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    Clinical Trial Results:
    A Phase I/II single-arm trial to evaluate the combination of cisplatin and gemcitabine with the mTOR inhibitor temsirolimus for treatment of advanced cancers, including first-line treatment of patients with advanced transitional cell carcinoma of the urothelium.

    Summary
    EudraCT number
    		 2007-007615-82
    Trial protocol
    		 GB  
    Global end of trial date
    15 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2017
    First version publication date
    13 May 2017
    Other versions
    Summary report(s)
    		 CONSORT diagram
    TOTEM upload

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SPON417-07
    Additional study identifiers
    ISRCTN number
    		 ISRCTN31546330
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cardiff University
    Sponsor organisation address
    30-36 Newport Road, Cardiff, United Kingdom,
    Public contact
    Ms Angela Casbard, Centre for Trials Research, 02920 687470, casbardac@cardiff.ac.uk
    Scientific contact
    Ms Angela Casbard, Centre for Trials Research, 02920 687470, casbardac@cardiff.ac.uk
    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
    23 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The overall objective of this trial is to assess whether the addition of temsirolimus to standard cipslatin/gemcitabine cancer chemotherapy is a safe and effective treatment for patients with advanced malignancy and an effective treatment for patients with advanced urothelial cancer. Phase I of the trial aims to establish the appropriate dose and schedule of temsirolimus when used in combination with gemcitabine and and cisplatin for patients with advanced non-haematological malignancy. Phase II of the trial aims to establish activity, safety and feasibility of this combination in participants with advanced transitional cell carcinoma of the urothelium. Activity will be measured by determining the number of patients who are alive at six months and have responded completely or partially to treatment or who have stable disease, according to strict radiological criteria i.e. progression-free survival (PFS) six months after enrolment.
    Protection of trial subjects
    The safety review committee (SRC) met to review each cohort of 3 patients and to decide whether or not to escalate to the next dose level, to recruit additional participants at the current dose level or to discontinue dose escalation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Dec 2012
    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
    United Kingdom: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    8
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Trial open date: 31 December 2012 and Open for 38 months. Recruitment was stopped August 2015.

    Pre-assignment
    Screening details
    		 Main Inclusion Criteria: For all participants: 1) Locally advanced and/or metastatic disease. Not suitable for radical radiotherapy or curative surgery 2) Life expectancy ≥3 months 3) WHO Performance status 0-2 4) Fit to receive cisplatin-containing combination chemotherapy 5) Informed consent.

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

    Arms
    Arm title
    		 Experimental
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    Other name
    Torisel
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mg at different days per cohort

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    70 mg day 1 of every cycle

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    1000 mg day 1, 8

    Number of subjects in period 1 [1]
    		Experimental
    Started
    14
    Completed
    7
    Not completed
    7
         Consent withdrawn by subject
    1
         Physician decision
    2
         Disease progression
    1
         Adverse event, non-fatal
    2
         Poor rationale for treatment in palliative setting
    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: One patient was found to not be eligible so did not receive any trial treatment or provide any data to the trial

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 -

    Reporting group values
    		 Experimental Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 63.5 (40 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 5 5
    Non-Urothelial Cancer Histology
    Units: Subjects
        Adenocarcinoma
    		 2 2
        Adenosquamous Carcinoma
    		 1 1
        Poorly differentiated/ insular carcinoma
    		 1 1
        Large cell undifferentiated carcinoma
    		 1 1
        Cholangiocarcinoma of biliary tract
    		 1 1
        Non-small cell carcinoma
    		 1 1
        Ovarian clear cell carcinoma
    		 1 1
        Not applicable
    		 6 6
    Location of primary disease for Non-Urothelial Cancer patients
    Units: Subjects
        Lung
    		 3 3
        Gallbladder
    		 1 1
        Uterus
    		 1 1
        Thyroid
    		 1 1
        Biliary Tract
    		 1 1
        Ovarian
    		 1 1
        Not applicable
    		 6 6
    T - Stage for Non-Urothelial Cancer patients
    Units: Subjects
        TX
    		 5 5
        T0
    		 1 1
        T1
    		 1 1
        T4A
    		 1 1
        Not applicable
    		 6 6
    N - Stage for Non-Urothelial Cancer patients
    Units: Subjects
        N0
    		 5 5
        N1
    		 3 3
        Not applicable
    		 6 6
    M-Stage for Non-Urothelial Cancer patients
    Units: Subjects
        M1
    		 8 8
        Not applicable
    		 6 6
    Urothelial Cancer histology
    Units: Subjects
        Pure TCC
    		 4 4
        Mixed TCC
    		 1 1
        Missing
    		 1 1
        Not applicable
    		 8 8
    Location of primary disease for Urothelial Cancer patients
    Units: Subjects
        Bladder
    		 3 3
        Renal Pelvis/Ureter
    		 2 2
        Missing
    		 1 1
        Not applicable
    		 8 8
    T - Stage for Urothelial Cancer patients
    Units: Subjects
        TX
    		 3 3
        T2
    		 1 1
        T3
    		 2 2
        Not applicable
    		 8 8
    N - Stage for Urothelial Cancer patients
    Units: Subjects
        NX
    		 1 1
        N0
    		 1 1
        N1
    		 3 3
        N3
    		 1 1
        Not applicable
    		 8 8
    M-Stage for Urothelial Cancer patients
    Units: Subjects
        M0
    		 1 1
        M1
    		 5 5
        Not applicable
    		 8 8
    Current metastases
    Units: Subjects
        Liver
    		 3 3
        Lung
    		 6 6
        Bone
    		 2 2
        Multiple
    		 1 1
        Other
    		 2 2
    Current nodes
    Units: Subjects
        Pelvic
    		 3 3
        Supraclavicular
    		 1 1
        Abdominal
    		 2 2
        Axillary
    		 2 2
        Multiple
    		 3 3
        Other
    		 3 3
    Previous (neo)adjuvant chemotherapy 
    Units: Subjects
        Yes
    		 9 9
        No
    		 5 5
    Did any previous (neo)adjuvant chemotherapy include cisplatin
    Units: Subjects
        Yes
    		 4 4
        No
    		 5 5
        Missing
    		 5 5
    Previous Radiotherapy
    Units: Subjects
        Yes
    		 2 2
        No
    		 12 12
    Median number of cycles of previous (neo)adjuvant chemotherapy
    Units: Number of cycles
        median (full range (min-max))
    		 6 (3 to 18) -
    Subject analysis sets

    Subject analysis set title
    Treated patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    One patient was deemed ineligible after they were recruited.

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 1

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 2

    Subject analysis set title
    Cohort 3
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 3

    Subject analysis set title
    Cohort 3b
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 3b

    Subject analysis set title
    Urothelial Cancer Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Urothelial Cancer Patients only

    Subject analysis set title
    Non-Urothelial Cancer Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Non-Urothelial Cancer Patients only

    Subject analysis set title
    Pure TCC patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pure TCC patients only

    Subject analysis sets values
    		 Treated patients Cohort 1 Cohort 2 Cohort 3 Cohort 3b Urothelial Cancer Patients Non-Urothelial Cancer Patients Pure TCC patients
    Number of subjects
    14
    3
    3
    4
    4
    6
    8
    4
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    63.5 (40 to 80)
    60 (50 to 68)
    72 (69 to 72)
    70.5 (40 to 80)
    56.5 (47 to 57)
    64 (50 to 73)
    62 (40 to 80)
    64 (56 to 72)
    Gender categorical
    Units: Subjects
        Female
    9
    1
    2
    3
    3
    2
    7
    0
        Male
    5
    2
    1
    1
    1
    4
    1
    4
    Non-Urothelial Cancer Histology
    Units: Subjects
        Adenocarcinoma
    2
    0
    2
    0
    0
        Adenosquamous Carcinoma
    1
    0
    0
    1
    0
        Poorly differentiated/ insular carcinoma
    1
    0
    0
    1
    0
        Large cell undifferentiated carcinoma
    1
    0
    0
    1
    0
        Cholangiocarcinoma of biliary tract
    1
    0
    0
    0
    1
        Non-small cell carcinoma
    1
    0
    0
    0
    1
        Ovarian clear cell carcinoma
    1
    0
    0
    0
    1
        Not applicable
    6
    0
    0
    0
    0
    Location of primary disease for Non-Urothelial Cancer patients
    Units: Subjects
        Lung
    3
    0
    1
    1
    1
        Gallbladder
    1
    0
    1
    0
    0
        Uterus
    1
    0
    0
    1
    0
        Thyroid
    1
    0
    0
    1
    0
        Biliary Tract
    1
    0
    0
    0
    1
        Ovarian
    1
    0
    0
    0
    1
        Not applicable
    6
    0
    0
    0
    0
    T - Stage for Non-Urothelial Cancer patients
    Units: Subjects
        TX
    5
    0
    1
    3
    1
        T0
    1
    0
    0
    0
    1
        T1
    1
    0
    1
    0
    0
        T4A
    1
    0
    0
    0
    1
        Not applicable
    6
    0
    0
    0
    0
    N - Stage for Non-Urothelial Cancer patients
    Units: Subjects
        N0
    5
    0
    1
    3
    1
        N1
    3
    0
    1
    0
    2
        Not applicable
    6
    0
    0
    0
    0
    M-Stage for Non-Urothelial Cancer patients
    Units: Subjects
        M1
    8
    0
    2
    3
    3
        Not applicable
    6
    0
    0
    0
    0
    Urothelial Cancer histology
    Units: Subjects
        Pure TCC
    4
    2
    1
    0
    1
        Mixed TCC
    1
    1
    0
    0
    0
        Missing
    1
    0
    0
    1
    0
        Not applicable
    8
    0
    0
    0
    0
    Location of primary disease for Urothelial Cancer patients
    Units: Subjects
        Bladder
    3
    1
    1
    0
    1
        Renal Pelvis/Ureter
    2
    2
    0
    0
    0
        Missing
    1
    0
    0
    1
    0
        Not applicable
    8
    0
    0
    0
    0
    T - Stage for Urothelial Cancer patients
    Units: Subjects
        TX
    3
    0
    1
    1
    1
        T2
    1
    1
    0
    0
    0
        T3
    2
    2
    0
    0
    0
        Not applicable
    8
    0
    0
    0
    0
    N - Stage for Urothelial Cancer patients
    Units: Subjects
        NX
    1
    0
    0
    1
    0
        N0
    1
    1
    0
    0
    0
        N1
    3
    2
    1
    0
    0
        N3
    1
    0
    0
    0
    1
        Not applicable
    8
    0
    0
    0
    0
    M-Stage for Urothelial Cancer patients
    Units: Subjects
        M0
    1
    0
    0
    0
    1
        M1
    5
    3
    1
    1
    0
        Not applicable
    8
    0
    0
    0
    0
    Current metastases
    Units: Subjects
        Liver
    3
    1
    0
    1
    1
        Lung
    6
    1
    1
    2
    2
        Bone
    2
    0
    1
    1
    0
        Multiple
    1
    0
    0
    1
    0
        Other
    4
    1
    1
    2
    0
    Current nodes
    Units: Subjects
        Pelvic
    3
    1
    1
    0
    1
        Supraclavicular
    1
    0
    0
    0
    1
        Abdominal
    2
    2
    0
    0
    0
        Axillary
    2
    0
    0
    0
    2
        Multiple
    3
    1
    0
    0
    2
        Other
    5
    0
    1
    2
    2
    Previous (neo)adjuvant chemotherapy 
    Units: Subjects
        Yes
    9
    1
    0
    4
    4
        No
    5
    2
    3
    0
    0
    Did any previous (neo)adjuvant chemotherapy include cisplatin
    Units: Subjects
        Yes
    4
    0
    0
    2
    2
        No
    5
    1
    0
    2
    2
        Missing
    5
    0
    0
    0
    0
    Previous Radiotherapy
    Units: Subjects
        Yes
    2
    0
    1
    1
    0
        No
    12
    3
    2
    3
    4
    Median number of cycles of previous (neo)adjuvant chemotherapy
    Units: Number of cycles
        median (full range (min-max))
    6 (3 to 18)
    4 (4 to 4)
    0 (0 to 0)
    10 (6 to 18)
    4 (3 to 6)

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 -

    Subject analysis set title
    Treated patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    One patient was deemed ineligible after they were recruited.

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 1

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 2

    Subject analysis set title
    Cohort 3
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 3

    Subject analysis set title
    Cohort 3b
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cohort 3b

    Subject analysis set title
    Urothelial Cancer Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Urothelial Cancer Patients only

    Subject analysis set title
    Non-Urothelial Cancer Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Non-Urothelial Cancer Patients only

    Subject analysis set title
    Pure TCC patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pure TCC patients only

    Primary: Dose Limiting Toxicities

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    End point title
    		 Dose Limiting Toxicities [1]
    End point description
    End point type
    Primary
    End point timeframe
    until cycle 2, day 1
    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 primary endpoint was purely descriptive and was reported as univariates with no statistical testing attached.
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Subjects
    4
    No statistical analyses for this end point

    Secondary: Deaths

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    End point title
    		 Deaths
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Subjects
        Number
    7
    No statistical analyses for this end point

    Secondary: Median doses cisplatin

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    End point title
    		 Median doses cisplatin
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: doses
        median (full range (min-max))
    70 (0 to 70)
    No statistical analyses for this end point

    Secondary: Median doses gemcitabine

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    End point title
    		 Median doses gemcitabine
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Doses
        median (full range (min-max))
    750 (0 to 1000)
    No statistical analyses for this end point

    Secondary: Median doses temsirolimus

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    End point title
    		 Median doses temsirolimus
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Doses
        median (full range (min-max))
    7.5 (0 to 10)
    No statistical analyses for this end point

    Secondary: Any dose reduction

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    End point title
    		 Any dose reduction
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Subjects
        Number
    13
    No statistical analyses for this end point

    Secondary: Median dose reduction cisplatin

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    End point title
    		 Median dose reduction cisplatin
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Doses
        median (full range (min-max))
    52 (0 to 68)
    No statistical analyses for this end point

    Secondary: Median dose reductions gemcitabine

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    End point title
    		 Median dose reductions gemcitabine
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Doses
        median (full range (min-max))
    563 (0 to 750)
    No statistical analyses for this end point

    Secondary: Median dose reductions temsirolimus

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    End point title
    		 Median dose reductions temsirolimus
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Doses
        median (full range (min-max))
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Any dose delays

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    End point title
    		 Any dose delays
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Subjects
        Number
    14
    No statistical analyses for this end point

    Secondary: Median dose delays

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    End point title
    		 Median dose delays
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Days
        median (full range (min-max))
    0.5 (0 to 14)
    No statistical analyses for this end point

    Secondary: Mean percent dose intensity Cisplatin

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    End point title
    		 Mean percent dose intensity Cisplatin
    End point description
    End point type
    Secondary
    End point timeframe
    Cycles 1-3
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Percent
        arithmetic mean (full range (min-max))
    87 (87 to 87)
    No statistical analyses for this end point

    Secondary: Mean percent dose intensity Gemcitabine

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    End point title
    		 Mean percent dose intensity Gemcitabine
    End point description
    End point type
    Secondary
    End point timeframe
    Cycles 1-3
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Percent
        arithmetic mean (full range (min-max))
    73 (73 to 73)
    No statistical analyses for this end point

    Secondary: Mean percent dose intensity temsirolimus

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    End point title
    		 Mean percent dose intensity temsirolimus
    End point description
    End point type
    Secondary
    End point timeframe
    Cycles 1-3
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Percent
        arithmetic mean (full range (min-max))
    73 (73 to 73)
    No statistical analyses for this end point

    Secondary: Mean percent dose intensity Cisplatin all

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    End point title
    		 Mean percent dose intensity Cisplatin all
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: percent
        arithmetic mean (full range (min-max))
    72 (72 to 72)
    No statistical analyses for this end point

    Secondary: Mean percent dose intensity gemcitabine all

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    End point title
    		 Mean percent dose intensity gemcitabine all
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: percent
        arithmetic mean (full range (min-max))
    61 (61 to 61)
    No statistical analyses for this end point

    Secondary: Mean percent dose intensity temsirolimus all

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    End point title
    		 Mean percent dose intensity temsirolimus all
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: percent
        arithmetic mean (full range (min-max))
    58 (58 to 58)
    No statistical analyses for this end point

    Secondary: Percent received at least 3 cycles of protocol treatment

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    End point title
    		 Percent received at least 3 cycles of protocol treatment
    End point description
    End point type
    Secondary
    End point timeframe
    First three cycles of treatment
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: percent
        number (not applicable)
    26.7
    No statistical analyses for this end point

    Secondary: Withdrawal, drop outs or discontinuations

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    End point title
    		 Withdrawal, drop outs or discontinuations
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Subjects
        Number
    8
    No statistical analyses for this end point

    Secondary: AE greater than Grade 3

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    End point title
    		 AE greater than Grade 3
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Number of AEs
    58
    No statistical analyses for this end point

    Secondary: Any AE

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    End point title
    		 Any AE
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Number of toxicities
    729
    No statistical analyses for this end point

    Secondary: Serious AEs

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    End point title
    		 Serious AEs
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Number of toxicities
    10
    No statistical analyses for this end point

    Secondary: Serious Adverse Reactions

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    End point title
    		 Serious Adverse Reactions
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Number of toxicities
    2
    No statistical analyses for this end point

    Secondary: AE leading to discontinuation of temsirolimus

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    End point title
    		 AE leading to discontinuation of temsirolimus
    End point description
    End point type
    Secondary
    End point timeframe
    Entire trial
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: Number of toxicities
    3
    No statistical analyses for this end point

    Secondary: Disease response at the end of cycle 3

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    End point title
    		 Disease response at the end of cycle 3
    End point description
    End point type
    Secondary
    End point timeframe
    End of cycle 3
    End point values
    		 Treated patients Urothelial Cancer Patients Non-Urothelial Cancer Patients
    Number of subjects analysed
    14
    6
    8
    Units: Subjects
        CR
    0
    0
    0
        PR
    5
    4
    1
        SD
    8
    2
    6
        PD
    0
    0
    0
        NE
    0
    0
    0
        Withdrawn but consented to follow up and missed vi
    1
    0
    1
        Missing
    0
    0
    0
        Died
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Disease response at the end of cycle 6

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    End point title
    		 Disease response at the end of cycle 6
    End point description
    End point type
    Secondary
    End point timeframe
    End of cycle 6
    End point values
    		 Treated patients Urothelial Cancer Patients Non-Urothelial Cancer Patients
    Number of subjects analysed
    14
    6
    8
    Units: Subjects
        CR
    0
    0
    0
        PR
    5
    4
    1
        SD
    1
    0
    1
        PD
    2
    1
    1
        NE
    0
    0
    0
        Withdrawn but consented to follow up and missed vi
    5
    1
    4
        Missing
    0
    0
    0
        Died
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Disease response at 6 months

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    End point title
    		 Disease response at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months follow up
    End point values
    		 Treated patients Urothelial Cancer Patients Non-Urothelial Cancer Patients Pure TCC patients
    Number of subjects analysed
    14
    6
    8
    4
    Units: Subjects
        CR
    1
    1
    0
    1
        PR
    0
    0
    0
    0
        SD
    1
    0
    1
    0
        PD
    7
    4
    3
    2
        NE
    0
    0
    0
    0
        Withdrawn but consented to follow up and missed vi
    4
    1
    3
    1
        Missing
    0
    0
    0
    0
        Died
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Disease response at 12 months

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    End point title
    		 Disease response at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months follow up
    End point values
    		 Treated patients Urothelial Cancer Patients Non-Urothelial Cancer Patients
    Number of subjects analysed
    14
    6
    8
    Units: Subjects
        CR
    1
    1
    0
        PR
    0
    0
    0
        SD
    0
    0
    0
        PD
    1
    1
    0
        NE
    0
    0
    0
        Withdrawn but consented to follow up and missed vi
    4
    1
    3
        Missing
    3
    1
    2
        Died
    5
    2
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Cycles 1-6, 6 and 12 months follow up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 -

    Serious adverse events
    		 Experimental
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 14 (57.14%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    0
    Investigations
    Neutropenia fever
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Vasovagal reaction
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Ano-rectal infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Low Potassium
         subjects affected / exposed
    1 / 14 (7.14%)
         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
    		 Experimental
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Phlebitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 14 (85.71%)
         occurrences all number
    47
    Fever
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Lethargy
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    14
    Flu like symptoms
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Weight loss
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences all number
    6
    Oral thrush
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastro-oesophageal reflux disease
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Inflammation in right wrist (possibly related to last infusion)
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Periorbital oedema
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    4
    Occasional headaches
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    4
    Dehydration
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Sore throat
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences all number
    7
    Flecks of blood when blowing nose
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Runny nose
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Mouth ulcers
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Mouth soreness
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Right eye bloodshot
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Urine stream stop/start
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Skin rash - left upper chest (insect bite)
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Left arm cellulitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Bleeding (bruise) left arm - picc line insertion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Swollen right hand
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Swollen left hand
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Allergic reaction
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Watering eyes
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Myalgias
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Left forearm swelling and pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pins and needles in hands and feet
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hot flushes
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 14 (50.00%)
         occurrences all number
    19
    Epistaxis
         subjects affected / exposed
    6 / 14 (42.86%)
         occurrences all number
    8
    Nose bleeds
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    7 / 14 (50.00%)
         occurrences all number
    17
    Haemoptysis/bronchopulmonary haemorphage
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Investigations
    ALT increased
         subjects affected / exposed
    5 / 14 (35.71%)
         occurrences all number
    12
    AST increased
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Cholesterol high
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Creatinine increased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    GGT increased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 14 (35.71%)
         occurrences all number
    15
    Neutrophil count decreased
         subjects affected / exposed
    12 / 14 (85.71%)
         occurrences all number
    36
    Platelet count decreased
         subjects affected / exposed
    11 / 14 (78.57%)
         occurrences all number
    30
    White blood cell count increased
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Increased platelets
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    10
    Thrombocytopaenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    9
    Dysgeusia (taste)
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    9
    Altered taste
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    4
    Neuropathy in left hand of uncertain origin
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Hypersensitivity to smells
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Paresthesia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 14 (57.14%)
         occurrences all number
    33
    Superficial left vein thrombosis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Tinnitus
         subjects affected / exposed
    5 / 14 (35.71%)
         occurrences all number
    16
    External otitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Eye disorders
    Inflamed left eye lid
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    7 / 14 (50.00%)
         occurrences all number
    14
    Constipation
         subjects affected / exposed
    10 / 14 (71.43%)
         occurrences all number
    27
    Diarrhoea
         subjects affected / exposed
    7 / 14 (50.00%)
         occurrences all number
    14
    Nausea
         subjects affected / exposed
    14 / 14 (100.00%)
         occurrences all number
    46
    Vomiting
         subjects affected / exposed
    9 / 14 (64.29%)
         occurrences all number
    20
    Stomatitis
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    4
    Mucositis
         subjects affected / exposed
    8 / 14 (57.14%)
         occurrences all number
    16
    Abdominal cramping
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastric reflux
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Blisters on tongue
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Sub acute bowel obstruction
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    5
    Eczema (non infected)
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    6
    Alopecia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    6
    Rash maculo-papular
         subjects affected / exposed
    5 / 14 (35.71%)
         occurrences all number
    11
    Folliculitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Itchy skin
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Skin rash
         subjects affected / exposed
    6 / 14 (42.86%)
         occurrences all number
    12
    Dry skin
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    9
    Acne form rash anterior chest
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Urinary frequency
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Nocturia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    7
    Dysuria
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Left loin pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Urinary urgency
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Endocrine disorders
    Salivary gland secretion increase
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Hypothyroidism
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Leg pain
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Coccygeal pain
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Cramp (calf muscle)
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Left chest wall pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Bilateral ankle oedema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Chest wall discomfort
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    6 / 14 (42.86%)
         occurrences all number
    8
    Back pain and left leg pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    5
    Whole body pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Pelvic pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cramp (hands and toes)
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    4
    Lower respiratory tract infection (chest)
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Chest infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypomagnesemia
         subjects affected / exposed
    6 / 14 (42.86%)
         occurrences all number
    16
    Hyponatraemia
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences all number
    15
    Hypophosphataemia
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    7
    Hyperglycaemia
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    4
    Hypokalaemia
         subjects affected / exposed
    7 / 14 (50.00%)
         occurrences all number
    9
    Appetite lost
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Reduced appetite
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Anorexia
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2011
    Change of documents: Cover Letter 18/08/2011 Protocol v2.0 04/08/2011 Protocol Amendment Log v2.0 04/08/2011 PIS Phase II Amendment Log v1.0 to v2.0 04/08/2011 PIS Phase I Amendment Log v1.0 to v2.0 04/08/2011 PIS Phase II v2.0 (clean and tracked changes versions) 04/08/2011 PIS Phase I v2.0 (clean and tracked changes versions) 04/08/2011 Pregnancy PIS supporting information Pregnancy PIS and Consent v1.0 04/08/2011 Phase I/Phase II Consent Form Amendment Log v2.0 04/08/2011 Phase I/Phase II Consent Form v2.0 (clean and tracked changes versions) 04/08/2011 Participant Trial Card v1.0 04/08/2011 Trial Summary v2.0 (clean and tracked changes versions) 04/08/2011 Additional Sites: Calderdale Royal-Uschi Hoffmann York Teaching Hospitals NHS Foundation Trust –David Bottomley Weston Park Hospital, Cancer Clinical Trials Centre –Linda Evans Bristol Haematology and Oncology Centre-Amit Bahl Huddersfield Royal Infirmary-Uschi Hoffmann Royal Free Hospital-Maria Vilarino-Varela Castle Hill Hospital-Mohammad Buitt Leicester Royal Infirmary-Steve Nicholson Changes of PI: Royal Bournemouth General Hospital-Susannah Brock (replaced Tom Geldart) Leeds St James’s –Satinder Jagdev (replaced John Chester) Removal of PI: Newcastle General Hospital –Trevor Roberts Velindre Cancer Centre-Jim Barber Queen Elizabeth Hospital (Bham)-Emilio Porfiri
    20 Mar 2012
    Addition of new sites and PI as follows: Addenbrookes Hospital –Simon Pacey
    03 May 2013
    Change of documents: Covering letter 08/07/2013 Protocol v3.0 dated 23/05/2013(clean copy) Protocol v3.0 dated 23/05/2013 (tracked changes) Protocol Amendment Log v2.0 to v3.0 04/07/2013 Phase I Participant Information Sheet v3.0 04/07/2013(clean copy) Phase I Participant Information Sheet v3.0 04/07/2013(tracked changes) Phase I Participant Information Sheet Amendment Log v2.0 to v3.0 08/07/2013 Phase II Participant Information Sheet v3.0 04/07/2013 (clean copy) Phase II Participant Information Sheet v3.0 04/07/2013 (tracked changes) Phase II Participant Information Sheet Amendment Log v2.0 to v3.0 08/07/2013 Phase I/Phase II Participant Consent Form v3.0 04/07/2013 (clean copy) Phase I/Phase II Participant Consent Form v3.0 04/07/2013 (tracked changes) Phase I/Phase II Participant Consent Form Amendment Log v2.0 to v3.0 08/07/2013
    19 Jun 2014
    Change of documents: TOTEM Clinical Trial Protocol (from v4.0 to version 5.0). Update the Reference Safety Information (RSI) for temsirolimus to the EMC update on 06/12/2013. Change the status of cisplatin and gemcitabine from nIMPs to IMPs. To seek a labelling exemption: for cisplatin and gemcitabine as IMPs. To change the person or organisation authorised by the sponsor responsible for the CTA: from Dr Gareth Griffiths to Dr Richard Adams. Provide simplified IMPD: for temsirolimus 11/07/14 Inform REC of non-substantial changes to protocol (v4.0 13.12.13)
    08 Dec 2015
    Change of documents: TOTEM Phase I PIS V7.0 12.11.15 TOTEM Consent Form Phase I/Phase II V7.0 12.11.15 TOTEM Clinical Trial Protocol (from v6.0 to v.7.0) To include Dr Simon Pacey as co-investigator To update Temsirolimus dose escalation schedule for Phase 1 with the inclusion of dose-level 3c To update Concomitant Medications Table

    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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