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    Clinical Trial Results:
    Phase II Dose Optimization, Open-Label Clinical Trial of Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients

    Summary
    EudraCT number
    		 2009-016054-40
    Trial protocol
    		 ES  
    Global end of trial date
    30 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PM104-B-002-09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharma Mar, S.A.
    Sponsor organisation address
    Avda de los Reyes, 1, Polígono Industrial La Mina, Colmenar Viejo, Madrid, Spain, 28770
    Public contact
    Clinical Development Department of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., +34 918466000, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Development Department of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., +34 918466000, 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
    01 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Dose optimization phase: Primary objective: To determine the recommended dose (RD) for PM00104 administered as 1-hour (h) intravenous (i.v.) infusion on Days (D) 1, 8 and 15 every four weeks (q4wk) in relapsed/refractory multiple myeloma (MM) patients Dose expansion phase: Primary objective: To analyze the efficacy following treatment with PM00104 in patients with MM relapsed or refractory to standard therapy at the RD established during the dose optimization phase.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2010
    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
    Spain: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    24
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 8 March 2010 to 12 December 2012 in ten sites in Spain

    Pre-assignment
    Screening details
    		 Patients had to give written informed consent, Age ≥ 18 years, previously diagnosed with MM,have relapsed or relapsed/refractory disease, have measurable disease, recovery from any toxicity derived from previous treatments, have some adequated laboratory values, performance status≤2, Life expectancy ≥ 3 months, LVEF of at least 50%.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose optimization phase
    Arm description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. A dose optimization phase was conducted to determine the appropriate dose of PM00104 in relapsed/refractory MM patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zalypsis®
    Investigational medicinal product code
    PM00104
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A treatment cycle consisted of the administration of three i.v. 1-h infusions of PM00104 on D1, D8 and D15. Treatment cycles were to be repeated every four weeks. PM00104 administration through a central catheter and by specialized on-site study personnel was mandatory. PM00104 was provided as a powder for concentrate for solution for infusion in only one strength of 2.5 mg per vial.

    Arm title
    		 Dose expansion phase
    Arm description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. Once the recommended dosis had been defined, up to 37 more patients were to be recruited into the dose expansion phase in order to evaluate the anti-MM effects of PM00104. These patients were to receive single-agent PM00104 at the RD established in the earlier dose optimization phase, given as 1-h i.v. infusion on D1, D8 and D15 in cycles of 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zalypsis®
    Investigational medicinal product code
    PM00104
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A treatment cycle consisted of the administration of three i.v. 1-h infusions of PM00104 on D1, D8 and D15. Treatment cycles were to be repeated every four weeks. PM00104 administration through a central catheter and by specialized on-site study personnel was mandatory. PM00104 was provided as a powder for concentrate for solution for infusion in only one strength of 2.5 mg per vial.

    Number of subjects in period 1 [1]
    		Dose optimization phase Dose expansion phase
    Started
    22
    13
    Treatment
    21
    13
    Completed
    0
    0
    Not completed
    22
    13
         Progression disease
    9
    6
         Physician decision
    2
    3
         Consent withdrawn by subject
    -
    2
         Toxicity
    2
    1
         Adverse event, non-fatal
    2
    1
         Death
    6
    -
         Not treated
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: There was a patient in the dose expansion phase that was excluded from all tables due to the overdose

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose optimization phase
    Reporting group description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. A dose optimization phase was conducted to determine the appropriate dose of PM00104 in relapsed/refractory MM patients

    Reporting group title
    Dose expansion phase
    Reporting group description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. Once the recommended dosis had been defined, up to 37 more patients were to be recruited into the dose expansion phase in order to evaluate the anti-MM effects of PM00104. These patients were to receive single-agent PM00104 at the RD established in the earlier dose optimization phase, given as 1-h i.v. infusion on D1, D8 and D15 in cycles of 28 days.

    Reporting group values
    		 Dose optimization phase Dose expansion phase Total
    Number of subjects
    		 22 13 35
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 60.5 (40 to 74) 62 (50 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 11 5 16
        Male
    		 11 8 19
    Race
    Units: Subjects
        Caucasian
    		 22 13 35
    ECOG
    Eastern Cooperative Oncology Group
    Units: Subjects
        PS 0
    		 3 2 5
        PS 1
    		 12 9 21
        PS 2
    		 5 1 6
        PS 4
    		 1 0 1
        Unk
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Dose optimization phase
    Reporting group description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. A dose optimization phase was conducted to determine the appropriate dose of PM00104 in relapsed/refractory MM patients

    Reporting group title
    Dose expansion phase
    Reporting group description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. Once the recommended dosis had been defined, up to 37 more patients were to be recruited into the dose expansion phase in order to evaluate the anti-MM effects of PM00104. These patients were to receive single-agent PM00104 at the RD established in the earlier dose optimization phase, given as 1-h i.v. infusion on D1, D8 and D15 in cycles of 28 days.

    Subject analysis set title
    DL1: 2.0 mg/m²
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients treated at dose Level 1: 2.0 mg/m²

    Subject analysis set title
    DL2: 2.2 mg/m²
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients treated at dose Level 2: 2.2 mg/m²

    Subject analysis set title
    DL3: 2.5 mg/m²
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients treated at dose level 3: 2.5 mg/m²

    Primary: Dose-limiting toxicities

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    End point title
    		 Dose-limiting toxicities [1] [2]
    End point description
    Number of DLTs per dose level
    End point type
    Primary
    End point timeframe
    Dose optimization phase. Treatment 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: This end point was conducted to determine the appropriate dose of PM00104 in relapsed/refractory MM patients. Statistical analyses do not apply because the RD was the dose level immediately below the MTD. The maximum tolerated dose (MTD) was defined as the level at which ≥33% evaluable patients have a DLT in Cycle 1.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point was conducted to determine the appropriate dose of PM00104 in relapsed/refractory MM patients and it only affects to the dose optimization phase population.
    End point values
    		 Dose optimization phase
    Number of subjects analysed
    13
    Units: percentage
        Patients with DLT
    4
        Patients without DLT
    9
    No statistical analyses for this end point

    Primary: Response rate

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    End point title
    		 Response rate [3]
    End point description
    Response rate (CR + sCR + VGPR + PR + MR)
    End point type
    Primary
    End point timeframe
    Overall treatment
    Notes
    [3] - 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: Non-comparative study designed
    End point values
    		 Dose optimization phase Dose expansion phase
    Number of subjects analysed
    17
    11
    Units: percentage of patients
        Disease controlled
    11
    7
        Disease not controlled
    6
    4
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Progression-free survival, defined as the time from the start of the study treatment to PD or death (regardless of the cause of death), whichever came first
    End point type
    Secondary
    End point timeframe
    Overall treatment
    End point values
    		 Dose optimization phase Dose expansion phase
    Number of subjects analysed
    17 [4]
    11 [5]
    Units: months
        median (confidence interval 95%)
    2.8 (0.9 to 3.7)
    1.8 (0.9 to 3)
    Notes
    [4] - Events: 14 (82.4%)
    [5] - Events: 10 (90.9%)
    No statistical analyses for this end point

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    Time to progression, defined as the time from the start of the study treatment to PD with death due to causes other than progression censored
    End point type
    Secondary
    End point timeframe
    Overall treatment
    End point values
    		 Dose optimization phase Dose expansion phase
    Number of subjects analysed
    17 [6]
    11 [7]
    Units: months
        median (confidence interval 95%)
    2.8 (0.9 to 3.7)
    1.8 (0.9 to 3)
    Notes
    [6] - Events: 13 (76.5%)
    [7] - Events: 10 (90.9%)
    No statistical analyses for this end point

    Secondary: Event-free Survival

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    End point title
    		 Event-free Survival
    End point description
    Event-free survival, defined as the time to progression, death or treatment discontinuation, whichever came first, due to PM00104-related AEs
    End point type
    Secondary
    End point timeframe
    Overall treatment
    End point values
    		 Dose optimization phase Dose expansion phase
    Number of subjects analysed
    17 [8]
    11 [9]
    Units: months
        median (confidence interval 95%)
    1.9 (0.9 to 3.7)
    1.8 (0.9 to 3)
    Notes
    [8] - Events: 16 (94.1%)
    [9] - Events: 10 (90.9%)
    No statistical analyses for this end point

    Secondary: Disease-free Survival

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    End point title
    		 Disease-free Survival
    End point description
    Disease-free survival was defined as the time from the start of CR or sCR to the time of relapse from CR/sCR
    End point type
    Secondary
    End point timeframe
    Overall treatment
    End point values
    		 Dose optimization phase Dose expansion phase
    Number of subjects analysed
    17 [10]
    11 [11]
    Units: months
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [10] - No patients in the study achieved CR/sCR, therefore, this parameter could not be assessed
    [11] - No patients in the study achieved CR/sCR, therefore, this parameter could not be assessed
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response, defined as the duration from the first observation of response to the time of disease progression, with deaths due to causes other than progression censored
    End point type
    Secondary
    End point timeframe
    Overall treatment
    End point values
    		 Dose optimization phase Dose expansion phase
    Number of subjects analysed
    17 [12]
    11 [13]
    Units: months
        median (confidence interval 95%)
    2.3 (0.5 to 7.4)
    0 (0 to 0)
    Notes
    [12] - Events: 4 (80.0%)
    [13] - No patients achieved an objective response; therefore this parameter could not be assessed
    No statistical analyses for this end point

    Secondary: Pharmacokinetics

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    End point title
    		 Pharmacokinetics
    End point description
    The complete plasma concentration-time profiles of PM00104 were analyzed by standard non-compartmental methods (NCA). NCA was performed using Phoenix WinNonlin v. 6.3 (Certara, USA).
    End point type
    Secondary
    End point timeframe
    Day 1 and day 8 of cycle 1
    End point values
    		 DL1: 2.0 mg/m² DL2: 2.2 mg/m² DL3: 2.5 mg/m²
    Number of subjects analysed
    17 [14]
    7 [15]
    9 [16]
    Units: units
    arithmetic mean (standard error)
        Cmax (μg/L) - Day 1
    14.9 ± 7.94
    41.86 ± 48.46
    22.39 ± 6.19
        Cmax (μg/L) - Day 8
    19.8 ± 6.8
    16.38 ± 7.98
    28.39 ± 13.03
        AUC (h*μg/L) - Day 1
    76.42 ± 38.96
    224.25 ± 253.18
    111.14 ± 38.07
        AUC (h*μg/L) - Day 8
    174.61 ± 210.53
    109.3 ± 72.6
    112.09 ± 34.1
        CL (L/h) - Day 1
    47.03 ± 33.01
    39.83 ± 25.19
    44.07 ± 18.7
        CL (L/h) - Day 8
    40.26 ± 25.17
    46.45 ± 23.32
    41.4 ± 13.23
    Notes
    [14] - Day 8: N=4
    [15] - Day 8: N=4
    [16] - Day 8: N=6
    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
    11.0
    Reporting groups
    Reporting group title
    Dose optimization phase
    Reporting group description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. A dose optimization phase was conducted to determine the appropriate dose of PM00104 in relapsed/refractory MM patients

    Reporting group title
    Dose expansion phase
    Reporting group description
    		 Zalypsis® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients. Once the recommended dosis had been defined, up to 37 more patients were to be recruited into the dose expansion phase in order to evaluate the anti-MM effects of PM00104. These patients were to receive single-agent PM00104 at the RD established in the earlier dose optimization phase, given as 1-h i.v. infusion on D1, D8 and D15 in cycles of 28 days.

    Serious adverse events
    		 Dose optimization phase Dose expansion phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 21 (57.14%)
    5 / 13 (38.46%)
         number of deaths (all causes)
    7
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic neoplasm malignant
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Gastroenteritis Escherichia coli
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose optimization phase Dose expansion phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 21 (95.24%)
    13 / 13 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    hepatic neoplasm malignant
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    Pallor
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Phlebitis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    Venous thrombosis limb
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 21 (61.90%)
    10 / 13 (76.92%)
         occurrences all number
    42
    30
    General physical health deterioration
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Injection site erythema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Injection site reaction
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Local swelling
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    Peripheral coldness
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    13 / 21 (61.90%)
    4 / 13 (30.77%)
         occurrences all number
    24
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 21 (28.57%)
    0 / 13 (0.00%)
         occurrences all number
    11
    0
    Dyspnoea
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 13 (0.00%)
         occurrences all number
    8
    0
    Epistaxis
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 13 (15.38%)
         occurrences all number
    7
    3
    Haemoptysis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    5
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 21 (23.81%)
    2 / 13 (15.38%)
         occurrences all number
    7
    12
    Insomnia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Protein S increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Crushing injury of trunk
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Bundle branch block
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Cardiac arrest
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 13 (0.00%)
         occurrences all number
    14
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    9
    0
    Headache
         subjects affected / exposed
    5 / 21 (23.81%)
    0 / 13 (0.00%)
         occurrences all number
    10
    0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Neuralgia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    13
    Neuropathy peripheral
         subjects affected / exposed
    7 / 21 (33.33%)
    2 / 13 (15.38%)
         occurrences all number
    14
    5
    Somnolence
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 21 (57.14%)
    8 / 13 (61.54%)
         occurrences all number
    40
    28
    Febrile neutropenia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    Neutropenia
         subjects affected / exposed
    9 / 21 (42.86%)
    9 / 13 (69.23%)
         occurrences all number
    20
    20
    Splenomegaly
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    10 / 21 (47.62%)
    5 / 13 (38.46%)
         occurrences all number
    27
    12
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Abdominal distension
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    5
    Abdominal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 13 (7.69%)
         occurrences all number
    1
    3
    Abdominal rigidity
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Aerophagia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    Ascites
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    5 / 21 (23.81%)
    6 / 13 (46.15%)
         occurrences all number
    10
    19
    Diarrhoea
         subjects affected / exposed
    6 / 21 (28.57%)
    2 / 13 (15.38%)
         occurrences all number
    8
    3
    Nausea
         subjects affected / exposed
    8 / 21 (38.10%)
    3 / 13 (23.08%)
         occurrences all number
    20
    14
    Vomiting
         subjects affected / exposed
    10 / 21 (47.62%)
    2 / 13 (15.38%)
         occurrences all number
    19
    3
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Hepatic pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Hepatomegaly
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    5
    0
    Rash
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    6
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Oliguria
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Renal failure
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    Renal failure acute
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 13 (7.69%)
         occurrences all number
    11
    3
    Back pain
         subjects affected / exposed
    9 / 21 (42.86%)
    4 / 13 (30.77%)
         occurrences all number
    25
    10
    Bone pain
         subjects affected / exposed
    5 / 21 (23.81%)
    2 / 13 (15.38%)
         occurrences all number
    12
    11
    Groin pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Muscular weakness
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 13 (7.69%)
         occurrences all number
    5
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Neck pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Osteoporosis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Pain in extremity
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 13 (15.38%)
         occurrences all number
    6
    2
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 13 (7.69%)
         occurrences all number
    6
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 13 (15.38%)
         occurrences all number
    6
    6
    Oral herpes
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    Pharyngitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Sinusitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    12 / 21 (57.14%)
    4 / 13 (30.77%)
         occurrences all number
    29
    14
    Hypercalcaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 13 (15.38%)
         occurrences all number
    2
    4
    Hyperuricaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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