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    Clinical Trial Results:
    A Study of the Pharmacokinetics of Melphalan During Treatment with Melflufen and Dexamethasone in Patients with Relapsed Refractory Multiple Myeloma and Impaired Renal Function

    Summary
    EudraCT number
    		 2018-000478-31
    Trial protocol
    		 CZ   PL   GR  
    Global end of trial date
    22 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    OP-107
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03639610
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Investigational New Drug Number: 116362
    Sponsors
    Sponsor organisation name
    Oncopeptides AB
    Sponsor organisation address
    Västra Trädgårdsgatan 15, Stockholm, Sweden, SE-111 53
    Public contact
    Clinical Trials Information Desk, Oncopeptides AB, trials@oncopeptides.com
    Scientific contact
    Clinical Trials Information Desk, Oncopeptides AB, trials@oncopeptides.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
    22 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    - To evaluate the relationship between renal function and the pharmacokinetic parameters for melphalan during treatment with melflufen - To assess the safety and tolerability of melflufen in patients with moderate (Cohorts 1a and 1b) and severe (Cohorts 2a and 2b) renal impairment Note: Cohort 2b was not enrolled as the study was terminated early.
    Protection of trial subjects
    This clinical study was designed, implemented, and reported in accordance with the ICH Harmonised Tripartite Guidelines for GCP, with applicable local regulations (including European Directive 2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles laid down in the Declaration of Helsinki. Eligible patients were only to be included in the study after providing written (witnessed, where required by law or regulation), IEC-approved informed consent. The clinical study was designed based on well-established guidance for oncology studies including RRMM management, response assessment, and National Comprehensive Cancer Network Guidelines.
    Background therapy
    		 Dexamethasone 40 mg administered orally on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged <75 years OR Dexamethasone 20 mg administered orally on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged ≥75 years
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    28 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Greece: 16
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    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)
    10
    From 65 to 84 years
    24
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient (in Cohort 1a) received their first dose of study drug on 17 September 2018. The last patient (in Cohort 2a) received their first dose of study drug on 29 June 2021.

    Pre-assignment
    Screening details
    		 Key inclusion criteria: age 18 or older; prior diagnosis of multiple myeloma; received at least 2 prior lines of therapy; measurable disease; life expectancy of at least 6 months; estimated glomerular filtration rate between ≥30 to <45 mL/min/1.73m² (Cohort 1) or between ≥15 to <30 mL/min/1.73m² (Cohort 2).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1a
    Arm description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melflufen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Melflufen at a starting dose of 40 mg administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter. Melflufen was distributed in the EU as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection.

    Arm title
    		 Cohort 1b
    Arm description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melflufen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Melflufen at a starting dose of 30 mg administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter. Melflufen was distributed in the EU as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection.

    Arm title
    		 Cohort 2a
    Arm description
    		 Patients with severe renal impairment (eGFR of ≥15 to <30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melflufen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Melflufen at a starting dose of 20 mg administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter. Melflufen was distributed in the EU as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection.

    Number of subjects in period 1
    		Cohort 1a Cohort 1b Cohort 2a
    Started
    21
    10
    4
    Completed
    0
    0
    0
    Not completed
    21
    10
    4
         Physician decision
    3
    1
    -
         Disease progression
    8
    5
    3
         Adverse event
    7
    1
    -
         Study terminated by sponsor
    2
    1
    1
         Patient request to stop treatment
    1
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1a
    Reporting group description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg

    Reporting group title
    Cohort 1b
    Reporting group description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg

    Reporting group title
    Cohort 2a
    Reporting group description
    		 Patients with severe renal impairment (eGFR of ≥15 to <30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg

    Reporting group values
    		 Cohort 1a Cohort 1b Cohort 2a Total
    Number of subjects
    		 21 10 4 35
    Age categorical
    Units: Subjects
        <65 years
    		 4 3 3 10
        ≥65 to ≤75 years
    		 9 5 0 14
        >75 years
    		 8 2 1 11
    Age continuous
    Units: years
        median (full range (min-max))
    		 70.0 (52 to 84) 72.0 (54 to 85) 62.5 (57 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 9 6 1 16
        Male
    		 12 4 3 19
    Race
    Units: Subjects
        Caucasian/White
    		 21 10 4 35
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 21 10 4 35
    Baseline Eastern Cooperative Oncology Group (ECOG)
    Units: Subjects
        Score=0
    		 11 3 3 17
        Score=1
    		 8 6 1 15
        Score=2
    		 2 1 0 3
    International Staging System (ISS) stage at study entry
    Units: Subjects
        Stage I
    		 2 0 0 2
        Stage II
    		 9 4 1 14
        Stage III
    		 9 6 3 18
        Unknown
    		 1 0 0 1
    Evidence of lytic bone disease at study entry
    Units: Subjects
        Yes
    		 16 9 4 29
        No
    		 5 1 0 6
    Evidence of extramedullary disease at study entry
    Units: Subjects
        Yes
    		 1 1 1 3
        No
    		 20 9 3 32
    Disease status at study entry
    Units: Subjects
        Relapsed
    		 13 3 2 18
        Relapsed-refractory
    		 8 7 2 17
    Prior autologous transplants
    Units: Subjects
        At least 1 prior autologous transplant
    		 9 1 1 11
        No prior autologous transplant
    		 12 9 3 24
    Number of prior systemic therapy lines
    There was one patient who reported 2 prior line of therapies but only one of them was multiple myeloma therapy. However, this exception was not reflected in the database since a minimum of 2 lines were possible to report. Although this patient was enrolled into the study incorrectly, the patient was not excluded from analyses.
    Units: Subjects
        2 prior lines of therapy
    		 5 6 2 13
        3 prior lines of therapy
    		 7 2 1 10
        4 prior lines of therapy
    		 9 2 1 12
    Baseline estimated glomerular filtration rate (eGFR)
    Note that eligibility was based on eGFR measured at Screening, while Baseline measurements are from Cycle 1 Day 1. For some patients, the eGFR value was derived using CKD-EPI formula when eGFR was not reported but the corresponding visit serum creatinine value was available.
    Units: Subjects
        ≥15 to <30 mL/min/1.73m²
    		 0 2 4 6
        ≥30 to <45 mL/min/1.73m²
    		 19 8 0 27
        ≥45 mL/min/1.73m²
    		 2 0 0 2
    Cytogenetics abnormalities identified by iFISH at study entry
    High-risk based on interphase fluorescence in situ hybridization (iFISH) is defined in case the following abnormalities were found: deletion (17p), gain 1q (+1q), gain (1q21); t (4;14), t(4;14) (p16;q32), t (14;16), t (14;16) (q32;q23), t(14;20), t(14;20) (q32;q11). Standard-risk based on iFISH consists of patients who have a genetic subtype recorded but none of the genetic subtypes categorized as high-risk based on iFISH. The category of unknown consists of patients for whom the iFISH procedure was not done or unevaluable.
    Units: Subjects
        High-risk abnormalities
    		 5 5 0 10
        Standard-risk abnormalities
    		 16 4 3 23
        Unknown
    		 0 0 1 1
        Missing
    		 0 1 0 1
    Baseline height
    Units: cm
        median (full range (min-max))
    		 165.0 (147 to 181) 169.0 (155 to 189) 172.5 (167 to 180) -
    Baseline weight
    Units: kg
        median (full range (min-max))
    		 73.0 (57.3 to 132.0) 75.25 (54.0 to 140.0) 85.50 (73.0 to 110.0) -
    Time since diagnosis
    Units: years
        median (full range (min-max))
    		 6.47 (1.1 to 11.1) 3.82 (0.9 to 8.0) 5.13 (1.6 to 7.7) -
    Time since most recent relapse/progression
    Units: months
        median (full range (min-max))
    		 1.12 (0.5 to 9.8) 1.49 (0.6 to 5.8) 3.29 (0.9 to 9.3) -
    Subject analysis sets

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set is defined as all patients who received at least 1 or partial dose of melflufen or dexamethasone.

    Subject analysis sets values
    		 Safety Analysis Set
    Number of subjects
    35
    Age categorical
    Units: Subjects
        <65 years
    10
        ≥65 to ≤75 years
    14
        >75 years
    11
    Age continuous
    Units: years
        median (full range (min-max))
    70.0 (52 to 85)
    Gender categorical
    Units: Subjects
        Female
    16
        Male
    19
    Race
    Units: Subjects
        Caucasian/White
    35
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    35
    Baseline Eastern Cooperative Oncology Group (ECOG)
    Units: Subjects
        Score=0
    17
        Score=1
    15
        Score=2
    3
    International Staging System (ISS) stage at study entry
    Units: Subjects
        Stage I
    2
        Stage II
    14
        Stage III
    18
        Unknown
    1
    Evidence of lytic bone disease at study entry
    Units: Subjects
        Yes
    29
        No
    6
    Evidence of extramedullary disease at study entry
    Units: Subjects
        Yes
    3
        No
    32
    Disease status at study entry
    Units: Subjects
        Relapsed
    18
        Relapsed-refractory
    17
    Prior autologous transplants
    Units: Subjects
        At least 1 prior autologous transplant
    11
        No prior autologous transplant
    24
    Number of prior systemic therapy lines
    There was one patient who reported 2 prior line of therapies but only one of them was multiple myeloma therapy. However, this exception was not reflected in the database since a minimum of 2 lines were possible to report. Although this patient was enrolled into the study incorrectly, the patient was not excluded from analyses.
    Units: Subjects
        2 prior lines of therapy
    13
        3 prior lines of therapy
    10
        4 prior lines of therapy
    12
    Baseline estimated glomerular filtration rate (eGFR)
    Note that eligibility was based on eGFR measured at Screening, while Baseline measurements are from Cycle 1 Day 1. For some patients, the eGFR value was derived using CKD-EPI formula when eGFR was not reported but the corresponding visit serum creatinine value was available.
    Units: Subjects
        ≥15 to <30 mL/min/1.73m²
    6
        ≥30 to <45 mL/min/1.73m²
    27
        ≥45 mL/min/1.73m²
    2
    Cytogenetics abnormalities identified by iFISH at study entry
    High-risk based on interphase fluorescence in situ hybridization (iFISH) is defined in case the following abnormalities were found: deletion (17p), gain 1q (+1q), gain (1q21); t (4;14), t(4;14) (p16;q32), t (14;16), t (14;16) (q32;q23), t(14;20), t(14;20) (q32;q11). Standard-risk based on iFISH consists of patients who have a genetic subtype recorded but none of the genetic subtypes categorized as high-risk based on iFISH. The category of unknown consists of patients for whom the iFISH procedure was not done or unevaluable.
    Units: Subjects
        High-risk abnormalities
    10
        Standard-risk abnormalities
    23
        Unknown
    1
        Missing
    1
    Baseline height
    Units: cm
        median (full range (min-max))
    168.0 (147 to 189)
    Baseline weight
    Units: kg
        median (full range (min-max))
    74.00 (54.0 to 140.0)
    Time since diagnosis
    Units: years
        median (full range (min-max))
    4.78 (0.9 to 11.1)
    Time since most recent relapse/progression
    Units: months
        median (full range (min-max))
    1.25 (0.5 to 9.8)

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1a
    Reporting group description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg

    Reporting group title
    Cohort 1b
    Reporting group description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg

    Reporting group title
    Cohort 2a
    Reporting group description
    		 Patients with severe renal impairment (eGFR of ≥15 to <30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set is defined as all patients who received at least 1 or partial dose of melflufen or dexamethasone.

    Primary: Maximum observed concentration (Cmax) of melphalan

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    End point title
    		 Maximum observed concentration (Cmax) of melphalan [1]
    End point description
    End point type
    Primary
    End point timeframe
    Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
    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: Only results based on non-compartmental method are available. An updated population PK analysis, including subjects from this study together with PK data from other studies with melflufen, will be reported separately in a population PK report.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    13 [2]
    6 [3]
    4 [4]
    22 [5]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1
    550.1538 ( 170.024 )
    472.2000 ( 141.505 )
    181.2500 ( 76.098 )
    465.3636 ( 202.478 )
        Cycle 2
    539.4444 ( 178.246 )
    469.5000 ( 177.340 )
    194.0000 ( 57.663 )
    458.5556 ( 201.121 )
    Notes
    [2] - 13 subjects in Cycle 1; 9 subjects in Cycle 2
    [3] - 5 subjects in Cycle 1; 6 subjects in Cycle 2
    [4] - 4 subjects in Cycle 1; 3 subjects in Cycle 2
    [5] - 22 subjects in Cycle 1; 18 subjects in Cycle 2
    No statistical analyses for this end point

    Primary: Time of maximum observed concentration (Tmax) of melphalan

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    End point title
    		 Time of maximum observed concentration (Tmax) of melphalan [6]
    End point description
    End point type
    Primary
    End point timeframe
    Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
    Notes
    [6] - 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: Only results based on non-compartmental method are available. An updated population PK analysis, including subjects from this study together with PK data from other studies with melflufen, will be reported separately in a population PK report.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    13 [7]
    6 [8]
    4 [9]
    22 [10]
    Units: minutes
    median (full range (min-max))
        Cycle 1
    38.0000 (35.0000 to 40.0000)
    40.0000 (35.0000 to 45.0000)
    37.0000 (36.0000 to 40.0000)
    37.5000 (35.0000 to 45.0000)
        Cycle 2
    37.0000 (35.0000 to 40.0000)
    40.0000 (38.0000 to 40.0000)
    36.0000 (35.0000 to 37.0000)
    38.5000 (35.0000 to 40.0000)
    Notes
    [7] - 13 subjects in Cycle 1; 9 subjects in Cycle 2
    [8] - 5 subjects in Cycle 1; 6 subjects in Cycle 2
    [9] - 4 subjects in Cycle 1; 3 subjects in Cycle 2
    [10] - 22 subjects in Cycle 1; 18 subjects in Cycle 2
    No statistical analyses for this end point

    Primary: Area under the curve (from 0 hours to the last measurable concentration) of melphalan

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    End point title
    		 Area under the curve (from 0 hours to the last measurable concentration) of melphalan [11]
    End point description
    AUC(0-t) is the area under the concentration-time curve from 0 hours to the last measurable concentration.
    End point type
    Primary
    End point timeframe
    Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
    Notes
    [11] - 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: Only results based on non-compartmental method are available. An updated population PK analysis, including subjects from this study together with PK data from other studies with melflufen, will be reported separately in a population PK report.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    13 [12]
    6 [13]
    4 [14]
    22 [15]
    Units: minutes*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1
    78250.3462 ( 21391.384 )
    70303.4400 ( 16874.787 )
    27912.7125 ( 10385.219 )
    67291.9341 ( 26514.196 )
        Cycle 2
    74415.5556 ( 21354.648 )
    67458.0000 ( 19241.040 )
    32146.0000 ( 5804.816 )
    65051.4444 ( 23811.614 )
    Notes
    [12] - 13 subjects in Cycle 1; 9 subjects in Cycle 2
    [13] - 5 subjects in Cycle 1; 6 subjects in Cycle 2
    [14] - 4 subjects in Cycle 1; 3 subjects in Cycle 2
    [15] - 22 subjects in Cycle 1; 18 subjects in Cycle 2
    No statistical analyses for this end point

    Primary: Area under the curve (from 0 hours to infinity) of melphalan

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    End point title
    		 Area under the curve (from 0 hours to infinity) of melphalan [16]
    End point description
    AUCinf is the area under the concentration-time profile from 0 hours to infinity.
    End point type
    Primary
    End point timeframe
    Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
    Notes
    [16] - 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: Only results based on non-compartmental method are available. An updated population PK analysis, including subjects from this study together with PK data from other studies with melflufen, will be reported separately in a population PK report.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    13 [17]
    6 [18]
    4 [19]
    22 [20]
    Units: minutes*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1
    85123.3635 ( 22765.646 )
    77173.0689 ( 15347.431 )
    31712.9042 ( 11597.404 )
    73605.4857 ( 27922.649 )
        Cycle 2
    80365.5468 ( 22334.049 )
    72830.2410 ( 20632.358 )
    39685.8277 ( 6405.267 )
    71073.8250 ( 24195.476 )
    Notes
    [17] - 13 subjects in Cycle 1; 9 subjects in Cycle 2
    [18] - 5 subjects in Cycle 1; 6 subjects in Cycle 2
    [19] - 4 subjects in Cycle 1; 3 subjects in Cycle 2
    [20] - 22 subjects in Cycle 1; 18 subjects in Cycle 2
    No statistical analyses for this end point

    Primary: Elimination half-life of melphalan

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    End point title
    		 Elimination half-life of melphalan [21]
    End point description
    End point type
    Primary
    End point timeframe
    Samples were collected 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
    Notes
    [21] - 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: Only results based on non-compartmental method are available. An updated population PK analysis, including subjects from this study together with PK data from other studies with melflufen, will be reported separately in a population PK report.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    13 [22]
    6 [23]
    4 [24]
    22 [25]
    Units: minutes
    arithmetic mean (standard deviation)
        Cycle 1
    89.1390 ( 15.575 )
    98.3568 ( 27.249 )
    109.5502 ( 22.221 )
    94.9451 ( 20.368 )
        Cycle 2
    87.5544 ( 15.860 )
    90.7844 ( 14.411 )
    136.2193 ( 13.679 )
    96.7419 ( 23.102 )
    Notes
    [22] - 13 subjects in Cycle 1; 9 subjects in Cycle 2
    [23] - 5 subjects in Cycle 1; 6 subjects in Cycle 2
    [24] - 4 subjects in Cycle 1; 3 subjects in Cycle 2
    [25] - 22 subjects in Cycle 1; 18 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Overall response rate

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    End point title
    		 Overall response rate
    End point description
    Overall response rate (ORR) is the proportion of patients who achieved a confirmed response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as best response, as assessed by the Investigator.
    End point type
    Secondary
    End point timeframe
    Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    21
    10
    4
    35
    Units: subjects
    10
    7
    1
    18
    No statistical analyses for this end point

    Secondary: Clinical benefit rate

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    End point title
    		 Clinical benefit rate
    End point description
    Clinical benefit rate (CBR) is the proportion of patients who achieved a confirmed minimal response (MR) or better (sCR [stringent complete response], CR [complete response], VGPR [very good partial response], PR [partial response], and MR [minimal response]) as their best response, as assessed by the Investigator.
    End point type
    Secondary
    End point timeframe
    Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    21
    10
    4
    35
    Units: subjects
    11
    8
    1
    20
    No statistical analyses for this end point

    Secondary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression-free survival (PFS) is defined as the time in months from initiation of therapy to the earlier of confirmed disease progression or death due to any cause. Patients were deemed ‘progressed’ in case of i) unconfirmed progressive disease (PD) as the final response assessment, ii) death after at least one response assessment or PD based on at least two consecutive response assessments at any time, or iii) death before the first response assessment. The distribution of PFS was summarized using the Kaplan-Meier (K-M) method. The median PFS was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median PFS was constructed using the method of Brookmeyer (Brookmeyer, 1982). (99999 = not estimable)
    End point type
    Secondary
    End point timeframe
    Patients were assessed from the first dose of study drug until confirmed disease progression, initiation of subsequent therapy or death, whichever comes first.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    15
    6
    3
    24
    Units: months
        median (confidence interval 95%)
    8.61 (4.30 to 14.52)
    7.66 (6.24 to 99999)
    3.43 (0.95 to 99999)
    7.66 (4.73 to 14.52)
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Duration of response (DOR) is defined as the time from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) to first confirmed disease progression, or to death due to any cause. The distribution of DOR was summarized using the Kaplan-Meier (K-M) method. The median DOR was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOR was constructed using the method of Brookmeyer (Brookmeyer, 1982). (99999 = not estimable)
    End point type
    Secondary
    End point timeframe
    Patients were assessed for response from the first measure of a confirmed response (PR or better) until confirmed progression, death, or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    10
    7
    1
    18
    Units: months
        median (confidence interval 95%)
    8.31 (5.82 to 23.49)
    13.83 (4.63 to 99999)
    99999 (99999 to 99999)
    13.83 (5.78 to 23.49)
    No statistical analyses for this end point

    Secondary: Duration of clinical benefit

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    End point title
    		 Duration of clinical benefit
    End point description
    Duration of clinical benefit (DOCB) was calculated as time in months from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) to first confirmed disease progression, or to death due to any cause. DOCB was defined only for patients with a confirmed MR or better. DOCB was summarized using the Kaplan-Meier (K-M) method. The median DOCB was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOCB was constructed using the method of Brookmeyer (Brookmeyer, 1982). (99999 = not estimable)
    End point type
    Secondary
    End point timeframe
    Patients were assessed from the first measure of a confirmed MR or better until confirmed progression, death, or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    11
    8
    1
    20
    Units: months
        median (confidence interval 95%)
    9.26 (5.82 to 23.49)
    10.58 (4.63 to 99999)
    99999 (99999 to 99999)
    9.26 (5.78 to 23.49)
    No statistical analyses for this end point

    Secondary: Time to response

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    End point title
    		 Time to response
    End point description
    Time from first dose of therapy to first documented confirmed response of partial response (PR) or better.
    End point type
    Secondary
    End point timeframe
    Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    10
    7
    1
    18
    Units: months
        median (full range (min-max))
    2.45 (1.0 to 11.3)
    1.18 (0.9 to 7.6)
    2.83 (2.83 to 2.83)
    2.45 (0.9 to 11.3)
    No statistical analyses for this end point

    Secondary: Time to clinical benefit

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    End point title
    		 Time to clinical benefit
    End point description
    Time to clinical benefit was defined as the time from first dose of therapy to first documented confirmed response of minimal response (MR) or better.
    End point type
    Secondary
    End point timeframe
    Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    11
    8
    1
    20
    Units: months
        median (full range (min-max))
    1.12 (1.0 to 8.7)
    1.12 (0.9 to 5.9)
    2.83 (2.83 to 2.83)
    1.15 (0.9 to 8.7)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was defined as the time in months from initiation of therapy to death due to any cause. Patients still alive at the end of the study, or lost to follow up, were censored at last day known alive. (99999 = not estimable)
    End point type
    Secondary
    End point timeframe
    Patients were followed for overall survival until death or until the last patient in the study had documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Safety Analysis Set
    Number of subjects analysed
    21
    10
    4
    35
    Units: months
        median (confidence interval 95%)
    9.76 (5.06 to 15.38)
    99999 (6.83 to 99999)
    99999 (3.15 to 99999)
    10.18 (6.31 to 99999)
    No statistical analyses for this end point

    Secondary: Best confirmed response

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    End point title
    		 Best confirmed response
    End point description
    Best confirmed response required 2 consecutive assessments with the same response result made at any time. In case at the second consecutive assessment (made at any time) the response is higher than the previous one, then confirmed response (linked to the first assessment visit) will be the first one (e.g., PR – VGPR consecutive pair will lead to a PR confirmed response at the first visit). In case the second consecutive response is lower than the first one, then confirmed response (linked to the first assessment visit) will be the second one (e.g. CR-VGPR consecutive pair will lead to a VGPR confirmed response at the first visit).
    End point type
    Secondary
    End point timeframe
    Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a
    Number of subjects analysed
    21
    10
    4
    Units: subjects
        Stringent complete response (sCR)
    0
    0
    0
        Complete response (CR)
    0
    2
    0
        Very good partial response (VGPR)
    3
    1
    0
        Partial response (PR)
    7
    4
    1
        Minimal response (MR)
    1
    1
    0
        Stable disease (SD)
    5
    2
    0
        Progressive disease (PD)
    2
    0
    3
        Non-evaluable
    3
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious adverse events (AEs) were reported from the first dose of study drug until 30 days after the last dose of study drug, or until the start of subsequent anticancer therapy (whichever occurred first).
    Adverse event reporting additional description
    Serious adverse events (SAEs) were to be reported from when the patient signed informed consent until 30 days after the last administration of any study drug. SAEs considered by the investigator to be treatment-related were reported also if they occurred later than 30 days after the last administration of any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Cohort 1a
    Reporting group description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg

    Reporting group title
    Cohort 1b
    Reporting group description
    		 Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg

    Reporting group title
    Cohort 2a
    Reporting group description
    		 Patients with severe renal impairment (eGFR of ≥15 to <30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg

    Serious adverse events
    		 Cohort 1a Cohort 1b Cohort 2a
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 21 (42.86%)
    5 / 10 (50.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    16
    3
    1
         number of deaths resulting from adverse events
    3
    1
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Product issues
    Device issue
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1a Cohort 1b Cohort 2a
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 21 (95.24%)
    10 / 10 (100.00%)
    3 / 4 (75.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 10 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Paraesthesia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    14 / 21 (66.67%)
    9 / 10 (90.00%)
    2 / 4 (50.00%)
         occurrences all number
    79
    42
    2
    Neutropenia
         subjects affected / exposed
    8 / 21 (38.10%)
    5 / 10 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    42
    17
    0
    Anaemia
         subjects affected / exposed
    7 / 21 (33.33%)
    4 / 10 (40.00%)
    1 / 4 (25.00%)
         occurrences all number
    31
    14
    1
    Leukopenia
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    4
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 10 (10.00%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    1
    Vomiting
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 10 (10.00%)
    1 / 4 (25.00%)
         occurrences all number
    5
    1
    1
    Nausea
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 10 (30.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    6
    0
    Oesophagitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Incontinence
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 21 (23.81%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    6
    0
    1
    Arthralgia
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Spinal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Spondyloarthropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 10 (40.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    6
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    3
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngitis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Myringitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Otosalpingitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2018
    * Addition of a potential Cohort 2 of at least 6 patients with severe renal impairment to further evaluate melflufen in this patient population * Change of the patient population to 2 - 4 prior lines of therapy * Change of the method of estimation of creatinine clearance (CrCl) * Addition of an alternate method of drug preparation of melflufen, to allow for dilution with saline to increase the time from drug reconstitution to start of infusion
    26 Sep 2019
    * The study will be divided into three cohorts; 1a, 1b and 2. To evaluate 30 mg of melflufen as starting dose in Cohort 1 (eGFR of ≥30 ml/min to <45 mL/min). There will be two groups of patients in Cohort 1; 1a that received 40 mg of melflufen as starting dose, and 1b that will receive 30 mg as starting dose. Cohort 1a will close for enrolment following approval of amendment 2. * The starting dose for Cohort 2 will be decided following evaluation of data from Cohort 1a and 1b and after recommendations by DSMC.
    26 Mar 2020
    * Reduced the number of patient visits to mitigate COVID-19-related patient risks. * Updated planned number of the subjects to be included. The rationale of this increase was a target of 25 PK-evaluable patients, and therefore 35-40 patients in total needed to be enrolled as not all patients are PK evaluable.
    22 Jan 2021
    *An interim analysis for an interim clinical study report (iCSR), to conclude the results from Cohort 1, has been included in the protocol. * Cohort 2 will consist of two groups (2a and 2b) and as more cohorts are added, the number of PK-evaluable patients have increased from 25 to approximately 35. * The DSMC-confirmed starting dose for Cohort 2a of 20 mg melflufen has been added, including dose reductions steps for this cohort. Furthermore Cohort 2b will only open if recommended by DSMC after evaluating data from Cohort 1a, 1b and Cohort 2a.
    30 Apr 2021
    The protocol has been updated with changes to inclusion criteria 3 and 10. The upper limits of allowed prior lines have been removed and a wider eGFR window allowed for patients to proceed from Screening 1 to Screening 2 has been updated in this version of the protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Jul 2021
    The head-to-head phase 3 OCEAN study evaluated the efficacy and safety of melflufen plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed refractory multiple myeloma who have received 2 – 4 prior lines of therapy. Based on the observed large differences in overall survival in pre-specified subgroups in the OCEAN study, the US Food and Drug Administration requested a partial clinical hold of all clinical studies with melflufen.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Between-group comparisons were not performed in this study due the small number of patients in each cohort, as well as differences with regards to some baseline characteristics.
    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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