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    Clinical Trial Results:
    A Phase II Study of Plitidepsin in Patients with Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma.

    Summary
    EudraCT number
    2015-001909-14
    Trial protocol
    ES   CZ  
    Global end of trial date
    02 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Aug 2019
    First version publication date
    10 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APL-B-021-13
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03070964
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharma Mar, S.A.
    Sponsor organisation address
    Avenida de los Reyes, 1 Polígono Industrial "La Mina", Colmenar Viejo, Madrid, Spain, 28770
    Public contact
    Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A., 34 91846 60 00, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A., 34 91846 60 00, clinicaltrials@pharmamar.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of plitidepsin on the basis of overall response rate (ORR) in patients with relapsing/refractory angioimmunoblastic T-cell lymphoma (AITL).
    Protection of trial subjects
    The study was in compliance with ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    All patients had to receive the following prophylactic medication 30-60 min before infusion of plitidepsin. • Dexamethasone (8 mg i.v. or equivalent). • Ondansetron (8 mg i.v.) or equivalent (granisetron 3 mg i.v. preferred when available), and • Diphenhydramine hydrochloride (25 mg i.v.) or equivalent, and • Ranitidine (50 mg i.v.) or equivalent. Oral metoclopramide and/or extended oral ondansetron (or their equivalents) could be used as per Investigator’s criteria/institutional guidelines. Additional dexamethasone only could be used as an antiemetic in the event that alternative antiemetics could not be used; and only if the Investigator had considered the options above as insufficient.
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Czech Republic: 1
    Worldwide total number of subjects
    14
    EEA total number of subjects
    13
    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)
    9
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first IC was signed on 25Oct2016 and the first study treatment administration was on 9Nov2016. The cutoff date was 2Jul2018 (date of last follow-up, clinical cutoff). At cutoff date, 14 patients had been included, of whom 13 were treated and evaluable for safety, and 12 were evaluable for the primary efficacy endpoint.

    Pre-assignment
    Screening details
    Age≥18 years;signed IC;ECOG PS≤2;Life expectancy≥3 months;Histologically confirmed diagnosis of R/R AITL;At least a two-week washout period;Adequate bone marrow (BM), renal, hepatic, and metabolic function;LVEF within normal range

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

    Arms
    Arm title
    Plitidepsin
    Arm description
    Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a four-week period. A 1-day window was allowed for plitidepsin administration.
    Arm type
    Experimental

    Investigational medicinal product name
    Plitidepsin
    Investigational medicinal product code
    Plitidepsin
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a four-week period. A 1-day window was allowed for plitidepsin administration.

    Number of subjects in period 1
    Plitidepsin
    Started
    14
    Completed
    0
    Not completed
    14
         Progressive disease
    8
         Treatment-unrelated adverse event
    2
         Never treated
    1
         Physician decision
    1
         Consent withdrawn by subject
    1
         Treatment-related adverse event
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Plitidepsin
    Reporting group description
    Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a four-week period. A 1-day window was allowed for plitidepsin administration.

    Reporting group values
    Plitidepsin Total
    Number of subjects
    14 14
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    9 9
        From 65-84 years
    5 5
    Age continuous
    Units: years
        median (full range (min-max))
    61 (40 to 75) -
    Gender categorical
    Units: Subjects
        Female
    6 6
        Male
    8 8
    Race
    Units: Subjects
        White
    13 13
        Hispanolatin
    1 1
    ECOG PS
    ECOG PS, Eastern Cooperative Oncology Group performance status
    Units: Subjects
        PS 0
    8 8
        PS 1
    5 5
        PS 2
    1 1
    Ann Arbor stage
    Units: Subjects
        III
    1 1
        III-A
    3 3
        III-B
    3 3
        IV-A
    3 3
        IV-B
    4 4
    Extranodal disease at diagnosis
    Units: Subjects
        No
    9 9
        Yes
    5 5
    Bulky lesion at diagnosis
    Units: Subjects
        No
    13 13
        Yes
    1 1
    IPI score at diagnosis
    IPI, international prognostic index
    Units: Subjects
        Low risk (0-1 risk factors)
    2 2
        Low-intermediate risk (2 risk factors)
    2 2
        High-intermediate risk (3 risk factors)
    2 2
        High risk (4-5 risk factors)
    4 4
        NA
    4 4
    PIT at diagnosis
    PIT, prognostic index for peripheral T-cell lymphoma
    Units: Subjects
        Group 1 (no adverse factors)
    1 1
        Group 2 (1 risk factor)
    1 1
        Group 4 (3-4 risk factors)
    2 2
        NA
    10 10
    PIAI score at diagnosis
    PIAI, prognostic index for angioimmunoblastic T-cell lymphoma
    Units: Subjects
        Low-risk group
    3 3
        High-risk group
    3 3
        NA
    8 8
    IPI score at current disease
    IPI, international prognostic index
    Units: Subjects
        Low risk (0-1 risk factors)
    3 3
        Low-intermediate risk (2 risk factors)
    3 3
        High-intermediate risk (3 risk factors)
    4 4
        High risk (4-5 risk factors)
    4 4
    PIT at current disease
    PIT, prognostic index for peripheral T-cell lymphoma
    Units: Subjects
        Group 1 (no adverse factors)
    2 2
        Group 2 (1 risk factor)
    3 3
        Group 3 (2 risk factors)
    1 1
        Group 4 (3-4 risk factors)
    1 1
        NA
    7 7
    PIAI score at current disease
    PIAI, prognostic index for angioimmunoblastic T-cell lymphoma
    Units: Subjects
        Low-risk group
    5 5
        High-risk group
    4 4
        NA
    5 5
    Prior anticancer therapy lines
    Units: Subjects
        1 line
    2 2
        2 lines
    5 5
        3 lines
    5 5
        4 lines
    1 1
        5 lines
    1 1
    Best response to last prior therapy
    CR, complete response; PD, disease progression; PR, partial response; SD, stable disease; UK, unknown
    Units: Subjects
        CR
    4 4
        PR
    4 4
        SD
    1 1
        PD
    3 3
        UK
    2 2
    Prior stem cell transplantation
    Units: Subjects
        No
    8 8
        Allogenic stem cell transplantation
    1 1
        Autologous stem cell transplantation
    5 5
    Weight
    Units: Kg
        median (full range (min-max))
    72.5 (44.7 to 145.0) -
    Height
    Units: cm
        median (full range (min-max))
    166.5 (152 to 190) -
    BSA
    BSA, body surface area
    Units: m2
        median (full range (min-max))
    1.8 (1.4 to 2.8) -
    Time from diagnosis to first plitidepsin infusion
    Units: months
        median (full range (min-max))
    24.1 (8.5 to 200.5) -
    Time from last progressive disease to first infusion
    Units: weeks
        median (full range (min-max))
    6.9 (0.9 to 54.0) -
    Prior anticancer therapy lines
    Units: number
        median (full range (min-max))
    2.5 (1 to 5) -
    TTP to last anticancer therapy
    TTP, time to progressions
    Units: months
        median (full range (min-max))
    4.6 (1.5 to 92.5) -

    End points

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    End points reporting groups
    Reporting group title
    Plitidepsin
    Reporting group description
    Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a four-week period. A 1-day window was allowed for plitidepsin administration.

    Primary: Overall Response Rate by the Lugano Classification per Independent Review Assessment

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    End point title
    Overall Response Rate by the Lugano Classification per Independent Review Assessment [1]
    End point description
    The study protocol established that the analysis of the primary endpoint should have been done once a total of 60 patients have received plitidepsin, with two futility analyses planned after the inclusion of approximately 15 and 30 patients, respectively (see Section 9.5.1.5). However, only a total of 14 patients were included, of whom 13 were treated, and 12 were evaluable for the primary efficacy endpoint (ORR per IRC in the “Per Protocol Patients” population). As a result of slow patient accrual, the study was closed before reaching the target enrollment of 15 patients for the first futility analysis, and the primary endpoint (ORR according to the Lugano classification criteria and per IRC) was not assessed. Overall Response Rate by the Lugano Classification per Independent Review Assessment.
    End point type
    Primary
    End point timeframe
    Overall period
    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: The study was closed before reaching the target enrollment of 15 patients for the first futility analysis, and the primary endpoint (ORR according to the Lugano classification criteria and per IRC) was not assessed.
    End point values
    Plitidepsin
    Number of subjects analysed
    12
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Overall Response Rate by Investigator’s Assessment - Per Protocol Patients Population

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    End point title
    Overall Response Rate by Investigator’s Assessment - Per Protocol Patients Population
    End point description
    CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease. ORR (95% CI) = 16.7% (2.1-48.4%) Clinical benefit rate (CR+PR+SD ≥ 6 months) (95% CI) = 25.0% (5.5-57.2%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    12 [2]
    Units: subjects
        CR
    1
        PR
    1
        SD
    1
        PD
    7
        NE
    2
    Notes
    [2] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation
    No statistical analyses for this end point

    Secondary: Overall Response Rate by Investigator’s Assessment - All Evaluable Patients Population

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    End point title
    Overall Response Rate by Investigator’s Assessment - All Evaluable Patients Population
    End point description
    CI, confidence interval; CR, complete response; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease. ORR (95% CI) = 20.0% (2.5-55.6%) Clinical benefit rate (CR+PR+SD ≥ 6 months) (95% CI) = 30.0% (6.7-65.2%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    10 [3]
    Units: subjects
        CR
    1
        PR
    1
        SD
    1
        PD
    7
    Notes
    [3] - Four patients were not evaluable for efficacy in the “All Evaluable Patients” population
    No statistical analyses for this end point

    Secondary: Overall Response Rate by Investigator’s Assessment - All Treated Patients Population

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    End point title
    Overall Response Rate by Investigator’s Assessment - All Treated Patients Population
    End point description
    CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease. ORR (95% CI) = 15.4% (1.9-45.4%) Clinical benefit rate (CR+PR+SD ≥ 6 months) (95% CI) = 23.1% (5.0-53.8%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    13 [4]
    Units: subjects
        CR
    1
        PR
    1
        SD
    1
        PD
    8
        NE
    2
    Notes
    [4] - 1 patient was never treated
    No statistical analyses for this end point

    Secondary: Complete Remission Rate by Investigator’s Assessment

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    End point title
    Complete Remission Rate by Investigator’s Assessment
    End point description
    CR rate in the “All Evaluable Patients” population was 10.0% (95% CI, 0.3-44.5%) CR rate in the “All Treated Patients” population was 7.7% (95% CI, 0.2-36%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    12 [5]
    Units: percentage
        number (confidence interval 95%)
    8.3 (0.2 to 38.5)
    Notes
    [5] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation
    No statistical analyses for this end point

    Secondary: Duration of Response by Investigator’s Assessment

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    End point title
    Duration of Response by Investigator’s Assessment
    End point description
    CI, confidence interval; DoR, duration of response DoR (months) at 3 months (95% CI) = 100% (100-100%) DoR (months) at 6 months (95% CI) = 50% (0-100%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    2 [6]
    Units: months
        median (confidence interval 95%)
    6.6 (3.7 to 9.4)
    Notes
    [6] - the two responders to plitidepsin
    No statistical analyses for this end point

    Secondary: Time to Response by Investigator’s Assessment

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    End point title
    Time to Response by Investigator’s Assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    14
    Units: months
        median (full range (min-max))
    2.9 (2.8 to 3.0)
    No statistical analyses for this end point

    Secondary: Progression-free Survival by Investigator’s Assessment - Per Protocol Patients Population

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    End point title
    Progression-free Survival by Investigator’s Assessment - Per Protocol Patients Population
    End point description
    CI, confidence interval; PFS, progression-free survival Events = 10 (83.3%) PFS at 6 months (95% CI) = 30.0% (1.6-58.4%) PFS at 12 months (95% CI) = 10.0% (0-28.6%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    12 [7]
    Units: months
        median (confidence interval 95%)
    2.5 (0.9 to 6.4)
    Notes
    [7] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation
    No statistical analyses for this end point

    Secondary: Progression-free Survival by Investigator’s Assessment - All Evaluable Patients Population

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    End point title
    Progression-free Survival by Investigator’s Assessment - All Evaluable Patients Population
    End point description
    CI, confidence interval; PFS, progression-free survival. Events 10 (100%) PFS at 6 months (95% CI) 30.0% (1.6-58.4%) PFS at 12 months (95% CI) 10.0% (0-28.6%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    10 [8]
    Units: months
        median (confidence interval 95%)
    2.5 (0.9 to 6.4)
    Notes
    [8] - Four patients were not evaluable for efficacy in the “All Evaluable Patients” population
    No statistical analyses for this end point

    Secondary: Progression-free Survival by Investigator’s Assessment - All Treated Patients population

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    End point title
    Progression-free Survival by Investigator’s Assessment - All Treated Patients population
    End point description
    CI, confidence interval; PFS, progression-free survival. Events 11 (84.6%) PFS at 6 months (95% CI) 27.3% (1.0-53.6%) PFS at 12 months (95% CI) 9.1% (0-26.1%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    13 [9]
    Units: months
        median (confidence interval 95%)
    2.6 (1.6 to 6.4)
    Notes
    [9] - 1 patient was never treated
    No statistical analyses for this end point

    Secondary: Overall survival - Per Protocol Patients population

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    End point title
    Overall survival - Per Protocol Patients population
    End point description
    CI, confidence interval; 999, not reached; OS, overall survival Events 7 (58.3%) OS at 6 months (95% CI) 65.6% (38.1-93.1%) OS at 12 months (95% CI) 29.2% (0-60.2%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    12 [10]
    Units: months
        median (confidence interval 95%)
    6.1 (3.4 to 999)
    Notes
    [10] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation
    No statistical analyses for this end point

    Secondary: Overall Survival - All Evaluable Patients Population

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    End point title
    Overall Survival - All Evaluable Patients Population
    End point description
    CI, confidence interval; 999, not reached; OS, overall survival Events 5 (50.0%) OS at 6 months (95% CI) 68.6% (38.9-98.3%) OS at 12 months (95% CI) 36.6% (0-73.5%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    10 [11]
    Units: months
        median (confidence interval 95%)
    6.1 (3.7 to 999)
    Notes
    [11] - Four patients were not evaluable for efficacy in the “All Evaluable Patients” population
    No statistical analyses for this end point

    Secondary: Overall Survival - All Treated Patients Population

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    End point title
    Overall Survival - All Treated Patients Population
    End point description
    CI, confidence interval; 999, not reached; OS, overall survival Events 7 (53.8%) OS at 6 months (95% CI) 68.4% (42.6-94.1%) OS at 12 months (95% CI) 32.6% (0-65.1%)
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Plitidepsin
    Number of subjects analysed
    13 [12]
    Units: months
        median (confidence interval 95%)
    6.1 (3.7 to 999)
    Notes
    [12] - 1 patient was never treated
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Plitidepsin
    Reporting group description
    Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a four-week period. A 1-day window was allowed for plitidepsin administration.

    Serious adverse events
    Plitidepsin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 13 (69.23%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    1
    Vascular disorders
    Peripheral embolism
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Plitidepsin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    Vascular disorders
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia/Fatigue
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    6
    Chills
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    6 / 13 (46.15%)
         occurrences all number
    17
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    6
    Weight decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    13
    Eosinophilia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    3
    Nasal congestion
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Dysaesthesia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Transient ischaemic attack
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    5 / 13 (38.46%)
         occurrences all number
    7
    Dysphagia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Epigastric discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastric mucosa erythema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Melaena
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    6 / 13 (46.15%)
         occurrences all number
    7
    Rectal haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    4
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Renal impairment
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    8
    Rash macular
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    3
    Myopathy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Hypomagnesaemia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    3
    Hyponatraemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Rhinovirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2016
    This substantial amendment was generated to include dexamethasone as prophylactic medication required before infusion with plitidepsin. Therefore, standard premedication for hypersensitivity reactions with anti H1 and H2 receptor antagonists and glucocorticoids had to be given intravenously before each plitidepsin infusion; this is mandatory in all ongoing studies with plitidepsin as stated in the Investigator Brochure. In v.1.0 of this protocol, dexamethasone was not part of the premedication regimen due to an omission at the time of writing the document. Additionally, the following changes, corrections, and clarifications were also included in this substantial amendment: - Clarifications to some of the parts of the text regarding the prior treatment, LVEF and hypersensitivity eligibility criteria were included to ensure patient safety - Muscular toxicity criteria for treatment continuation and dose reduction were revised to ensure patient safety - The list of excipients of plitidepsin was added to the study drug formulation information - Clarifications to some assessments and procedures windows were included as follow: tumor assessment timing after Cycle 3 was changed to avoid delays in starting Cycle 4; the frequency of follow-up until disease progression during the first year of follow-up was corrected in line with standard clinical practice; laboratory analyses required in the event of grade 3/4 nausea/vomiting or a treatment-related SAE were corrected to require only biochemistry-A laboratory tests. - The use of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 5 was revised to align with current Pharmacovigilance Department standard practice. - ICH Topic E6 Guideline for Good Clinical Practice reference to R1 was removed in anticipation of a revised version (R2). - Study contact details were updated and some minor typographical errors were corrected
    09 Jun 2017
    This substantial amendment was generated to: - Implement additional information on imaging requirements and periods for radiological tumor assessment with PET-CT in combination with diagnostic quality CT. - Modify the exclusion criterion #5 to allow the inclusion of patients concurrently treated with low doses of corticosteroids (an equivalent prednisone dose of ≤10 mg daily) for controlling symptoms derived from the disease. - Modify section referred to prohibited medications/therapies to clarify that patients were allowed to receive hydrocortisone treatment by any administration, not only by single bolus, and also to be consistent with the amended Exclusion criterion #5 (see above). - Simplify the follow-up procedures and periods for patients discontinuing treatment with or without disease progression, to be similar to the procedures used in clinical practice for monitoring these patients. Therefore, both groups of patients would be followed up ‘every four months during the first two years and then once every six months’. - Update the study contacts and correct some minor typographical errors.
    07 May 2018
    Additionally, according to an FDA request, a new Substantial Amendment No. 3 (7 May 2018) was issued to include several changes as additional precautionary measures to mitigate any likely rhythm abnormality. This amendment was based on the occurrence of one episode of grade 4 cardiac arrest due to Torsades de pointes (TdP) reported in one patient during Cycle 4 that resolved but led to treatment discontinuation. Precautionary measures to avoid TdP risk were to be implemented in this ongoing phase II study, including more stringent eligibility criteria, continuation of treatment criteria, prohibited medications (excluding prophylactic antiemetic ondansetron), and more extensive cardiac monitoring. Furthermore, as preliminary data from the APL-C-001-09 ADMYRE study showed that the greatest increases in QTcF, although being below the safety threshold of 20 milliseconds (ms), occurred 30 and 60 min after the end of infusion, thus the FDA requested that protocol of APL-B-021-13 study had to be modified to check ECGs 30 and 60 min post-infusion, timed with pharmacokinetic sample collections. Nevertheless, the study APL-B-021-13 was closed before this new substantial amendment was implemented.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 May 2018
    On 14 May 2018, the Sponsor informed to the study centers and Investigators regarding its decision to close the recruitment of the APL-B-021-13 study. The study was terminated before reaching the target enrollment due to slow patient accrual, and the negative opinion of the European Medicines Agency recommending the refusal of the marketing authorization for plitidepsin for the treatment of MM; all together prompted this Sponsor decision.
    -

    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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