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    Clinical Trial Results:
    GEMCITABINE COMBINED WITH THE mTOR INHIBITOR TEMSIROLIMUS (CCI-779) IN PATIENTS WITH INOPERABLE OR METASTATIC PANCREATIC CANCER

    Summary
    EudraCT number
    		 2008-002791-10
    Trial protocol
    		 GR  
    Global end of trial date
    27 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2019
    First version publication date
    19 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HE 3/07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ANZCTR: ACTRN12611000643976
    Sponsors
    Sponsor organisation name
    Hellenic Cooperative Oncology Group
    Sponsor organisation address
    Hatzikonstandi 18, Athens, Greece, 11524
    Public contact
    Hellenic Cooperative Oncology Group, Hellenic Cooperative Oncology Group, hecogoff@otenet.gr
    Scientific contact
    Hellenic Cooperative Oncology Group, Hellenic Cooperative Oncology Group, hecogoff@otenet.gr
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is: 1. Determine the maximum tolerated dose and recommended phase II dose of temsirolimus and gemcitabine in patients with pancreatic cancer. 2. To estimate the progression free survival in patients treated with the temsirolimus+gemcitabine combination.
    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. A copy of the IEC/IRB approval was received by the sponsor before recruitment of subjects into the study and all subjects provided written informed consent before undergoing any study-related procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 May 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 85
    Worldwide total number of subjects
    85
    EEA total number of subjects
    85
    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)
    52
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled in the study from 19 May 2009 until 8 October 2014 from 8 sites in Greece.

    Pre-assignment
    Screening details
    		 Patients signed the informed consent form and were screened for eligibility before entering the study

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I
    Arm description
    		 Chemotherapy naive patients with inoperable or metastatic pancreatic carcinoma were enrolled to the study in 6 dose levels in order to determine the maximum tolerated dose and recommended Phase II dose of temsirolimus and gemcitabine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TORISEL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Level 1: 10mg Level 2: 15mg Level 3: 20mg Level 4: 25mg Level 5: 20mg Level 6: 25mg

    Arm title
    		 Phase II
    Arm description
    		 Dose level 6 of gemcitabine 1000mg/m2 and temsirolimus 25mg was the recomended dose for the Phase II study in patients with inoperable or metastatic pancreatic cancer
    Arm type
    		 Experimental

    Investigational medicinal product name
    TORISEL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Torisel 25mg was the recomended dose for the Phase II study

    Number of subjects in period 1
    		Phase I Phase II
    Started
    30
    55
    Completed
    3
    4
    Not completed
    27
    51
         Clinical progression
    2
    -
         Adverse event, serious fatal
    -
    4
         Consent withdrawn by subject
    -
    5
         Physician decision
    -
    1
         Disease progression
    16
    31
         Adverse event, non-fatal
    3
    8
         Non-starter
    1
    -
         Death
    1
    2
         More than one month elapsed
    1
    -
         Performance status lower than 50
    1
    -
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Chemotherapy naive patients with inoperable or metastatic pancreatic carcinoma were enrolled to the study in 6 dose levels in order to determine the maximum tolerated dose and recommended Phase II dose of temsirolimus and gemcitabine.

    Reporting group title
    Phase II
    Reporting group description
    		 Dose level 6 of gemcitabine 1000mg/m2 and temsirolimus 25mg was the recomended dose for the Phase II study in patients with inoperable or metastatic pancreatic cancer

    Reporting group values
    		 Phase I Phase II Total
    Number of subjects
    		 30 55 85
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 19 33 52
        From 65-84 years
    		 11 22 33
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 62.4 (42.2 to 81.3) 62.1 (38.7 to 77.8) -
    Gender categorical
    Units: Subjects
        Female
    		 14 23 37
        Male
    		 16 32 48

    End points

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    End points reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Chemotherapy naive patients with inoperable or metastatic pancreatic carcinoma were enrolled to the study in 6 dose levels in order to determine the maximum tolerated dose and recommended Phase II dose of temsirolimus and gemcitabine.

    Reporting group title
    Phase II
    Reporting group description
    		 Dose level 6 of gemcitabine 1000mg/m2 and temsirolimus 25mg was the recomended dose for the Phase II study in patients with inoperable or metastatic pancreatic cancer

    Primary: Maximum Tolerated Dose of Gemcitabine (G) and Temsirolimus (T)

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    End point title
    		 Maximum Tolerated Dose of Gemcitabine (G) and Temsirolimus (T) [1] [2]
    End point description
    In the Phase I part of the study, 30 patients were enrolled, at least 3 subjects at each dose level in order to determine the recommended dose for the Phase II part of the study.
    End point type
    Primary
    End point timeframe
    From study initiation until the determination of the maximum tolerated dose.
    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: Gemcitabine doses per dose level are described for patients enrolled in the Phase I part of the study.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The determination of the maximum tolerated dose of Gemcitabine and Temsirolimus was the primary endpoint of the Phase I part of the study. The number of patients evaluable for DLT per dose level is described for patients enrolled in the Phase I part of the study.
    End point values
    		 Phase I
    Number of subjects analysed
    30 [3]
    Units: number of patients evaluable for DLT
        Dose Level 1 G (800mg/m2),T (10 mg)
    7
        Dose Level 2 G (800mg/m2), T(15mg)
    3
        Dose Level 3 G(800mg/m2),T(20 mg)
    6
        Dose Level 4 G(800mg/m2),T(25 mg)
    3
        Dose Level 5 G (1000 mg/m2),T(20 mg)
    3
        Dose Level 6 G(1000 mg/m2),T(25 mg)
    3
    Notes
    [3] - In the first dose level one patient did not start treatment and one was ineligible.
    No statistical analyses for this end point

    Primary: 6-month Progression Free Survival

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    End point title
    		 6-month Progression Free Survival [4] [5]
    End point description
    Progression- Free Survival (PFS) was calculated from the date of study entry to the date of first documented progression, death or last contact.
    End point type
    Primary
    End point timeframe
    tumor assessments were performed in cycles 2,4 and 7
    Notes
    [4] - 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: Since this was a single arm Phase I/II trial and all patients were treated with Gemcitabine and Temsirolimus, no comparisons between different treatment arms were performed. The percentage of patients surviving 6 months since study entry has been provided for the patients included in the Phase II part of the study.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The 6-month progression free survival rate was the primary endpoint of the Phase II part of the study. The percentage of Phase II patients surviving 6 months since study entry is described.
    End point values
    		 Phase II
    Number of subjects analysed
    55
    Units: percentage of surviving patients
        number (not applicable)
    30.9
    Attachments
    		 Kaplan-Meier for PFS
    No statistical analyses for this end point

    Secondary: Quality of life benefits

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    End point title
    		 Quality of life benefits [6]
    End point description
    Quality of life was assessed using the EUROQOL 5D Questionnaire. The descriptive system consists of 5 dimensions including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The single summary EQ-5D Index was calculated using the European value set.
    End point type
    Secondary
    End point timeframe
    Quality of life questionnaires were completed on screening-baseline, on cycles 4, 7 and 6 months after completion of treatment
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Quality of Life assessment was a secondary endpoint of the Phase II part of the trial and therefore measures of central tendency and dispersion of the calculated EQ-5D Index are provided for Phase II patients that completed the EQ-5D questionnaire at baseline and at the last treatment cycle.
    End point values
    		 Phase II
    Number of subjects analysed
    55 [7]
    Units: EQ-5D Index
    arithmetic mean (standard deviation)
        Baseline
    0.67 ( 0.21 )
        Last treatment cycle
    0.65 ( 0.26 )
    Attachments
    		 Histogram of the difference of EQ-5D Index
    Notes
    [7] - 51 patients (92.7%) completed the EQ-5D questionnaire at baseline and 30 at the last treatment cycle
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival [8]
    End point description
    End point type
    Secondary
    End point timeframe
    overall survival was measured from the date of patient's study entry to the date of death or last contact.
    Notes
    [8] - 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: Overall Survival was a secondary endpoint of the Phase II part of the trial. Therefore, the median overall survival (in months) with the corresponding 95% confidence intervals are provided for the 55 patients included in the Phase II part of the study.
    End point values
    		 Phase II
    Number of subjects analysed
    55
    Units: months
        median (confidence interval 95%)
    4.95 (3.54 to 6.85)
    Attachments
    		 Kaplan-Meier for Overall Survival
    No statistical analyses for this end point

    Secondary: Adverse events and serious adverse events of temsirolimus combination and gemcitabine

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    End point title
    		 Adverse events and serious adverse events of temsirolimus combination and gemcitabine
    End point description
    Assessment of the nature, incidence and severity of adverse events and serious adverse events of the combination of temsirolmus and gemcitabine.
    End point type
    Secondary
    End point timeframe
    Adverse events and serious adverse events of all participants were recorded and assessed upon signature of the inform consent until 30 days after the last administration of study treatment.
    End point values
    		 Phase I Phase II
    Number of subjects analysed
    29 [9]
    55
    Units: number of patients
        Any Adverse Event
    29
    53
        Adverse Events grade ≥3
    28
    47
        Adverse Events grade ≥4
    8
    25
        Fatal Adverse Events
    1
    5
        Serious Adverse Events
    14
    31
    Notes
    [9] - One patient never started treatment and was therefore excluded from the safety population.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Upon signature of the informed consent form until 30 days after the last administration of the investigational medicinal product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 chemotherapy naive patients with inoperable or metastatic pancreatic carcinoma were enrolled to the study in 6 dose levels in order to determine the maximum tolerated dose and recomended Phase II dose of temsirolimus and gemcitabine

    Reporting group title
    Phase II
    Reporting group description
    		 dose level 6 of gemcitabine 1000mg/m2 and temsirolimus 25mg was the recomended dose for the Phase II study in patients with inoperable or metastatic pancreatic cancer

    Serious adverse events
    		 Phase I Phase II
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 29 (48.28%)
    31 / 55 (56.36%)
         number of deaths (all causes)
    1
    54
         number of deaths resulting from adverse events
    1
    5
    Investigations
    bilirubin total increased
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 29 (3.45%)
    6 / 55 (10.91%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Thrombosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    fever
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 55 (9.09%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tumour progression
    Additional description: clinical tumour progression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multiple organ failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    fatigue
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
    6 / 55 (10.91%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hemorrhage upper gastrointestinal NOS
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    stent obstruction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    obstruction of the bile duct
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    obstruction of the biliary tract
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (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
    Additional description: pneumonia infection which was caused due to Klebsiella
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection bladder
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 29 (0.00%)
    4 / 55 (7.27%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bacteraemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 55 (5.45%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection with grade 3 lymphopenia
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    stent infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Phase I Phase II
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 29 (96.55%)
    52 / 55 (94.55%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 55 (1.82%)
         occurrences all number
    2
    1
    Flushing
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Phlebitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Embolism
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 55 (5.45%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    15 / 29 (51.72%)
    19 / 55 (34.55%)
         occurrences all number
    25
    21
    fever
         subjects affected / exposed
    8 / 29 (27.59%)
    12 / 55 (21.82%)
         occurrences all number
    11
    28
    Chills
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 55 (1.82%)
         occurrences all number
    2
    2
    flu like symptoms
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    other-paraneoplastic fever
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    other-cold
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Oedema mouth
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Inflammation
    Additional description: inflammation of toe
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    oedema limb
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 55 (5.45%)
         occurrences all number
    3
    3
    other-oedema head and neck
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Immune system disorders
    allergic reaction
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    0
    2
    other-allergic in food factor
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    vagina pain
    alternative dictionary used: ctcae 3
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    4 / 29 (13.79%)
    4 / 55 (7.27%)
         occurrences all number
    4
    6
    other-pharynx pain
    alternative dictionary used: CTC AE 3
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    Dyspnoea
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 55 (0.00%)
         occurrences all number
    2
    0
    Hiccups
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    voice alteration
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Pneumonitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    Mood altered
         subjects affected / exposed
    0 / 29 (0.00%)
    5 / 55 (9.09%)
         occurrences all number
    0
    5
    Hallucination
    Additional description: occasionally
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    25 / 29 (86.21%)
    36 / 55 (65.45%)
         occurrences all number
    98
    130
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    5
    2
    Neutrophil count decreased
         subjects affected / exposed
    23 / 29 (79.31%)
    33 / 55 (60.00%)
         occurrences all number
    77
    120
    Platelet count decreased
         subjects affected / exposed
    16 / 29 (55.17%)
    32 / 55 (58.18%)
         occurrences all number
    47
    74
    Weight decreased
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 55 (1.82%)
         occurrences all number
    3
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 29 (79.31%)
    31 / 55 (56.36%)
         occurrences all number
    57
    52
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 29 (65.52%)
    29 / 55 (52.73%)
         occurrences all number
    55
    56
    Alkaline Phosphatase Increased
    Additional description: ALP serum increased
    alternative dictionary used: CTCAE 4.03
         subjects affected / exposed
    8 / 29 (27.59%)
    19 / 55 (34.55%)
         occurrences all number
    11
    23
    Blood bilirubin increased
         subjects affected / exposed
    4 / 29 (13.79%)
    14 / 55 (25.45%)
         occurrences all number
    8
    18
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 55 (7.27%)
         occurrences all number
    3
    4
    creatinine increased
    Additional description: serum creatinine increased
    alternative dictionary used: CTCAE 4.03
         subjects affected / exposed
    4 / 29 (13.79%)
    4 / 55 (7.27%)
         occurrences all number
    5
    7
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    14 / 29 (48.28%)
    25 / 55 (45.45%)
         occurrences all number
    14
    27
    Injury, poisoning and procedural complications
    Vascular access complication
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    Nightmare
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    3
    0
    Somnolence
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 55 (0.00%)
         occurrences all number
    4
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 29 (58.62%)
    33 / 55 (60.00%)
         occurrences all number
    30
    52
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 29 (10.34%)
    7 / 55 (12.73%)
         occurrences all number
    3
    9
    Diarrhoea
         subjects affected / exposed
    6 / 29 (20.69%)
    13 / 55 (23.64%)
         occurrences all number
    7
    16
    Dry mouth
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Cheilitis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Stomatitis
         subjects affected / exposed
    5 / 29 (17.24%)
    12 / 55 (21.82%)
         occurrences all number
    5
    14
    Nausea
         subjects affected / exposed
    7 / 29 (24.14%)
    9 / 55 (16.36%)
         occurrences all number
    12
    12
    Vomiting
         subjects affected / exposed
    4 / 29 (13.79%)
    7 / 55 (12.73%)
         occurrences all number
    9
    11
    Abdominal pain
         subjects affected / exposed
    12 / 29 (41.38%)
    10 / 55 (18.18%)
         occurrences all number
    26
    16
    Haemorrhoids
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 55 (0.00%)
         occurrences all number
    4
    0
    Dysphagia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    0
    2
    Haemorrhage
    Additional description: lower GI NOS
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    4
    0
    Rash
         subjects affected / exposed
    8 / 29 (27.59%)
    13 / 55 (23.64%)
         occurrences all number
    11
    16
    Pruritus
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    nail changes
    alternative dictionary used: ctcae 3
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    urinary frequency
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    Urinary retention
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    0
    2
    Haematuria
    Additional description: microscopic
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Endocrine disorders
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 29 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    muscle weakness
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 55 (9.09%)
         occurrences all number
    9
    5
    Infections and infestations
    other-dermatology herpes
    alternative dictionary used: ctcae 3
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    0
    2
    Catheter site infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    4 / 55 (7.27%)
         occurrences all number
    1
    4
    Viral infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 55 (0.00%)
         occurrences all number
    2
    0
    Fungal infection
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Nail infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    other-herpetic mucositis
    alternative dictionary used: ctcae 3
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    2
    Candida infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    anorexia
         subjects affected / exposed
    13 / 29 (44.83%)
    11 / 55 (20.00%)
         occurrences all number
    17
    11
    Hyperglycaemia
         subjects affected / exposed
    18 / 29 (62.07%)
    21 / 55 (38.18%)
         occurrences all number
    46
    34
    Hyperkalaemia
         subjects affected / exposed
    6 / 29 (20.69%)
    4 / 55 (7.27%)
         occurrences all number
    11
    5
    Hypermagnesaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 55 (5.45%)
         occurrences all number
    1
    6
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 29 (13.79%)
    6 / 55 (10.91%)
         occurrences all number
    4
    8
    Hyperuricaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 55 (5.45%)
         occurrences all number
    1
    6
    Hypoalbuminaemia
         subjects affected / exposed
    14 / 29 (48.28%)
    13 / 55 (23.64%)
         occurrences all number
    22
    20
    Hypocalcaemia
         subjects affected / exposed
    5 / 29 (17.24%)
    13 / 55 (23.64%)
         occurrences all number
    7
    21
    Hypoglycaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Hypokalaemia
         subjects affected / exposed
    8 / 29 (27.59%)
    7 / 55 (12.73%)
         occurrences all number
    16
    11
    Hyponatraemia
         subjects affected / exposed
    7 / 29 (24.14%)
    15 / 55 (27.27%)
         occurrences all number
    15
    28
    Hypomagnesaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    other-LDH
    alternative dictionary used: ctcae 4.03
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 55 (1.82%)
         occurrences all number
    10
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2012
    changes in reporting requirements of serious adverse events

    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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