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    Clinical Trial Results:
    Torch: A phase II study to determine the safety and efficacy of the dual mTORC inhibitor AZD2014 and to investigate additional toxicities in combination with rituximab in relapsed refractory DLBCL

    Summary
    EudraCT number
    		 2014-003588-39
    Trial protocol
    		 GB  
    Global end of trial date
    05 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2020
    First version publication date
    14 Feb 2020
    Other versions
    Summary report(s)
    		 TORCH original article Haematological Oncology

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_14-212
    Additional study identifiers
    ISRCTN number
    		 ISRCTN10760016
    US NCT number
    		 NCT02752204
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CAS number: NH2003
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    CRCTU, University of Birmingham, Edgbaston, Birmingham, United Kingdom, B15 2TT
    Public contact
    TORCH Trial Cordinator, CRCTU, 44 1213717863, torch@trials.bham.ac.uk
    Scientific contact
    TORCH Trial Cordinator, University of Birmingham, 44 1213717863, torch@trials.bham.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
    05 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and activity of AZD2014 as a single agent in the treatment of Diffuse large B-Cell Lymphoma (DLBCL) by measuring the best overall response to the treatment within 6 cycles.
    Protection of trial subjects
    Specific dose modifications were recommended to decrease the incidence and relieve the symptoms of: nausea and vomiting; stomatitis, oral mucositis, and mouth ulcers; rash and/or skin toxicity; hyperglycaemia; interstitial lung disease; changes to ECG; Severe fatigue; diarrhoea; and electrolite changes.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2015
    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: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    13
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 36 patients were recruited between November 2015 and April 2017. Patients from 13 Haemato-oncology centres (those selected for the LLR Trials Acceleration Programme) in the UK were invited to join the trial.

    Pre-assignment
    Screening details
    		 Screening commenced following consent and prior to patient registration in order to confirm eligibility. Screening assessments included: medical history, height, weight, demographic data, blood tests, clinical and cardiac assessments, ECOG performance, assessment of constitutional symptoms, urinalysis, bone marrow biopsy, pregnancy test and PET-CT.

    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
    		 Monotherapy
    Arm description
    		 Vistusertib was administered to 30 patients in an intermittent dosing schedule of 125 mg b.d. for two days per week, for up to six 28-day cycles.
    Arm type
    		 Stage 1

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    125mg tablet given twice daily. 2 days on, 5 days off for up to 6 cycles.

    Arm title
    		 combination (stage 2)
    Arm description
    		 Patients received up to 6 cycles of vistusertib (125mg) BD, 2 days on and 5 days off, in addition to 375mg/m2 rituximab on day 1 of each cycle.
    Arm type
    		 Stage 2

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    125mg tablet given twice daily. 2 days on, 5 days off for up to 6 cycles.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera, Rixathon, Truxima
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m2 administered by intravenous infusion on day 1 of a weekly cycle.

    Number of subjects in period 1
    		Monotherapy combination (stage 2)
    Started
    30
    6
    Completed
    4
    1
    Not completed
    26
    5
         death
    2
    1
         Toxicity
    2
    -
         disease recurrence
    22
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 All patients that entered the trial

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 36 36
    Age categorical
    Ages of all patients who entered the trial
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 13 13
        From 65-84 years
    		 23 23
        85 years and over
    		 0 0
    Age continuous
    Summary of age
    Units: years
        median (full range (min-max))
    		 68.5 (33 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 15 15
    Disease status
    Number of patients with refractory or relapsed lymphoma
    Units: Subjects
        Refractory Lymphoma
    		 17 17
        Relapsed Lymphoma
    		 19 19
    Baseline Haematology - Haemoglobin
    Baseline levels of haemoglobin
    Units: g/L
        arithmetic mean (full range (min-max))
    		 117.3 (86 to 147) -
    HbA1C
    Measurement of glycated haemoglobin
    Units: mmol/mol
        arithmetic mean (full range (min-max))
    		 37.8 (28 to 67) -
    Lymphocytes
    Haematology assessment, number of lymphocytes (x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    		 1.0 (0.1 to 2.6) -
    Neutrophils
    Number of neutrophils (x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    		 6.7 (1.1 to 16.7) -
    Platelets
    Number of platelets(x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    		 235.1 (73 to 417) -
    White blood cell count
    Number of white blood cells (x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    		 8.3 (1.7 to 18.4) -
    ALT
    Amount of alanine aminotransferase
    Units: U/L
        arithmetic mean (full range (min-max))
    		 21.8 (10 to 55) -
    Bilirubin
    Amount of bilirubin
    Units: U/L
        arithmetic mean (full range (min-max))
    		 9.5 (3 to 20) -
    Cholesterol
    Amount of cholesterol
    Units: mmol/L
        arithmetic mean (full range (min-max))
    		 5.1 (3.4 to 8.8) -
    Serum Creatine
    Amount of serum creatine
    Units: umol/L
        arithmetic mean (full range (min-max))
    		 77.9 (38 to 169) -
    Glucose
    Baseline blood glucose levels
    Units: mmol/L
        arithmetic mean (full range (min-max))
    		 5.9 (3.7 to 10.9) -
    HDL Cholesterol
    Baseline blood levels of HDL cholesterol
    Units: mmol/L
        arithmetic mean (full range (min-max))
    		 1.5 (0.8 to 5.3) -
    Time from diagnosis
    Time from diagnosis to date of registration to the trial
    Units: days
        median (full range (min-max))
    		 691 (15 to 5670) -
    Subject analysis sets

    Subject analysis set title
    All patients across trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who entered the trial

    Subject analysis sets values
    		 All patients across trial
    Number of subjects
    36
    Age categorical
    Ages of all patients who entered the trial
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    13
        From 65-84 years
    23
        85 years and over
    0
    Age continuous
    Summary of age
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
        Male
    Disease status
    Number of patients with refractory or relapsed lymphoma
    Units: Subjects
        Refractory Lymphoma
        Relapsed Lymphoma
    Baseline Haematology - Haemoglobin
    Baseline levels of haemoglobin
    Units: g/L
        arithmetic mean (full range (min-max))
    HbA1C
    Measurement of glycated haemoglobin
    Units: mmol/mol
        arithmetic mean (full range (min-max))
    Lymphocytes
    Haematology assessment, number of lymphocytes (x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    Neutrophils
    Number of neutrophils (x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    Platelets
    Number of platelets(x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    White blood cell count
    Number of white blood cells (x 10^9) per L
    Units: 10^9/L
        arithmetic mean (full range (min-max))
    ALT
    Amount of alanine aminotransferase
    Units: U/L
        arithmetic mean (full range (min-max))
    Bilirubin
    Amount of bilirubin
    Units: U/L
        arithmetic mean (full range (min-max))
    Cholesterol
    Amount of cholesterol
    Units: mmol/L
        arithmetic mean (full range (min-max))
    Serum Creatine
    Amount of serum creatine
    Units: umol/L
        arithmetic mean (full range (min-max))
    Glucose
    Baseline blood glucose levels
    Units: mmol/L
        arithmetic mean (full range (min-max))
    HDL Cholesterol
    Baseline blood levels of HDL cholesterol
    Units: mmol/L
        arithmetic mean (full range (min-max))
    Time from diagnosis
    Time from diagnosis to date of registration to the trial
    Units: days
        median (full range (min-max))

    End points

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    End points reporting groups
    Reporting group title
    Monotherapy
    Reporting group description
    		 Vistusertib was administered to 30 patients in an intermittent dosing schedule of 125 mg b.d. for two days per week, for up to six 28-day cycles.

    Reporting group title
    combination (stage 2)
    Reporting group description
    		 Patients received up to 6 cycles of vistusertib (125mg) BD, 2 days on and 5 days off, in addition to 375mg/m2 rituximab on day 1 of each cycle.

    Subject analysis set title
    All patients across trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who entered the trial

    Primary: Best Overall Response during the first 6 cycles of treatment

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    End point title
    		 Best Overall Response during the first 6 cycles of treatment [1]
    End point description
    End point type
    Primary
    End point timeframe
    Best response achieved during the first 6 cycles of treatment
    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: No statistical analysis were conducted in relation to this primary outcome as this is a single arm trial so the interpretation of the primary outcome was made in relation to desirable characteristics defined in the sample size calculation.
    End point values
    		 Monotherapy combination (stage 2)
    Number of subjects analysed
    30
    6
    Units: Response
        Partial Response
    2
    0
        No response / stable disease
    6
    1
        Progressive disease
    13
    1
        Discontinued treatment prior to response assesment
    0
    1
        Discontinued treatment, died prior to assessment
    9
    2
        Died prior to response assessment
    0
    1
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Time from date of registration to the date of death from any cause
    End point values
    		 Monotherapy combination (stage 2)
    Number of subjects analysed
    30
    6
    Units: months
        median (confidence interval 95%)
    6.45 (3.42 to 13.87)
    0.94 (0.32 to 9000000000)
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Secondary
    End point timeframe
    Calculated from date of registration until date of disease progression or death from any cause
    End point values
    		 Monotherapy combination (stage 2)
    Number of subjects analysed
    30
    6
    Units: months
        median (confidence interval 95%)
    1.7 (1.61 to 1.97)
    0.79 (0.07 to 900000)
    No statistical analyses for this end point

    Secondary: Maximum percentage decrease during the first 6 cycles

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    End point title
    		 Maximum percentage decrease during the first 6 cycles
    End point description
    End point type
    Secondary
    End point timeframe
    The first 6 treatment cycles
    End point values
    		 All patients across trial
    Number of subjects analysed
    Units: percentage decrease
        arithmetic mean (full range (min-max))
    33.9 (-85.5 to 720)
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate Post 6 Cycles

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    End point title
    		 Best Overall Response Rate Post 6 Cycles
    End point description
    End point type
    Secondary
    End point timeframe
    Best overall response rate post 6 cycles of treatment until the end of the trial
    End point values
    		 Monotherapy combination (stage 2)
    Number of subjects analysed
    16 [2]
    1 [3]
    Units: Response
        Complete Response
    1
    0
        Partial Response
    5
    0
        Progressive Disease
    2
    0
        Response Assessment Not Performed
    8
    1
    Notes
    [2] - Only 16 of the 30 patients randomized to this group attended follow up visits post 6 cycles
    [3] - Only 1 of the 6 patients randomized to this group attended follow up visits post 6 cycles
    No statistical analyses for this end point

    Secondary: Tolerability

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    End point title
    		 Tolerability
    End point description
    Tolerability of AZD2014 both alone and in combination with Rituximab was assessed using toxicities recorded during trial treatment. The study needed to observe at least 21 tolerable outcomes (i.e at most 9 toxicities that lead to treatment delays or dose modification) during the first 2 cycles to conclude that the treatment was tolerable at the current dose. For the combination therapy at least 4 tolerable outcomes (i.e at most 2 toxicities that lead to treatment delay or dose modification) during the first 2 cycles needed to be observed to conclude the combination therapy was tolerable at the current dose.
    End point type
    Secondary
    End point timeframe
    First 2 cycles of treatment
    End point values
    		 Monotherapy combination (stage 2)
    Number of subjects analysed
    30
    6
    Units: Response
        Tolerated
    21
    5
        Not Tolerated
    9
    1
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of response was dened to be the time from rst documented response until relapse/progression, as determined by the Revised Response Criteria, or date of last follow up if relapse/progression free. Patients who die before a relapse/progression
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome was defined to be the time from first documented response until relapse/progression, since responses during this trial were observed only in the monotherapy group with no responses documented within the combination group results are given for only the monotherapy group as per the outcome definition.
    End point values
    		 Monotherapy
    Number of subjects analysed
    7 [5]
    Units: Months
        median (confidence interval 95%)
    0 (0 to 0)
    Notes
    [5] - Responses were only observed within 7 of the 30 patients randomized to this group.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the date of commencement of protocol defined treatment until 30 days after administration of the last treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    All patients entered in the trial
    Reporting group description
    		 All patients who entered the trial

    Serious adverse events
    		 All patients entered in the trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 36 (47.22%)
         number of deaths (all causes)
    32
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Diarrhea
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mucositis oral
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders - other
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations - other
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 36 (2.78%)
         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
    		 All patients entered in the trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 36 (97.22%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    4
    Neutrophil count decreased
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Weight loss
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Dysgeusia
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    General disorders and administration site conditions
    edema limbs
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    14 / 36 (38.89%)
         occurrences all number
    20
    Fever
         subjects affected / exposed
    6 / 36 (16.67%)
         occurrences all number
    9
    General disorders and administration site conditions - other
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    7
    Pain
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 36 (19.44%)
         occurrences all number
    9
    Constipation
         subjects affected / exposed
    6 / 36 (16.67%)
         occurrences all number
    6
    Diarrhoea
         subjects affected / exposed
    15 / 36 (41.67%)
         occurrences all number
    21
    Dyspepsia
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    5
    Gastrointestinal disorder
         subjects affected / exposed
    7 / 36 (19.44%)
         occurrences all number
    15
    Mucositis oral
         subjects affected / exposed
    10 / 36 (27.78%)
         occurrences all number
    14
    Nausea
         subjects affected / exposed
    16 / 36 (44.44%)
         occurrences all number
    21
    Vomiting
         subjects affected / exposed
    9 / 36 (25.00%)
         occurrences all number
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    4
    Dyspnea
         subjects affected / exposed
    6 / 36 (16.67%)
         occurrences all number
    7
    Productive cough
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders - other
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    7
    Skin and subcutaneous tissue disorders - other
         subjects affected / exposed
    6 / 36 (16.67%)
         occurrences all number
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Psychiatric disorders - other
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Renal and urinary disorders
    Renal and urinary disorders - other
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Urinary frequency
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorder - other
         subjects affected / exposed
    10 / 36 (27.78%)
         occurrences all number
    11
    Infections and infestations
    Infections and infestations - other
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    6
    Skin infection
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    6
    Dehydration
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2015
    SA2: Substantial amendment made for ethical approval. This included reduction of patient identifiable data collected from Date of Birth to Year of Birth. Minor clarifications and typographical corrections were made.
    18 May 2015
    SA 3: Substantial amendment made for MHRA approval. This included an update to exclusion criteria (platelet count). Addition of exclusions for rituximab patients added. Additional advice for toxicities with rituximab added.
    06 Jul 2016
    SA 9: Substantial amendment made. This included an update to saliva sample (no longer optional), clarification of screening assessment, and insertion of ISRCTN number. Removal of QT interval prolonging drugs drugs and ECG requirements from the exclusions. Rewording of the eligibility criteria relating to patients with hepatitis infection. Amendment of dose modification information. Reduction of ECG frequency. Updated list of concomitant medications to be avoided.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31385336
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