed
    23 [4]
    25
    48
    Units: Months
        median (full range (min-max))
    0 (0 to 0)
    10.4 (1.4 to 56.4)
    36.5 (1.4 to 58.7)
    Notes
    [4] - Median DOR was not reached in Cohort 2. Full range (Min - Max): 1.4 to 58.7 months.
    No statistical analyses for this end point

    Secondary: Disease Assessment for Disease Control Rate

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    End point title
    		 Disease Assessment for Disease Control Rate [5]
    End point description
    Evaluate the efficacy endpoints of disease control rate (DCR) as assessed by the IRC and by the investigator per RECIST v1.1. Due to the high concordance between the objective response as assessed by the Investigator and the IRC (89.4% in Cohort 2 and 92.0% in Cohort 4), the efficacy results as assessed by the IRC are presented.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analyses of efficacy and safety data were performed for Cohort 2, Cohort 4, and pooled Cohorts 2 and 4 in order to evaluate cryopreserved TIL product. Cohort 3 patients had progressed following initial treatment in Cohorts 1, 2, 4 and then were retreated with a second TIL regimen. These patients are accounted for in their original cohorts. Tumor assessments for Cohort 1 patients were not assessed by the IRC.
    End point values
    		 Cohort 2 Cohort 4 Pooled Cohorts 2 & 4
    Number of subjects analysed
    66
    87
    153
    Units: %
        number (confidence interval 95%)
    72.7 (60.0 to 83.0)
    82.8 (73.2 to 90.0)
    78.4 (71.1 to 84.7)
    No statistical analyses for this end point

    Secondary: Disease Assessment for Progression-Free Survival

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    End point title
    		 Disease Assessment for Progression-Free Survival [6]
    End point description
    Evaluate the efficacy endpoints of progression-free survival (PFS) as assessed by the IRC and by the investigator per RECIST v1.1. The Full Analysis Set is defined as patients who received the lifileucel infusion that met product manufacturing specifications. Due to the high concordance between the objective response as assessed by the Investigator and the IRC (89.4% in Cohort 2 and 92.0% in Cohort 4), the efficacy results as assessed by the IRC are presented.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analyses of efficacy and safety data were performed for Cohort 2, Cohort 4, and pooled Cohorts 2 and 4 in order to evaluate cryopreserved TIL product. Cohort 3 patients had progressed following initial treatment in Cohorts 1, 2, 4 and then were retreated with a second TIL regimen. These patients are accounted for in their original cohorts. Tumor assessments for Cohort 1 patients were not assessed by the IRC.
    End point values
    		 Cohort 2 Cohort 4 Pooled Cohorts 2 & 4
    Number of subjects analysed
    66
    87
    153
    Units: months
        median (confidence interval 95%)
    4.1 (2.8 to 8.4)
    3.9 (2.8 to 4.9)
    4.1 (2.8 to 4.4)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival [7]
    End point description
    Measure Description Evaluate overall survival (OS). The Full Analysis Set is defined as patients who received the lifileucel infusion that met product manufacturing specifications.
    End point type
    Secondary
    End point timeframe
    Until death or up to 60 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analyses of efficacy and safety data were performed for Cohort 2, Cohort 4, and pooled Cohorts 2 and 4 in order to evaluate cryopreserved TIL product. Cohort 3 patients had progressed following initial treatment in Cohorts 1, 2, 4 and then were retreated with a second TIL regimen. These patients are accounted for in their original cohorts.
    End point values
    		 Cohort 2 Cohort 4 Pooled Cohorts 2 & 4
    Number of subjects analysed
    66
    87
    153
    Units: months
        median (confidence interval 95%)
    15.6 (11.0 to 23.3)
    12.7 (8.3 to 17.8)
    13.9 (10.6 to 17.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment to end of follow-up (up to 5 years)
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs), clinical laboratory data assessments, serious adverse events (SAEs), and adverse events (AEs) were collected and evaluated for the duration of the study until resolution or permanent sequelae. The Safety Analysis Set is defined as patients who have received TIL infusion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Non-cryopreserved TIL (LN-144, Gen 1)

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product)

    Reporting group title
    Cohort 3
    Reporting group description
    		 Retreatment cohort: patients from Cohort 1, Cohort 2 or Cohort 4 may rescreen for a second TIL regimen therapy if they meet all Inclusion and Exclusion Criteria (except exclusion criterion b).

    Reporting group title
    Cohort 4
    Reporting group description
    		 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product)

    Serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 23 (39.13%)
    23 / 67 (34.33%)
    2 / 12 (16.67%)
    31 / 89 (34.83%)
         number of deaths (all causes)
    18
    49
    0
    71
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 9
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 23 (13.04%)
    6 / 67 (8.96%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 67 (5.97%)
    2 / 12 (16.67%)
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    67 / 67 (100.00%)
    12 / 12 (100.00%)
    89 / 89 (100.00%)
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    8 / 67 (11.94%)
    2 / 12 (16.67%)
    10 / 89 (11.24%)
         occurrences all number
    0
    9
    2
    13
    Flushing
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 67 (5.97%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    3
    4
    1
    4
    Hypertension
         subjects affected / exposed
    4 / 23 (17.39%)
    9 / 67 (13.43%)
    2 / 12 (16.67%)
    17 / 89 (19.10%)
         occurrences all number
    4
    12
    2
    27
    Hypotension
         subjects affected / exposed
    7 / 23 (30.43%)
    24 / 67 (35.82%)
    5 / 12 (41.67%)
    27 / 89 (30.34%)
         occurrences all number
    8
    26
    5
    38
    Thrombophlebitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    1 / 89 (1.12%)
         occurrences all number
    0
    1
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 23 (8.70%)
    8 / 67 (11.94%)
    0 / 12 (0.00%)
    14 / 89 (15.73%)
         occurrences all number
    2
    8
    0
    16
    Chills
         subjects affected / exposed
    15 / 23 (65.22%)
    52 / 67 (77.61%)
    9 / 12 (75.00%)
    64 / 89 (71.91%)
         occurrences all number
    21
    77
    11
    76
    Fatigue
         subjects affected / exposed
    8 / 23 (34.78%)
    26 / 67 (38.81%)
    1 / 12 (8.33%)
    25 / 89 (28.09%)
         occurrences all number
    9
    36
    1
    30
    Malaise
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    5 / 89 (5.62%)
         occurrences all number
    2
    4
    0
    5
    Mucosal inflammation
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    4 / 89 (4.49%)
         occurrences all number
    0
    5
    0
    4
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    3
    2
    0
    2
    Oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    8 / 89 (8.99%)
         occurrences all number
    1
    1
    1
    8
    Oedema peripheral
         subjects affected / exposed
    8 / 23 (34.78%)
    17 / 67 (25.37%)
    3 / 12 (25.00%)
    15 / 89 (16.85%)
         occurrences all number
    8
    20
    3
    19
    Pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    2 / 89 (2.25%)
         occurrences all number
    2
    1
    1
    2
    Pyrexia
         subjects affected / exposed
    9 / 23 (39.13%)
    39 / 67 (58.21%)
    6 / 12 (50.00%)
    42 / 89 (47.19%)
         occurrences all number
    10
    110
    11
    78
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    0
    1
    2
    4
    Hypersensitivity
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    2
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 23 (26.09%)
    13 / 67 (19.40%)
    0 / 12 (0.00%)
    12 / 89 (13.48%)
         occurrences all number
    7
    15
    0
    13
    Dyspnoea
         subjects affected / exposed
    4 / 23 (17.39%)
    14 / 67 (20.90%)
    0 / 12 (0.00%)
    15 / 89 (16.85%)
         occurrences all number
    4
    16
    0
    16
    Epistaxis
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    4 / 89 (4.49%)
         occurrences all number
    2
    1
    0
    4
    Hypoxia
         subjects affected / exposed
    1 / 23 (4.35%)
    16 / 67 (23.88%)
    2 / 12 (16.67%)
    18 / 89 (20.22%)
         occurrences all number
    1
    19
    2
    21
    Lung disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 67 (1.49%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences all number
    2
    1
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    1
    4
    0
    3
    Pleural effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    6 / 67 (8.96%)
    0 / 12 (0.00%)
    8 / 89 (8.99%)
         occurrences all number
    0
    10
    0
    8
    Pleuritic pain
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences all number
    0
    4
    0
    3
    Pulmonary oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 67 (2.99%)
    1 / 12 (8.33%)
    9 / 89 (10.11%)
         occurrences all number
    1
    3
    1
    9
    Respiratory distress
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    2 / 89 (2.25%)
         occurrences all number
    0
    0
    1
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    1 / 12 (8.33%)
    1 / 89 (1.12%)
         occurrences all number
    0
    2
    1
    1
    Tachypnoea
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    1 / 12 (8.33%)
    10 / 89 (11.24%)
         occurrences all number
    0
    2
    1
    11
    Wheezing
         subjects affected / exposed
    0 / 23 (0.00%)
    6 / 67 (8.96%)
    0 / 12 (0.00%)
    7 / 89 (7.87%)
         occurrences all number
    0
    7
    0
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 67 (7.46%)
    0 / 12 (0.00%)
    9 / 89 (10.11%)
         occurrences all number
    0
    6
    0
    9
    Confusional state
         subjects affected / exposed
    1 / 23 (4.35%)
    9 / 67 (13.43%)
    1 / 12 (8.33%)
    5 / 89 (5.62%)
         occurrences all number
    1
    9
    1
    5
    Delirium
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    5 / 89 (5.62%)
         occurrences all number
    0
    5
    0
    6
    Insomnia
         subjects affected / exposed
    2 / 23 (8.70%)
    6 / 67 (8.96%)
    1 / 12 (8.33%)
    7 / 89 (7.87%)
         occurrences all number
    2
    6
    1
    7
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 23 (30.43%)
    15 / 67 (22.39%)
    4 / 12 (33.33%)
    13 / 89 (14.61%)
         occurrences all number
    11
    26
    6
    19
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 23 (21.74%)
    19 / 67 (28.36%)
    4 / 12 (33.33%)
    13 / 89 (14.61%)
         occurrences all number
    7
    31
    9
    23
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 23 (26.09%)
    14 / 67 (20.90%)
    2 / 12 (16.67%)
    9 / 89 (10.11%)
         occurrences all number
    8
    20
    3
    16
    Blood bilirubin increased
         subjects affected / exposed
    3 / 23 (13.04%)
    5 / 67 (7.46%)
    1 / 12 (8.33%)
    7 / 89 (7.87%)
         occurrences all number
    5
    10
    1
    12
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 67 (7.46%)
    1 / 12 (8.33%)
    5 / 89 (5.62%)
         occurrences all number
    0
    7
    1
    8
    Blood creatinine increased
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 67 (7.46%)
    2 / 12 (16.67%)
    9 / 89 (10.11%)
         occurrences all number
    1
    5
    3
    10
    Breath sounds abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    0
    3
    6
    12
    International normalised ratio increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    2 / 89 (2.25%)
         occurrences all number
    0
    2
    1
    2
    Urine output decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    4
    0
    1
    Weight decreased
         subjects affected / exposed
    3 / 23 (13.04%)
    9 / 67 (13.43%)
    3 / 12 (25.00%)
    8 / 89 (8.99%)
         occurrences all number
    5
    17
    4
    10
    Weight increased
         subjects affected / exposed
    1 / 23 (4.35%)
    16 / 67 (23.88%)
    1 / 12 (8.33%)
    10 / 89 (11.24%)
         occurrences all number
    1
    27
    1
    20
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    3 / 89 (3.37%)
         occurrences all number
    0
    0
    1
    3
    Infusion related reaction
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 67 (4.48%)
    0 / 12 (0.00%)
    5 / 89 (5.62%)
         occurrences all number
    1
    3
    0
    5
    Skin laceration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    3 / 89 (3.37%)
         occurrences all number
    1
    1
    1
    3
    Sinus tachycardia
         subjects affected / exposed
    6 / 23 (26.09%)
    10 / 67 (14.93%)
    1 / 12 (8.33%)
    13 / 89 (14.61%)
         occurrences all number
    8
    16
    1
    16
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 67 (4.48%)
    1 / 12 (8.33%)
    1 / 89 (1.12%)
         occurrences all number
    0
    3
    1
    1
    Tachycardia
         subjects affected / exposed
    3 / 23 (13.04%)
    23 / 67 (34.33%)
    6 / 12 (50.00%)
    22 / 89 (24.72%)
         occurrences all number
    5
    25
    6
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 23 (8.70%)
    6 / 67 (8.96%)
    1 / 12 (8.33%)
    5 / 89 (5.62%)
         occurrences all number
    2
    6
    1
    5
    Headache
         subjects affected / exposed
    3 / 23 (13.04%)
    8 / 67 (11.94%)
    0 / 12 (0.00%)
    12 / 89 (13.48%)
         occurrences all number
    6
    9
    0
    14
    Lethargy
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    2 / 12 (16.67%)
    0 / 89 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 23 (78.26%)
    46 / 67 (68.66%)
    11 / 12 (91.67%)
    54 / 89 (60.67%)
         occurrences all number
    53
    146
    35
    148
    Febrile neutropenia
         subjects affected / exposed
    11 / 23 (47.83%)
    30 / 67 (44.78%)
    5 / 12 (41.67%)
    27 / 89 (30.34%)
         occurrences all number
    11
    33
    5
    27
    Leukopenia
         subjects affected / exposed
    12 / 23 (52.17%)
    28 / 67 (41.79%)
    2 / 12 (16.67%)
    29 / 89 (32.58%)
         occurrences all number
    17
    53
    8
    49
    Lymphopenia
         subjects affected / exposed
    6 / 23 (26.09%)
    23 / 67 (34.33%)
    3 / 12 (25.00%)
    28 / 89 (31.46%)
         occurrences all number
    19
    71
    7
    59
    Neutropenia
         subjects affected / exposed
    11 / 23 (47.83%)
    37 / 67 (55.22%)
    5 / 12 (41.67%)
    30 / 89 (33.71%)
         occurrences all number
    20
    55
    5
    44
    Normocytic anaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    0
    3
    1
    9
    Pancytopenia
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 67 (7.46%)
    0 / 12 (0.00%)
    4 / 89 (4.49%)
         occurrences all number
    1
    5
    0
    4
    Thrombocytopenia
         subjects affected / exposed
    17 / 23 (73.91%)
    60 / 67 (89.55%)
    10 / 12 (83.33%)
    72 / 89 (80.90%)
         occurrences all number
    54
    220
    31
    223
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 67 (4.48%)
    1 / 12 (8.33%)
    2 / 89 (2.25%)
         occurrences all number
    0
    4
    1
    2
    Vision blurred
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    4 / 89 (4.49%)
         occurrences all number
    0
    4
    0
    4
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 67 (1.49%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    2
    1
    1
    4
    Abdominal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 67 (5.97%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    2
    4
    1
    4
    Abdominal pain upper
         subjects affected / exposed
    0 / 23 (0.00%)
    6 / 67 (8.96%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    0
    6
    0
    2
    Constipation
         subjects affected / exposed
    4 / 23 (17.39%)
    13 / 67 (19.40%)
    1 / 12 (8.33%)
    7 / 89 (7.87%)
         occurrences all number
    4
    15
    1
    7
    Diarrhoea
         subjects affected / exposed
    9 / 23 (39.13%)
    19 / 67 (28.36%)
    5 / 12 (41.67%)
    29 / 89 (32.58%)
         occurrences all number
    14
    27
    5
    36
    Dry mouth
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 67 (7.46%)
    0 / 12 (0.00%)
    8 / 89 (8.99%)
         occurrences all number
    1
    5
    0
    10
    Dyspepsia
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    2
    2
    0
    1
    Nausea
         subjects affected / exposed
    13 / 23 (56.52%)
    16 / 67 (23.88%)
    2 / 12 (16.67%)
    21 / 89 (23.60%)
         occurrences all number
    18
    17
    2
    27
    Stomatitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    1
    0
    1
    4
    Vomiting
         subjects affected / exposed
    9 / 23 (39.13%)
    14 / 67 (20.90%)
    2 / 12 (16.67%)
    20 / 89 (22.47%)
         occurrences all number
    14
    18
    2
    30
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 23 (26.09%)
    19 / 67 (28.36%)
    0 / 12 (0.00%)
    19 / 89 (21.35%)
         occurrences all number
    6
    21
    0
    20
    Dry skin
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    4 / 89 (4.49%)
         occurrences all number
    3
    4
    0
    4
    Erythema
         subjects affected / exposed
    4 / 23 (17.39%)
    4 / 67 (5.97%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences all number
    4
    4
    0
    3
    Petechiae
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences all number
    3
    2
    0
    3
    Pruritus
         subjects affected / exposed
    4 / 23 (17.39%)
    13 / 67 (19.40%)
    1 / 12 (8.33%)
    11 / 89 (12.36%)
         occurrences all number
    5
    16
    1
    12
    Rash
         subjects affected / exposed
    0 / 23 (0.00%)
    16 / 67 (23.88%)
    3 / 12 (25.00%)
    23 / 89 (25.84%)
         occurrences all number
    0
    19
    4
    33
    Rash maculo-papular
         subjects affected / exposed
    4 / 23 (17.39%)
    14 / 67 (20.90%)
    1 / 12 (8.33%)
    10 / 89 (11.24%)
         occurrences all number
    5
    22
    1
    13
    Vitiligo
         subjects affected / exposed
    3 / 23 (13.04%)
    6 / 67 (8.96%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences all number
    3
    6
    0
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 23 (4.35%)
    6 / 67 (8.96%)
    0 / 12 (0.00%)
    9 / 89 (10.11%)
         occurrences all number
    1
    12
    0
    16
    Haematuria
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 67 (7.46%)
    1 / 12 (8.33%)
    4 / 89 (4.49%)
         occurrences all number
    0
    5
    1
    4
    Oliguria
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 67 (4.48%)
    0 / 12 (0.00%)
    5 / 89 (5.62%)
         occurrences all number
    0
    3
    0
    5
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 67 (0.00%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    2
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 23 (8.70%)
    6 / 67 (8.96%)
    2 / 12 (16.67%)
    3 / 89 (3.37%)
         occurrences all number
    2
    8
    2
    3
    Back pain
         subjects affected / exposed
    1 / 23 (4.35%)
    9 / 67 (13.43%)
    2 / 12 (16.67%)
    7 / 89 (7.87%)
         occurrences all number
    1
    11
    2
    9
    Bone pain
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 67 (2.99%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 67 (7.46%)
    0 / 12 (0.00%)
    3 / 89 (3.37%)
         occurrences all number
    0
    6
    0
    3
    Muscular weakness
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 67 (4.48%)
    1 / 12 (8.33%)
    3 / 89 (3.37%)
         occurrences all number
    3
    3
    1
    3
    Myalgia
         subjects affected / exposed
    2 / 23 (8.70%)
    5 / 67 (7.46%)
    0 / 12 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    2
    5
    0
    2
    Pain in extremity
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    0 / 12 (0.00%)
    5 / 89 (5.62%)
         occurrences all number
    0
    3
    0
    8
    Infections and infestations
    Klebsiella infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 67 (0.00%)
    1 / 12 (8.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 23 (30.43%)
    19 / 67 (28.36%)
    2 / 12 (16.67%)
    11 / 89 (12.36%)
         occurrences all number
    8
    22
    2
    12
    Dehydration
         subjects affected / exposed
    6 / 23 (26.09%)
    5 / 67 (7.46%)
    0 / 12 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    6
    5
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 67 (2.99%)
    1 / 12 (8.33%)
    3 / 89 (3.37%)
         occurrences all number
    0
    4
    1
    5
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 23 (30.43%)
    14 / 67 (20.90%)
    0 / 12 (0.00%)
    14 / 89 (15.73%)
         occurrences all number
    22
    31
    0
    25
    Hypocalcaemia
         subjects affected / exposed
    4 / 23 (17.39%)
    16 / 67 (23.88%)
    1 / 12 (8.33%)
    13 / 89 (14.61%)
         occurrences all number
    8
    27
    5
    33
    Hypokalaemia
         subjects affected / exposed
    5 / 23 (21.74%)
    17 / 67 (25.37%)
    3 / 12 (25.00%)
    26 / 89 (29.21%)
         occurrences all number
    8
    30
    6
    47
    Hypomagnesaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    16 / 67 (23.88%)
    4 / 12 (33.33%)
    15 / 89 (16.85%)
         occurrences all number
    3
    19
    5
    21
    Hyponatraemia
         subjects affected / exposed
    5 / 23 (21.74%)
    11 / 67 (16.42%)
    2 / 12 (16.67%)
    8 / 89 (8.99%)
         occurrences all number
    6
    17
    3
    14
    Hypophosphataemia
         subjects affected / exposed
    6 / 23 (26.09%)
    30 / 67 (44.78%)
    5 / 12 (41.67%)
    28 / 89 (31.46%)
         occurrences all number
    12
    74
    7
    57

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2015
    Updated text from “The final cell product will be formulated after harvesting and washing in 500 mL of a 1:1 (v/v) solution of HypoThermosol™ and Plasma-Lyte A™ containing 1% HSA (compatible for human infusion).” To “The final cell product is formulated in a minimum of 50% HypoThermosol™ in Plasma-Lyte A™ (volume/volume) and up to 1% HSA (compatible for human infusion) containing 300 IU/mL IL2. The final product will be available for administration in one of two volumes for infusion: 1) 250 mL (in a 300-mL capacity infusion bag) when the total TIL harvested are ≤ 75x10^9 OR 2)500 mL (in a 600-mL capacity infusion bag) when the total TIL harvested are >75 x 10^9. The cell concentration range is 5.5 x 10^6 to 300 x 10^6/mL in the final product, with a dose range of 1.5 to 150 x 10^9 total viable cells. “ Changed “Lonza” to “Central TIL Manufacturing Facility”. Chest CT - language added to include neck imaging. Added clarifying information that eye exam is a Slit Lamp Eye exam. Previously stated, “The sample size is driven by the need to obtain 20 eligible patients. An eligible patient is one that meets all screening criteria, has been resected for TIL preparation and successfully infused treatment. Complete treatment is defined as successful infusion with LN-144 followed by IL-2”. This has been changed to, “The sample size is driven by the need to obtain 20 patients who complete treatment. Complete treatment is defined as successful infusion with LN-144 followed by IL-2”. Updated cardiac test text to the following “Cardiac evaluation (stress thallium) for all patients. Echocardiogram/ or MUGA if patient is ≥ 60 years of age or older; patients who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias. Stress thallium must show normal LVEF and unimpaired wall movement". Changed age from "18- 70, inclusive" to "Greater than 18". ...
    18 Jul 2016
    Additional objective added. Study design updated to reflect addition of TIL + durvalumab cohort. Change in sample size from 20 TIL alone patients to 15 TIL alone (Cohort 1) + 10 TIL & durvalumab (Cohort 2) patients. Clarified upper age limit: >65 with consultation with Medical Monitor & PI. Correct inclusion criterion regarding EBV testing. Allow palliative radiation during TIL manufacture period. Eased requirement for mandatory colonoscopy in patients with prior colitis. Eased requirement regarding brain metastases.
    08 Aug 2016
    CD4 count added back to the Schedule of Events table at the Day 28, Day 42, Day 84 and 6 Months visits
    04 Feb 2017
    The main purposes for revising the C-144-01 protocol are to: Addition of cohort of patients receiving LN-144 produced with a shortened process. Addition of cohort of patients harvested and treated a second time. Addition of an additional assessment time point. Addition of exploratory endpoint of HRQoL. Numerous clarifications to statistical section and minor operational changes addressing operational issues. Numerous typographical changes were made for clarity and consistency.
    13 May 2017
    The major changes and purposes for revising the C-144-01 protocol are to: Update of Primary and Secondary Objectives and Endpoints. Clarification of Exploratory Objectives and Endpoints. Adjustment of Eligibility Criteria for definition of Patient Population. Adjustment of Sample Size and rationale for determination. Clarification around requirements for Cohort 3 patients. Clarification around assessment and procedure timing. Numerous clarifications to Safety and Statistical sections. Updating of key Sponsor and designee contact information
    23 Mar 2018
    Number of clinical sites and sample size of patients per cohort were updated. Dose and treatment schedule revised in Synopsis and Protocol body to clarify changes to IL-2 administration, delineate between noncryopreserved product (Gen 1 [Cohort 1]), cryopreserved product (Gen 2 [Cohort 2]), and Cohort 3 [Gen 2] retreatment cohort, including Sponsor decision to close enrollment in Cohort 1. Inclusion criteria revised to clarify requirement for surgical resection of lesion, approved methods of birth control (ie, true sexual abstinence) and duration of contraception use, washout for prior anticancer therapies (targeted therapies, chemotherapies, immunotherapy, and palliative radiation) and specify that patients must have no other treatment options. Exclusion criteria revised to clarify exclusion of patients have received an organ allograph or those with specific conditions, such as active systemic infection, (eg, syphilis infection) or others, addition of exclusion for patients with a history of hypersensitivity reaction for aminoglycoside antibiotics, components of TIL product; requirements for echocardiogram and multiple gated acquisition scan at Screening, and cardia stress testing for assessment per NYHA functional classification related to atrial and/or ventricular arrhythmias, left ventricular ejection fraction, and wall movement abnormalities; exclusion window for live or attenuated vaccines; exclusion of patients who require immediate attention or would be at a disadvantage in participating and those who are protected or otherwise unable to provide proper consent. Treatment Cohorts more clearly delineated as first generation (Gen 1 infusion product [for Cohort 1]), second generation (Gen 2 infusion product [for Cohort 2]), and retreatment cohort for second TIL therapy (Cohort 3), including sponsor decision to close Cohort 1; and further to have all newly enrolled patients in Cohort 3 receive Gen 2 LN-144 infusion product.
    20 Dec 2018
    The main purpose of the amendment is to add a confirmatory and pivotal cohort, Cohort 4, to allow additional enrollment of approximately 75 patients to further investigate the efficacy and safety of LN-144. The sample size is based on a response rate of 4–10% to chemotherapy given second line in Phase 3 studies of PD-1 blocking antibodies. The Primary Endpoint of ORR assessment has been upgraded from Investigator assessment to an Independent Review Committee (IRC) per the FDA’s recommendation for a study intended to support product registration. The inclusion criteria for the study have been updated to clarify eligibility: Patients with unresectable or metastatic melanoma who have previously been treated with at least one systemic therapy including a PD-1 blocking antibody and if BRAF V600 mutation positive, a BRAF inhibitor or BRAF inhibitor with MEK inhibitor. Updated the Statistical and Analytical Plans to reflect current status and future analysis of all cohorts. There will be a blinded independent review (BIRC) implemented to review the efficacy data in Cohort 4. Confirmatory scans will be performed at least 4 weeks after initial response is documented for partial responders and complete responders per RECIST v1.1. irRECIST was part of Cohort 1 and Cohort 2 as assessed by an IRC and will now be assessed by the Investigator for Cohort 4 patients as an exploratory endpoint. Cohort 1 is now closed to Screening and enrollment, and patients who remain on study are in OS Follow-up. Cohort 2 is closed to enrollment, but a few patients were being screened at the time of the study closing for enrollment, therefore these patients will still be enrolled and/or treated. Cohort 3 remains open to enrollment for up to 10 patients who previously received treatment under Cohort 1, Cohort 2, or Cohort 4.
    22 Oct 2019
    Incorporation of the product release specification for total viable cells and clarification that patients will receive the full dose of product manufactured and released. Addition of the Independent Data Monitoring Committee (IDMC). Clarification of the Data Safety Monitoring Board (DSMB) responsibility for Cohort 3. Clarification on the interim analysis. Changes/clarification of study procedures, including hospitalization requirement, acceptable laboratory tests for viral infection and coagulation, and dosing calculation of chemotherapy using body weight. Change of baseline brain MRI window from 3 weeks to 4 weeks prior to Day 0, to minimize unnecessary scan if not clinically indicated.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36600653
    http://www.ncbi.nlm.nih.gov/pubmed/40454684
    http://www.ncbi.nlm.nih.gov/pubmed/40693376
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