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    Clinical Trial Results:
    A randomized, two-period, cross-over, Phase 2 study, comparing the pharmacokinetics, and assessing safety and tolerability of peripheral and central intravenous administration of melflufen in patients with relapsed and refractory multiple myeloma.

    Summary
    EudraCT number
    		 2019-004127-21
    Trial protocol
    		 HU   BG   CZ  
    Global end of trial date
    10 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Mar 2023
    First version publication date
    09 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OP-109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04412707
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oncopeptides AB
    Sponsor organisation address
    Västra Trädgårdsgatan 15 SE-111 53, Stockholm, Sweden,
    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
    14 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    - To evaluate and compare the pharmacokinetic (PK) variables Cmax, AUC(0-t) and AUC(0-∞) of melphalan after central and peripheral intravenous infusion of melflufen. - To assess the local tolerability of peripheral intravenous administration of melflufen
    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 was to be given PO at the standard dose of 40 mg weekly, at Days 1, 8, 15, and 22. Patients ≥75 years of age were to receive a dose of dexamethasone PO of 20 mg weekly.
    Evidence for comparator
    		 not applicable
    Actual start date of recruitment
    22 Jun 2020
    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
    Bulgaria: 7
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Ukraine: 5
    Worldwide total number of subjects
    27
    EEA total number of subjects
    22
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    12
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient received their first dose of study drug on 04 August 2020. The last patient received their first dose of study drug on 05 April 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; adequate peripheral arm veins; life expectancy of at least 6 months; ECOG <=2; adequate organ function based on lab results; have had or be willing to get CVC and PVC.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC.
    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
    In Cycle 1, melflufen 40 mg was administered as a 30-minute infusion via PVC. From Cycle 2 onwards, melflufen was administered as a 30-minute infusion via CVC

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was given PO at the standard dose of 40 mg weekly, at Days 1, 8, 15, and 22. Patients ≥75 years of age received a dose of dexamethasone PO of 20 mg weekly

    Arm title
    		 Arm B
    Arm description
    		 Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC.
    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
    In Cycle 1, melflufen 40 mg was administered as a 30-minute infusion via CVC. At Cycle 2, melflufen was administered as a 30-minute infusion via PVC. From Cycle 3 onwards, melflufen was to be administered as a 30-minute infusion via a CVC.

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was given PO at the standard dose of 40 mg weekly, at Days 1, 8, 15, and 22. Patients ≥75 years of age received a dose of dexamethasone PO of 20 mg weekly

    Number of subjects in period 1
    		Arm A Arm B
    Started
    14
    13
    Completed
    0
    0
    Not completed
    14
    13
         Adverse event, serious fatal
    -
    1
         patient request
    1
    -
         Adverse event, non-fatal
    1
    3
         physician decision
    -
    1
         study terminated by sponsor
    3
    2
         disease progression
    9
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC.

    Reporting group title
    Arm B
    Reporting group description
    		 Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC.

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 14 13 27
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 8 4 12
        From 65-84 years
    		 6 9 15
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 60.5 (44 to 76) 72.0 (47 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7 14
        Male
    		 7 6 13
    Race
    Units: Subjects
        Caucasian/White
    		 14 13 27
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 13 13 26
        Not reported
    		 1 0 1
    Baseline ECOG
    Units: Subjects
        Score=0
    		 4 4 8
        Score=1
    		 10 8 18
        Score=2
    		 0 1 1
    Derived International Staging System (ISS) at study entry
    Units: Subjects
        Stage I
    		 5 4 9
        Stage II
    		 6 6 12
        Stage III
    		 2 3 5
        Missing
    		 1 0 1
    Derived Revised International Staging System (R-ISS) at study entry
    Units: Subjects
        R-I
    		 2 2 4
        R-II
    		 10 9 19
        R-III
    		 0 1 1
        Missing
    		 2 1 3
    Evidence of lytic bone disease at study entry
    Units: Subjects
        yes
    		 14 12 26
        no
    		 0 1 1
    Evidence of extramedullary disease at study entry
    Units: Subjects
        yes
    		 2 0 2
        no
    		 12 13 25
    Refractory status to the last prior systemic therapy
    Units: Subjects
        Refractory
    		 12 13 25
        Not refractory
    		 1 0 1
        Unknown
    		 1 0 1
    Prior autologous transplants
    Units: Subjects
        at least 1 prior autologous transplant
    		 5 4 9
        at least 2 prior autologous transplants
    		 0 2 2
        no prior autologous transplants
    		 9 7 16
    Number of prior systemic lines
    Units: Subjects
        2 prior lines of therapy
    		 5 1 6
        3 prior lines of therapy
    		 2 2 4
        4 prior lines of therapy
    		 1 6 7
        5 prior lines of therapy
    		 1 1 2
        6 prior lines of therapy
    		 0 2 2
        7 prior lines of therapy
    		 2 1 3
        8 prior lines of therapy
    		 2 0 2
        10 prior lines of therapy
    		 1 0 1
    Cytogenetic 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 consisted of patients who have a genetic subtype recorded but none of the genetic subtypes categorized as high-risk. Unknown: consists of patients for whom the iFISH procedure was not done or unevaluable.
    Units: Subjects
        High-risk
    		 0 5 5
        Standard-risk
    		 4 0 4
        Unknown
    		 10 8 18
    Baseline weight
    Units: kg
        median (full range (min-max))
    		 80.6 (46.0 to 103.5) 72.0 (52.0 to 82.0) -
    Baseline height
    Units: cm
        median (full range (min-max))
    		 165.0 (156 to 188) 167.0 (150 to 190) -
    Time since diagnosis
    Units: years
        median (full range (min-max))
    		 3.49 (2.1 to 15.1) 5.65 (1.0 to 8.6) -
    Time since most recent relapse/progression
    Units: months
        median (full range (min-max))
    		 1.71 (0.5 to 4.3) 2.37 (0.5 to 5.5) -
    Subject analysis sets

    Subject analysis set title
    PVC
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a PVC and Cycle 2 will be administered via a CVC. From Cycle 3 and onwards melflufen will be administered via CVC.

    Subject analysis set title
    CVC
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a Central Venous Catheter (CVC) and cycle 2 will be administered via a Peripheral Venous Catheter (PVC). From cycle 3 and onwards melflufen will be administered via CVC.

    Subject analysis sets values
    		 PVC CVC
    Number of subjects
    14
    13
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    8
    4
        From 65-84 years
    6
    9
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    60.5 (44 to 76)
    72.0 (47 to 80)
    Gender categorical
    Units: Subjects
        Female
    7
    7
        Male
    7
    6
    Race
    Units: Subjects
        Caucasian/White
    14
    13
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    13
    13
        Not reported
    1
    0
    Baseline ECOG
    Units: Subjects
        Score=0
    4
    4
        Score=1
    10
    8
        Score=2
    0
    1
    Derived International Staging System (ISS) at study entry
    Units: Subjects
        Stage I
    5
    4
        Stage II
    6
    6
        Stage III
    2
    3
        Missing
    1
    0
    Derived Revised International Staging System (R-ISS) at study entry
    Units: Subjects
        R-I
    2
    2
        R-II
    10
    9
        R-III
    0
    1
        Missing
    2
    1
    Evidence of lytic bone disease at study entry
    Units: Subjects
        yes
    14
    12
        no
    0
    1
    Evidence of extramedullary disease at study entry
    Units: Subjects
        yes
    2
    0
        no
    12
    13
    Refractory status to the last prior systemic therapy
    Units: Subjects
        Refractory
    12
    13
        Not refractory
    1
    0
        Unknown
    1
    0
    Prior autologous transplants
    Units: Subjects
        at least 1 prior autologous transplant
    5
    4
        at least 2 prior autologous transplants
    0
    2
        no prior autologous transplants
    9
    7
    Number of prior systemic lines
    Units: Subjects
        2 prior lines of therapy
    5
    1
        3 prior lines of therapy
    2
    2
        4 prior lines of therapy
    1
    6
        5 prior lines of therapy
    1
    1
        6 prior lines of therapy
    0
    2
        7 prior lines of therapy
    2
    1
        8 prior lines of therapy
    2
    0
        10 prior lines of therapy
    1
    0
    Cytogenetic 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 consisted of patients who have a genetic subtype recorded but none of the genetic subtypes categorized as high-risk. Unknown: consists of patients for whom the iFISH procedure was not done or unevaluable.
    Units: Subjects
        High-risk
    0
    5
        Standard-risk
    4
    0
        Unknown
    10
    8
    Baseline weight
    Units: kg
        median (full range (min-max))
    80.6 (46.0 to 103.5)
    72.0 (52.0 to 82.0)
    Baseline height
    Units: cm
        median (full range (min-max))
    165.0 (156 to 188)
    167.0 (150 to 190)
    Time since diagnosis
    Units: years
        median (full range (min-max))
    3.49 (2.1 to 15.1)
    5.65 (1.0 to 8.6)
    Time since most recent relapse/progression
    Units: months
        median (full range (min-max))
    1.71 (0.5 to 4.3)
    2.37 (0.5 to 5.5)

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC.

    Reporting group title
    Arm B
    Reporting group description
    		 Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC.

    Subject analysis set title
    PVC
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a PVC and Cycle 2 will be administered via a CVC. From Cycle 3 and onwards melflufen will be administered via CVC.

    Subject analysis set title
    CVC
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a Central Venous Catheter (CVC) and cycle 2 will be administered via a Peripheral Venous Catheter (PVC). From cycle 3 and onwards melflufen will be administered via CVC.

    Primary: Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan

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    End point title
    		 Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan
    End point description
    To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    8 [1]
    13 [2]
    Units: min x ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    49518.36 ± 23.71
    59543.2 ± 17.698
        Cycle 2
    60273.95 ± 30.037
    46173.13 ± 43.336
    Notes
    [1] - 12 subjects in Cycle 1, 8 subjects in Cycle 2
    [2] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    Statistical analysis title
    		 Statistical Analysis 1 for AUC(0-t) of melphalan
    Statistical analysis description
    Based on a geometric mean ratio (GMR) peripheral vs. central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.
    Comparison groups
    PVC v CVC
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 adjusted GMR
    Point estimate
    0.952
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.861
         upper limit
    		 1.053
    Notes
    [3] - The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25.

    Primary: Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan

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    End point title
    		 Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan
    End point description
    To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    8 [4]
    13 [5]
    Units: min x ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    54216.7 ± 23.794
    66835.47 ± 18.171
        Cycle 2
    67403.07 ± 30.149
    50835.59 ± 44.728
    Notes
    [4] - 12 subjects in Cycle 1, 8 subjects in Cycle 2
    [5] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    Statistical analysis title
    		 GMR of AUC(0-inf) of melphalan
    Comparison groups
    PVC v CVC
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 geometric mean ratio
    Point estimate
    0.955
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.863
         upper limit
    		 1.058
    Variability estimate
    Standard deviation

    Primary: Peak plasma concentration for melphalan

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    End point title
    		 Peak plasma concentration for melphalan
    End point description
    To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    8 [6]
    13 [7]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Geometric mean
    486.1 ± 21.34
    530.1 ± 25.23
        Cycle 2 geometric mean
    546.3 ± 31.83
    449.2 ± 40.66
    Notes
    [6] - 12 subjects in Cycle 1, 8 subjects in Cycle 2
    [7] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    Statistical analysis title
    		 GMR of maximum observed concentration of melphalan
    Comparison groups
    PVC v CVC
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 geometric mean ratio
    Point estimate
    0.946
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.849
         upper limit
    		 1.053
    Variability estimate
    Standard deviation

    Secondary: Area under the plasma concentration vs time curve of melflufen (0-t)

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    End point title
    		 Area under the plasma concentration vs time curve of melflufen (0-t)
    End point description
    To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melflufen after central and peripheral intravenous infusion of melflufen
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [8]
    8 [9]
    Units: min x ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    3617.03 ± 52.244
    2828.69 ± 51.646
        Cycle 2
    3083.74 ± 80.639
    3078.21 ± 49.443
    Notes
    [8] - 11 subjects in Cycle 1, 7 subjects in Cycle 2
    [9] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration vs time curve of melflufen (0-inf)

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    End point title
    		 Area under the plasma concentration vs time curve of melflufen (0-inf)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [10]
    8 [11]
    Units: min x ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    3639.34 ± 52.379
    2841.23 ± 51.632
        Cycle 2
    3099.7 ± 80.708
    3093.96 ± 49.295
    Notes
    [10] - 11 subjects in Cycle 1, 7 subjects in Cycle 2
    [11] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Peak plasma concentration for melflufen

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    End point title
    		 Peak plasma concentration for melflufen
    End point description
    To evaluate and compare the pharmacokinetic (PK) variable Cmax of melflufen after central and peripheral intravenous infusion of melflufen.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle). 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.
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [12]
    8 [13]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    151.11 ± 59.74
    123.0 ± 47.498
        Cycle 2
    127.27 ± 75.872
    141.75 ± 47.921
    Notes
    [12] - 11 subjects in Cycle 1, 7 subjects in Cycle 2
    [13] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration vs time curve (0-t) of desethyl-melflufen

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    End point title
    		 Area under the plasma concentration vs time curve (0-t) of desethyl-melflufen
    End point description
    To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of desethyl-melflufen after central and peripheral intravenous infusion of melflufen
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [14]
    8 [15]
    Units: min x ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    563.34 ± 42.086
    693.39 ± 34.053
        Cycle 2
    636.06 ± 51.627
    391.11 ± 49.458
    Notes
    [14] - 11 subjects in Cycle 1, 8 subjects in Cycle 2
    [15] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration vs time curve (0-inf) of desethyl-melflufen

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    End point title
    		 Area under the plasma concentration vs time curve (0-inf) of desethyl-melflufen
    End point description
    To evaluate and compare the PK variable AUC(0-inf) of desethyl-melflufen after central and peripheral intravenous infusion of melflufen.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [16]
    8 [17]
    Units: min x ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    609.44 ± 40.778
    759.25 ± 34.619
        Cycle 2
    695.29 ± 51.722
    440.65 ± 43.547
    Notes
    [16] - 11 subjects in Cycle 1, 8 subjects in Cycle 2
    [17] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Peak plasma concentration for desethyl-melflufen

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    End point title
    		 Peak plasma concentration for desethyl-melflufen
    End point description
    To evaluate and compare the pharmacokinetic (PK) variable Cmax of desethyl-melflufen after central and peripheral intravenous infusion of melflufen.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 & Cycle 2 Day 1-13 PK samples during & post infusion. Samples collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; & 5, 10, 15, & 30 minutes & 1, 2 & 4 hr after end of infusion
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [18]
    8 [19]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    16.721 ± 33.2618
    16.352 ± 25.4952
        Cycle 2
    16.801 ± 43.8965
    11.851 ± 41.3587
    Notes
    [18] - 11 subjects in Cycle 1, 8 subjects in Cycle 2
    [19] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Elimination half-life melphalan

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    End point title
    		 Elimination half-life melphalan
    End point description
    To evaluate elimination half-life (t½) for melphalan after central and peripheral intravenous infusion of melflufen.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    12 [20]
    8 [21]
    Units: minutes
    geometric mean (geometric coefficient of variation)
        Cycle 1
    72.51 ± 14.993
    80.09 ± 12.85
        Cycle 2
    78.09 ± 18.118
    72.97 ± 16.840
    Notes
    [20] - 12 subjects in Cycle 1, 8 subjects in Cycle 2
    [21] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Elimination half-life of melflufen

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    End point title
    		 Elimination half-life of melflufen
    End point description
    To evaluate elimination half-life (t½) for melflufen after central and peripheral intravenous infusion of melflufen.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [22]
    8 [23]
    Units: minutes
    geometric mean (geometric coefficient of variation)
        Cycle 1
    7.42 ± 106.832
    4.45 ± 90.634
        Cycle 2
    6.15 ± 81.278
    5.74 ± 80.837
    Notes
    [22] - 11 subjects in Cycle 1, 7 subjects in Cycle 2
    [23] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Elimination half-life of desethyl-melflufen

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    End point title
    		 Elimination half-life of desethyl-melflufen
    End point description
    To evaluate elimination half-life (t½) for desethyl-melflufen after central and peripheral intravenous infusion of melflufen.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
    End point values
    		 PVC CVC
    Number of subjects analysed
    11 [24]
    8 [25]
    Units: minutes
    geometric mean (geometric coefficient of variation)
        Cycle 1
    18.44 ± 49.680
    23.49 ± 43.423
        Cycle 2
    25.04 ± 83.298
    17.43 ± 37.708
    Notes
    [24] - 11 subjects in Cycle 1, 8 subjects in Cycle 2
    [25] - 8 subjects in Cycle 1, 13 subjects in Cycle 2
    No statistical analyses for this end point

    Secondary: Best response

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    End point title
    		 Best response
    End point description
    Two consecutive assessments with the same response result made at any time prior to new therapy initiation. (sCR, CR, VGPR, PR, MR, SD or PD) assessed by the investigator according to IMWG-URC.
    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
    		 Arm A Arm B
    Number of subjects analysed
    14
    13
    Units: patients
        sCR
    0
    0
        CR
    1
    0
        VGPR
    0
    0
        PR
    3
    1
        MR
    4
    1
        SD
    2
    6
        PD
    2
    1
        Not available
    2
    4
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) and clinical benefit rate (CBR)

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    End point title
    		 Overall response rate (ORR) and clinical benefit rate (CBR)
    End point description
    The ORR is estimated as the proportion of patients who achieved a confirmed response (two consecutive assessments) of stringent sCR, CR, VGPR, or PR as their best response. CBR is the proportion of patients who achieved a confirmed response of sCR, CR, VGPR, PR and MR.
    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
    		 Arm A Arm B
    Number of subjects analysed
    14
    13
    Units: patients
        ORR
    4
    1
        CBR
    8
    2
    No statistical analyses for this end point

    Secondary: Number of participants with local reactions including phlebitis at infusion site after peripheral intravenous administration

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    End point title
    		 Number of participants with local reactions including phlebitis at infusion site after peripheral intravenous administration
    End point description
    Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction. Combined treatment ARM for all PVC administration from both Arm A & Arm B during Cycle 1 and 2. Note: this was a primary endpoint; however, no statistical analysis is available since no patients experienced local infusion reactions.
    End point type
    Secondary
    End point timeframe
    15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8
    End point values
    		 PVC CVC
    Number of subjects analysed
    27
    27
    Units: patients
        Cycle 1 Day 1 pre-infusion
    13
    13
        VIP score=0
    13
    13
        Cycle 1 Day 1 post-infusion
    13
    13
        VIP score= 0
    13
    13
        Cycle 1 Day 8
    10
    10
        VIP score =0
    10
    10
        Cycle 2 Day 1 pre-infusion
    8
    8
        VIP score = 0
    8
    8
        Cycle 2 Day 1 post-infusion
    8
    8
        VIP score equals 0
    8
    8
        Cycle 2 Day 8
    7
    7
        VIP score is 0
    7
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: collected from signing of the ICF until 30 days after last dose of study treatment or start of subsequent therapy. Non-serious AEs: collected from the start of study treatment until 30 days after the last dose or start of subsequent therapy
    Adverse event reporting additional description
    Adverse events cannot be compared for Arm A versus Arm B. Due to the crossover design of the study, all patients had a different route of administration in Cycle 2 than Cycle 1; later AEs could be due to a cumulative effect of multiple treatment cycles. Thus, AEs occurring in Cycle 2 and beyond cannot be attributed to only 1 route of administration
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 -

    Reporting group title
    Arm B
    Reporting group description
    		 -

    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A Arm B Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 14 (35.71%)
    9 / 13 (69.23%)
    14 / 27 (51.85%)
         number of deaths (all causes)
    1
    6
    7
         number of deaths resulting from adverse events
    1
    1
    2
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 13 (15.38%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Asymptomatic COVID-19
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 13 (23.08%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pneumonia
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 13 (15.38%)
    4 / 27 (14.81%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         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
    		 Arm A Arm B Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 14 (92.86%)
    13 / 13 (100.00%)
    26 / 27 (96.30%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Vascular pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Fatigue
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 13 (15.38%)
    3 / 27 (11.11%)
         occurrences all number
    2
    2
    4
    General physical health deterioration
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 14 (14.29%)
    3 / 13 (23.08%)
    5 / 27 (18.52%)
         occurrences all number
    2
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 13 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    3
    SARS-CoV-2 test positive
         subjects affected / exposed
    2 / 14 (14.29%)
    4 / 13 (30.77%)
    6 / 27 (22.22%)
         occurrences all number
    2
    4
    6
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Cognitive disorder
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 14 (64.29%)
    7 / 13 (53.85%)
    16 / 27 (59.26%)
         occurrences all number
    16
    12
    28
    Leukopenia
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 13 (7.69%)
    3 / 27 (11.11%)
         occurrences all number
    7
    2
    9
    Lymphopenia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    2
    3
    5
    Neutropenia
         subjects affected / exposed
    9 / 14 (64.29%)
    9 / 13 (69.23%)
    18 / 27 (66.67%)
         occurrences all number
    36
    33
    69
    Thrombocytopenia
         subjects affected / exposed
    10 / 14 (71.43%)
    10 / 13 (76.92%)
    20 / 27 (74.07%)
         occurrences all number
    34
    23
    57
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Dyspepsia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Dysphagia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 13 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    2
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 13 (15.38%)
    3 / 27 (11.11%)
         occurrences all number
    1
    2
    3
    Back pain
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 13 (7.69%)
    3 / 27 (11.11%)
         occurrences all number
    2
    1
    3
    Bone pain
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 13 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    2
    Muscular weakness
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    3
    Infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    2
    Respiratory tract infection
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 13 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    3
    Rhinitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Apr 2020
    Define PK parameters add QoL variables increase number of enrolled patients to approximately 25 and PK evaluable patients to 20 require enrolled patients to be refractory to IMid and PI add CRO Medical Monitor to DSMC define completion of the PK study define duration of treatment add R-ISS stage to MM history collect any SAEs considered related to melflufen or study participation beyond 30 days after the end of study treatment or initiation of subsequent therapy add myeloma response assessment to visits
    23 Dec 2020
    update the text in the synopsis with Melphalan flufenamide (hereinafter referred to as melflufen) update the study schema with correct number of patients in each study arm update and clarify the Schedule of Activities table update the section Melflufen preparation and Administration clarify the study procedures during End of Treatment visit and M protein Response assessment correct the section 8.10 Health outcome and Quality of Life measures on which study visit days the questionnaires are to be completed correct the section 9.4 Interim analyses and section 9.4.1 Data Safety Monitoring Committee clarify in Appendix 2 Clinical Laboratory Tests regarding M protein assessment at Local Lab update the reference list correct typographical and transcription errors

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 Nov 2021
    The study was terminated early by the Sponsor following an FDA-requested partial clinical hold on the melflufen clinical study program.
    -

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