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    Clinical Trial Results:
    Phase III trial on Concurrent and Adjuvant Temozolomide chemotherapy in non-1p/19q deleted anaplastic glioma. The CATNON Intergroup trial.

    Summary
    EudraCT number
    		 2006-001533-17
    Trial protocol
    		 NL   DE   FR   IT   BE   ES   GB   AT  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2021
    First version publication date
    18 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EORTC26053-22054
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    EORTC
    Sponsor organisation address
    83 Avenue Mounier, Brussels, Belgium, 1200
    Public contact
    Project Mgt & Regulatory Unit, European Organisation for Research and Treatment of Cancer (EORTC), 00 32 2774 10 72/, regulatory@eortc.be
    Scientific contact
    Project Mgt & Regulatory Unit, European Organisation for Research and Treatment of Cancer (EORTC), 00 32 2774 10 72/, regulatory@eortc.be
    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
    Interim
    Date of interim/final analysis
    07 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Feb 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To assess whether concurrent radiotherapy with daily temozolomide chemotherapy improves overall survival as compared to no daily temozolomide in patients with non-1p/19q deleted anaplastic glioma. To assess whether adjuvant temozolomide chemotherapy improves survival as compared to no adjuvant temozolomide chemotherapy in patients with non-1p/19q deleted anaplastic glioma
    Protection of trial subjects
    The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh amendments) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol was written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice . The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    United Kingdom: 143
    Country: Number of subjects enrolled
    Netherlands: 72
    Country: Number of subjects enrolled
    Belgium: 73
    Country: Number of subjects enrolled
    France: 93
    Country: Number of subjects enrolled
    Germany: 70
    Country: Number of subjects enrolled
    Italy: 50
    Country: Number of subjects enrolled
    Switzerland: 26
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    United States: 101
    Country: Number of subjects enrolled
    Australia: 82
    Country: Number of subjects enrolled
    Canada: 23
    Worldwide total number of subjects
    751
    EEA total number of subjects
    515
    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)
    696
    From 65 to 84 years
    55
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All patients were initially registered into the trial as soon as possible after surgery. After this point, material was sent for 1p/19q analysis and MGMT promoter methylation assay. Patients could only be randomized into the trial within 8 days from the start of radiotherapy; at this time, all baseline requirements for the study had to be fulfilled

    Period 1
    Period 1 title
    Randomization (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Radiotherapy
    Arm description
    		 Arm 1: Radiotherapy and further treatment including chemotherapy if indicated at progression
    Arm type
    		 Radiotherapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 TMZ/RT
    Arm description
    		 Arm 2: Radiotherapy & concurrent temozolomide
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomized to concomitant temozolomide received temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy. The drug was administered orally 1 hour before each session of radiotherapy during weekdays. During weekends without radiotherapy, the drug was taken in the morning. The dose administered was determined using the body surface area (BSA) calculated at the beginning of the concomitant treatment. The daily dose was rounded to the nearest 5 mg. In case of high value of BSA, an upper limit of 2.1 m² is suggested to calculate the dose. Patients was told to swallow the whole capsules in rapid succession without chewing them. If vomiting occurs during the course of the treatment, no re-dosing of the patient was allowed before the next scheduled dose.

    Arm title
    		 RT->TMZ
    Arm description
    		 Arm 3: Radiotherapy + adjuvant temozolomide for 12 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomized to adjuvant temozolomide started adjuvant temozolomide after a 4 week resting period after the end of radiotherapy. Temozolomide was administered orally once a day for 5 consecutive days (days 1-5). The starting dose for the first cycle was 150 mg/m²/day with a single dose escalation to 200mg/m²/day in subsequent cycles if no significant toxicity was observed in the first cycle. One cycle was defined as 28 days and a maximum of 12 cycles was administered. Treatment could be discontinued earlier in case of significant toxicity interfering with further treatment and not responding to dose reductions, or at the patient wish. The dose administered was determined using the BSA calculated at the beginning of each treatment cycle. The dose was rounded to the nearest 5 mg. In case of high value of BSA, an upper limit of 2.1 m² was suggested to calculate the dose.

    Arm title
    		 TMZ/RT->TMZ
    Arm description
    		 Arm 4: Radiotherapy & concurrent temozolomide + adjuvant temozolomide for 12 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Both concomitant and adjuvant Temozolomide (see other corresponding arms for details)

    Number of subjects in period 1
    		Radiotherapy TMZ/RT RT->TMZ TMZ/RT->TMZ
    Started
    189
    188
    186
    188
    Completed
    175
    163
    109
    93
    Not completed
    14
    25
    77
    95
         Consent withdrawn by subject
    3
    1
    5
    11
         RT was prematurely stopped by mistake
    1
    -
    -
    -
         Adverse event, non-fatal
    1
    7
    14
    28
         Multiple reasons
    1
    6
    7
    13
         Death not due to malig. disease or toxicity
    -
    1
    -
    -
         Missing
    -
    -
    1
    -
         Lack of efficacy
    6
    7
    49
    40
         Missing reason
    2
    2
    -
    3
         Protocol deviation
    -
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Radiotherapy
    Reporting group description
    		 Arm 1: Radiotherapy and further treatment including chemotherapy if indicated at progression

    Reporting group title
    TMZ/RT
    Reporting group description
    		 Arm 2: Radiotherapy & concurrent temozolomide

    Reporting group title
    RT->TMZ
    Reporting group description
    		 Arm 3: Radiotherapy + adjuvant temozolomide for 12 cycles

    Reporting group title
    TMZ/RT->TMZ
    Reporting group description
    		 Arm 4: Radiotherapy & concurrent temozolomide + adjuvant temozolomide for 12 cycles

    Reporting group values
    		 Radiotherapy TMZ/RT RT->TMZ TMZ/RT->TMZ Total
    Number of subjects
    		 189 188 186 188 751
    Age categorical
    Age at randomization
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 174 168 174 180 696
        From 65-84 years
    		 15 20 12 8 55
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 75 68 82 82 307
        Male
    		 114 120 104 106 444
    Presence of oligodendroglial elements
    Presence of oligodendroglial elements (Yes vs No)
    Units: Subjects
        No oligodendroglial elements
    		 146 144 143 144 577
        Oligodendroglial elements
    		 43 44 43 44 174
    WHO Performance Status
    WHO Performance Status (PS >0 vs PS 0)
    Units: Subjects
        PS 0
    		 111 110 108 112 441
        PS >0
    		 78 78 78 76 310
    Presence of 1p LOH
    Presence of 1p LOH (Yes vs No)
    Units: Subjects
        1p no loss
    		 175 176 172 175 698
        1p loss
    		 14 12 14 13 53
    MGMT Methylation Status
    MGMT (Methylated/Unmethylated/Undetermined /invalid)
    Units: Subjects
        Methylated
    		 62 55 66 56 239
        Unmethylated
    		 83 79 78 87 327
        Undetermined/invalid
    		 44 54 42 45 185
    Subject analysis sets

    Subject analysis set title
    Intent to Treat with concomitant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients with concomitant TMZ

    Subject analysis set title
    Intent to Treat without concomitant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients without concomitant TMZ

    Subject analysis set title
    Intent to Treat with adjuvant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients with adjuvant TMZ.

    Subject analysis set title
    Intent to Treat without adjuvant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients without adjuvant TMZ.

    Subject analysis sets values
    		 Intent to Treat with concomitant TMZ Intent to Treat without concomitant TMZ Intent to Treat with adjuvant TMZ Intent to Treat without adjuvant TMZ
    Number of subjects
    376
    375
    374
    377
    Age categorical
    Age at randomization
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    348
    348
    354
    342
        From 65-84 years
    28
    27
    20
    35
        85 years and over
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    150
    157
    164
    143
        Male
    126
    218
    210
    234
    Presence of oligodendroglial elements
    Presence of oligodendroglial elements (Yes vs No)
    Units: Subjects
        No oligodendroglial elements
    288
    289
    187
    290
        Oligodendroglial elements
    88
    86
    87
    87
    WHO Performance Status
    WHO Performance Status (PS >0 vs PS 0)
    Units: Subjects
        PS 0
    222
    219
    220
    221
        PS >0
    154
    156
    154
    156
    Presence of 1p LOH
    Presence of 1p LOH (Yes vs No)
    Units: Subjects
        1p no loss
    351
    347
    347
    351
        1p loss
    25
    28
    27
    26
    MGMT Methylation Status
    MGMT (Methylated/Unmethylated/Undetermined /invalid)
    Units: Subjects
        Methylated
    111
    128
    122
    117
        Unmethylated
    166
    161
    165
    162
        Undetermined/invalid
    99
    86
    87
    98

    End points

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    End points reporting groups
    Reporting group title
    Radiotherapy
    Reporting group description
    		 Arm 1: Radiotherapy and further treatment including chemotherapy if indicated at progression

    Reporting group title
    TMZ/RT
    Reporting group description
    		 Arm 2: Radiotherapy & concurrent temozolomide

    Reporting group title
    RT->TMZ
    Reporting group description
    		 Arm 3: Radiotherapy + adjuvant temozolomide for 12 cycles

    Reporting group title
    TMZ/RT->TMZ
    Reporting group description
    		 Arm 4: Radiotherapy & concurrent temozolomide + adjuvant temozolomide for 12 cycles

    Subject analysis set title
    Intent to Treat with concomitant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients with concomitant TMZ

    Subject analysis set title
    Intent to Treat without concomitant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients without concomitant TMZ

    Subject analysis set title
    Intent to Treat with adjuvant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients with adjuvant TMZ.

    Subject analysis set title
    Intent to Treat without adjuvant TMZ
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients analyzed in the arm they were allocated by randomization. Patients without adjuvant TMZ.

    Primary: Overall Survival with concomitant TMZ

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    End point title
    		 Overall Survival with concomitant TMZ
    End point description
    The duration of survival is the time interval between randomization and the date of death due to any cause. Patients not reported dead or lost to follow up will be censored at the date of the last follow up examination.
    End point type
    Primary
    End point timeframe
    All patients had to be followed every 3 months until death.
    End point values
    		 Intent to Treat with concomitant TMZ Intent to Treat without concomitant TMZ
    Number of subjects analysed
    376
    375
    Units: Month
        median (confidence interval 95%)
    66.9 (48.5 to 82.3)
    60.4 (45.7 to 71.5)
    Statistical analysis title
    		 Adjusted OS Cox model for concomitant TMZ question
    Statistical analysis description
    Cox overall survival model with question adjusted by the stratification factors at randomization
    Comparison groups
    Intent to Treat with concomitant TMZ v Intent to Treat without concomitant TMZ
    Number of subjects included in analysis
    751
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.76
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 99.1%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.28

    Primary: Overall Survival with adjuvant TMZ

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    End point title
    		 Overall Survival with adjuvant TMZ
    End point description
    The duration of survival is the time interval between randomization and the date of death due to any cause. Patients not reported dead or lost to follow up will be censored at the date of the last follow up examination.
    End point type
    Primary
    End point timeframe
    All patients hat to be followed every 3 months until death
    End point values
    		 Intent to Treat with adjuvant TMZ Intent to Treat without adjuvant TMZ
    Number of subjects analysed
    374
    377
    Units: Month
        median (confidence interval 95%)
    82.3 (67.2 to 116.6)
    46.9 (37.9 to 56.9)
    Statistical analysis title
    		 Adjusted Cox OS model for adjuvant TMZ
    Statistical analysis description
    Cox overall survival model with adjuvant TMZ question adjusted by the stratification factors at randomization
    Comparison groups
    Intent to Treat with adjuvant TMZ v Intent to Treat without adjuvant TMZ
    Number of subjects included in analysis
    751
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.79

    Secondary: Progression-free Survival with concomitant TMZ

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    End point title
    		 Progression-free Survival with concomitant TMZ
    End point description
    End point type
    Secondary
    End point timeframe
    MRI was obtained prior to surgery, post-surgery, prior to initiation of the concurrent radiation and temozolomide therapy, then within 72 hours prior to initiating adjuvant chemotherapy, then every 3 cycles, and at the time of neurologic deterioration.
    End point values
    		 Radiotherapy TMZ/RT RT->TMZ TMZ/RT->TMZ Intent to Treat with concomitant TMZ Intent to Treat without concomitant TMZ
    Number of subjects analysed
    189
    188
    186
    188
    376
    375
    Units: Months
        median (confidence interval 95%)
    17.0 (11.3 to 20.9)
    23.0 (15.0 to 34.9)
    28.6 (20.6 to 46.4)
    55.8 (32.2 to 77.0)
    33.0 (23.8 to 46.1)
    20.9 (17.3 to 26.6)
    Statistical analysis title
    		 Adjusted Cox PFS model for concomitant TMZ
    Statistical analysis description
    Adjusted Cox Progression-free Survival model for the concomitant TMZ question
    Comparison groups
    Intent to Treat without concomitant TMZ v Intent to Treat with concomitant TMZ
    Number of subjects included in analysis
    751
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.03

    Secondary: Progression-free Survival with adjuvant TMZ

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    End point title
    		 Progression-free Survival with adjuvant TMZ
    End point description
    End point type
    Secondary
    End point timeframe
    MRI was obtained prior to surgery, post-surgery, prior to initiation of the concurrent radiation and temozolomide therapy, then within 72 hours prior to initiating adjuvant chemotherapy, then every 3 cycles, and at the time of neurologic deterioration.
    End point values
    		 Intent to Treat with adjuvant TMZ Intent to Treat without adjuvant TMZ
    Number of subjects analysed
    374
    377
    Units: Months
        median (confidence interval 95%)
    42.8 (27.8 to 56.4)
    19.1 (14.6 to 23.8)
    Statistical analysis title
    		 Adjusted Cox PFS model for adjuvant TMZ
    Statistical analysis description
    Adjusted Cox PFS model for adjuvant TMZ question
    Comparison groups
    Intent to Treat with adjuvant TMZ v Intent to Treat without adjuvant TMZ
    Number of subjects included in analysis
    751
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Before trt start, during radiotherapy trt, weekly visits, evaluation at week 4 and 6, evaluation 4 weeks after the end of radiotherapy, six monthly disease evaluation after the end of radiotherapy, prior to each cycle of adjuvant therapy.
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. (xx% AEs are reported as "other" and are not reported as not available from the list of SOC). AEs and SAEs are evaluated using CTC grading. Non-SAEs has not been collected specifically, all AEs will be reported in non-SAE section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Radiotherapy
    Reporting group description
    		 Radiotherapy

    Reporting group title
    RT->TMZ
    Reporting group description
    		 RT->TMZ

    Reporting group title
    TMZ/RT->TMZ
    Reporting group description
    		 TMZ/RT->TMZ

    Reporting group title
    TMZ/RT
    Reporting group description
    		 TMZ/RT

    Serious adverse events
    		 Radiotherapy RT->TMZ TMZ/RT->TMZ TMZ/RT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 186 (6.99%)
    32 / 183 (17.49%)
    32 / 185 (17.30%)
    27 / 185 (14.59%)
         number of deaths (all causes)
    129
    92
    86
    108
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    VASCULAR
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
    0 / 185 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CONSTITUTIONAL SYMPTOMS
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 183 (1.09%)
    2 / 185 (1.08%)
    7 / 185 (3.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    2 / 186 (1.08%)
    4 / 183 (2.19%)
    3 / 185 (1.62%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    ALLERGY/IMMUNOLOGY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 183 (1.09%)
    2 / 185 (1.08%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY/UPPER RESPIRATORY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 183 (0.00%)
    1 / 185 (0.54%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC(GENERAL)
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
    1 / 185 (0.54%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    NEUROLOGY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    9 / 186 (4.84%)
    12 / 183 (6.56%)
    10 / 185 (5.41%)
    15 / 185 (8.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    BLOOD
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 183 (1.09%)
    5 / 185 (2.70%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPHATICS
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 183 (0.55%)
    0 / 185 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    OCULAR/VISUAL
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 183 (0.00%)
    1 / 185 (0.54%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    GASTROINTESTINAL
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 186 (0.54%)
    4 / 183 (2.19%)
    5 / 185 (2.70%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATOLOGY/SKIN
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
    2 / 185 (1.08%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL/GENITOURINARY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
    1 / 185 (0.54%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL/SOFT TISSUE
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
    0 / 185 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    INFECTION
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    6 / 186 (3.23%)
    8 / 183 (4.37%)
    6 / 185 (3.24%)
    4 / 185 (2.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    METABOLIC/LABORATORY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 183 (0.55%)
    1 / 185 (0.54%)
    2 / 185 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Radiotherapy RT->TMZ TMZ/RT->TMZ TMZ/RT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    182 / 186 (97.85%)
    182 / 183 (99.45%)
    185 / 185 (100.00%)
    183 / 185 (98.92%)
    Vascular disorders
    VASCULAR
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    2 / 186 (1.08%)
    5 / 183 (2.73%)
    7 / 185 (3.78%)
    7 / 185 (3.78%)
         occurrences all number
    2
    11
    22
    26
    Surgical and medical procedures
    SURGERY/INTRA-OPERATIVE INJURY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 183 (0.00%)
    1 / 185 (0.54%)
    0 / 185 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    CONSTITUTIONAL SYMPTOMS
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    151 / 186 (81.18%)
    170 / 183 (92.90%)
    176 / 185 (95.14%)
    160 / 185 (86.49%)
         occurrences all number
    925
    2182
    2302
    1144
    PAIN
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    129 / 186 (69.35%)
    138 / 183 (75.41%)
    132 / 185 (71.35%)
    131 / 185 (70.81%)
         occurrences all number
    656
    1219
    960
    738
    Immune system disorders
    ALLERGY/IMMUNOLOGY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    7 / 186 (3.76%)
    11 / 183 (6.01%)
    15 / 185 (8.11%)
    9 / 185 (4.86%)
         occurrences all number
    16
    19
    45
    14
    Reproductive system and breast disorders
    SEXUAL/REPRODUCTIVE FUNCTION
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    2 / 186 (1.08%)
    7 / 183 (3.83%)
    13 / 185 (7.03%)
    4 / 185 (2.16%)
         occurrences all number
    4
    33
    23
    4
    Respiratory, thoracic and mediastinal disorders
    PULMONARY/UPPER RESPIRATORY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    8 / 186 (4.30%)
    17 / 183 (9.29%)
    18 / 185 (9.73%)
    9 / 185 (4.86%)
         occurrences all number
    13
    33
    59
    14
    Cardiac disorders
    CARDIAC(GENERAL)
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    9 / 186 (4.84%)
    17 / 183 (9.29%)
    20 / 185 (10.81%)
    15 / 185 (8.11%)
         occurrences all number
    23
    50
    74
    43
    Nervous system disorders
    NEUROLOGY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    147 / 186 (79.03%)
    148 / 183 (80.87%)
    154 / 185 (83.24%)
    153 / 185 (82.70%)
         occurrences all number
    1431
    2026
    1777
    1575
    Blood and lymphatic system disorders
    BLOOD
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    5 / 186 (2.69%)
    10 / 183 (5.46%)
    14 / 185 (7.57%)
    12 / 185 (6.49%)
         occurrences all number
    11
    15
    44
    64
    LYMPHATICS
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    12 / 186 (6.45%)
    14 / 183 (7.65%)
    11 / 185 (5.95%)
    10 / 185 (5.41%)
         occurrences all number
    33
    44
    34
    40
    Ear and labyrinth disorders
    AUDITORY/EAR
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    30 / 186 (16.13%)
    33 / 183 (18.03%)
    39 / 185 (21.08%)
    23 / 185 (12.43%)
         occurrences all number
    75
    157
    185
    67
    Eye disorders
    OCULAR/VISUAL
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    51 / 186 (27.42%)
    48 / 183 (26.23%)
    56 / 185 (30.27%)
    62 / 185 (33.51%)
         occurrences all number
    207
    253
    271
    261
    Gastrointestinal disorders
    GASTROINTESTINAL
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    107 / 186 (57.53%)
    158 / 183 (86.34%)
    161 / 185 (87.03%)
    136 / 185 (73.51%)
         occurrences all number
    468
    1428
    1761
    795
    Hepatobiliary disorders
    HEPATOBILIAR/PANCREAS
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 183 (0.00%)
    2 / 185 (1.08%)
    0 / 185 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Skin and subcutaneous tissue disorders
    DERMATOLOGY/SKIN
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    146 / 186 (78.49%)
    147 / 183 (80.33%)
    157 / 185 (84.86%)
    139 / 185 (75.14%)
         occurrences all number
    881
    1248
    1259
    984
    Renal and urinary disorders
    RENAL/GENITOURINARY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    11 / 186 (5.91%)
    16 / 183 (8.74%)
    9 / 185 (4.86%)
    7 / 185 (3.78%)
         occurrences all number
    24
    34
    19
    22
    Endocrine disorders
    ENDOCRINE
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    6 / 186 (3.23%)
    9 / 183 (4.92%)
    15 / 185 (8.11%)
    8 / 185 (4.32%)
         occurrences all number
    27
    24
    41
    23
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL/SOFT TISSUE
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    16 / 186 (8.60%)
    23 / 183 (12.57%)
    23 / 185 (12.43%)
    17 / 185 (9.19%)
         occurrences all number
    39
    102
    101
    63
    Infections and infestations
    INFECTION
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    37 / 186 (19.89%)
    72 / 183 (39.34%)
    66 / 185 (35.68%)
    35 / 185 (18.92%)
         occurrences all number
    57
    144
    131
    71
    Metabolism and nutrition disorders
    METABOLIC/LABORATORY
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    7 / 186 (3.76%)
    8 / 183 (4.37%)
    10 / 185 (5.41%)
    7 / 185 (3.78%)
         occurrences all number
    10
    10
    16
    41

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

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

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

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