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    Clinical Trial Results:
    Prospective Trial for the diagnosis and treatment of children, adolescents and young adults with Intracranial Germ Cell Tumours

    Summary
    EudraCT number
    		 2009-018072-33
    Trial protocol
    		 DE   SE   GB   FR   AT   IT  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2021
    First version publication date
    07 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UKM08_0057
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Münster
    Sponsor organisation address
    Albert-Schweitzer-Campus 1, Gebäude D5, Münster, Germany, 48149
    Public contact
    SIOP CNS GCT II-Studienleitung, Universitätsklinikum Münster, 0049 15144048563, Gabriele.Calaminus@ukmuenster.de
    Scientific contact
    SIOP CNS GCT II-Studienleitung, Universitätsklinikum Münster, 0049 15144048563, Gabriele.Calaminus@ukmuenster.de
    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
    10 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Germinoma: -To maintain current high event-free survival (EFS) rates using a risk adapted approach -In localised germinoma: to omit whole brain and spinal irradiation by using combined treatment with standard chemotherapy and ventricular irradiation (+/- boosts) -In bifocal tumours (pineal + suprasellar): to treat as non-metastatic disease and to omit whole brain and spinal irradiation by using combined treatment with standard chemotherapy and ventricular irra-diation (+/- boosts) -In metastatic disease: to maintain current excellent EFS in metastatic germinoma with craniospinal irradiation Malignant non-germinoma: -To improve EFS in high risk patients by intensifying treatment -by dose escalation of chemotherapy in patients identified as high risk at diagnosis -by standardising the surgical approach for residual disease after treatment Teratoma: -To register patients and collect data regarding diagnostics, treatment and outcome in order to develop future treatment strategies
    Protection of trial subjects
    This study was conducted in accordance with applicable laws and regulations including, but not limited to, the ethical principles that have their origins in the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP). Prior to recruitment of subjects, the relevant authorities and ethics committees had to approve and authorize this clinical trial. Amendments were only implemented after approval. Before the procedures mentioned in the protocol were performed, the subject or his/her parent/legal guardian had to sign and date the approved informed consent form according to the requirements of national law.
    Background therapy
    		 Supportive care during chemotherapy Diabetes Insipidus (DI) is a common complication encountered in the treatment of malignant CNS GCTs. DI should be controlled prior to starting chemotherapy, and particular attention should be paid to sodium and fluid balance throughout treatment in all cases. Clinicians were advised to work closely with their colleagues in endocrinology. Anti-emetic treatment should have included a 5HT antagonist. Administration of steroids (e.g. dexamethasone) during chemotherapy should be avoided if at all possible, and only used for anti-emesis if other therapies had failed. If symptoms of raised intracranial pressure developed during treatment, the cause (e.g. hydrocephalus) should be actively sought. Steroids should only be used as a short-term measure prior to definitive treatment of raised pressure. In patients with raised intracranial pressure at the time of the first chemotherapy course, particular care should be taken about hyperhydration. In such cases therapy modifications should be discussed with the co-ordinator. The prophylactic use of cotrimoxazole (sulfamethoxazole/trimethoprim) was optional and should be based on local practice, as no case of pneumocystis carinii infection had been reported in the SIOP CNS GCT 96 series. Prophylactic antibiotic/antifungal decontamination could be used if it is the normal practice in the treating hospital. The choice of antibiotics used during episodes of febrile neutropenia should be based on local guidelines.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 18
    Country: Number of subjects enrolled
    United Kingdom: 83
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    France: 128
    Country: Number of subjects enrolled
    Germany: 140
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Switzerland: 9
    Worldwide total number of subjects
    394
    EEA total number of subjects
    385
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    5
    Infants and toddlers (28 days-23 months)
    5
    Children (2-11 years)
    134
    Adolescents (12-17 years)
    156
    Adults (18-64 years)
    94
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were recruited from 100 trial sites in 8 countries. The recruitment period was from 06 October 2011 to 01 July 2018. The first patient was enrolled on the 07 February 2012 and the last one was diagnosed on the 26 June 2018.

    Pre-assignment
    Screening details
    		 The study included patients with Intracranial Germ Cell tumours of any histology and intracranial site and dissemination.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mal. Non-Germinoma
    Arm description
    		 Study patients with a malignant non-germinoma GCT. In this diagnostic group, patients received the following treatment: - Patients with standard risk received standard chemotherapy consisting of four courses of cisplatin, etoposide and ifosfamide. High risk patients received 2 cycles of standard chemotherapy followed by two dose intensified courses of cisplatin, etoposide and ifosfamide with stem cell support. - After 3 courses of chemotherapy, resection of the residual tumor was performed (if indicated), If viable cells were found in the resected tumour specimen, the patients were transferred to the high risk arm. - Chemotherapy was followed by radiotherapy for both risk groups.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered on days 1 to 5 of 21-day cycles 1 to 4 at a dose of 20 mg/m²/day.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard risk: Etoposide was administered on days 1 to 3 of 21-day cycles 1 to 4 at a dose of 100 mg/m²/day. High risk: Etoposide was given on days 1 to 3 of the first two 21-day cycles at a dose of 100 mg/m²/day. On cycles 3 and 4, Etoposide was administered on days 1 to 5 at a dose of 300 mg/m²/day (high dose).

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard risk: Ifosfamide was administered on days 1 to 5 of 21-day cycles 1 to 4 at a dose of 1500 mg/m²/day. High risk: Ifosfamide was given on days 1 to 5 of the first two 21-day cycles at a dose of 1500 mg/m²/day. On cycles 3 and 4, Ifosfamide was administered on days 1 to 5 at a dose of 2000 mg/m²/day (high dose).

    Arm title
    		 Germinoma
    Arm description
    		 Study patients with a germinoma GCT. In this diagnostic group, patients received the following treatment: - Non-metastatic fully staged germinoma (± teratoma): Chemotherapy consisting of two courses (1 and 3) of carboplatin and etoposide, alternating with two courses (2 and 4) of ifosfamide and etoposide. Chemotherapy was followed by radiotherapy. - Metastatic or incompletely staged germinomas (± teratoma): Received only radiotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was given on day 1 of 21-day cycles 1 and 3 at a dose of 600 mg/m²/day.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ifosfamide was administered on day 1 to 5 of 21-day cycles 2 and 4 at a dose of 1800 mg/m²/day.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide was given on days 1 to 3 of 21-day cycles 1 to 4 at a dose of 100 mg/m²/day.

    Arm title
    		 Teratoma
    Arm description
    		 Study patients with intracranial teratomas were registered in order to obtain better information regarding the epidemiology and biology of this rare disease. Teratoma were treated by surgery as main treatment option and additional treatment according to histology and resection status. Treatment for mature and immature teratoma had to be individualised, based on the age of the patient, clinical status, tumour stage and histology. Thus, no overall therapeutic strategy was outlined in the protocol but recommendations were given on an individual basis.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Mal. Non-Germinoma Germinoma Teratoma
    Started
    112
    261
    21
    Completed
    97
    260
    20
    Not completed
    15
    1
    1
         Tumor-related death
    15
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mal. Non-Germinoma
    Reporting group description
    		 Study patients with a malignant non-germinoma GCT. In this diagnostic group, patients received the following treatment: - Patients with standard risk received standard chemotherapy consisting of four courses of cisplatin, etoposide and ifosfamide. High risk patients received 2 cycles of standard chemotherapy followed by two dose intensified courses of cisplatin, etoposide and ifosfamide with stem cell support. - After 3 courses of chemotherapy, resection of the residual tumor was performed (if indicated), If viable cells were found in the resected tumour specimen, the patients were transferred to the high risk arm. - Chemotherapy was followed by radiotherapy for both risk groups.

    Reporting group title
    Germinoma
    Reporting group description
    		 Study patients with a germinoma GCT. In this diagnostic group, patients received the following treatment: - Non-metastatic fully staged germinoma (± teratoma): Chemotherapy consisting of two courses (1 and 3) of carboplatin and etoposide, alternating with two courses (2 and 4) of ifosfamide and etoposide. Chemotherapy was followed by radiotherapy. - Metastatic or incompletely staged germinomas (± teratoma): Received only radiotherapy.

    Reporting group title
    Teratoma
    Reporting group description
    		 Study patients with intracranial teratomas were registered in order to obtain better information regarding the epidemiology and biology of this rare disease. Teratoma were treated by surgery as main treatment option and additional treatment according to histology and resection status. Treatment for mature and immature teratoma had to be individualised, based on the age of the patient, clinical status, tumour stage and histology. Thus, no overall therapeutic strategy was outlined in the protocol but recommendations were given on an individual basis.

    Reporting group values
    		 Mal. Non-Germinoma Germinoma Teratoma Total
    Number of subjects
    		 112 261 21 394
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 5 5
        Infants and toddlers (28 days-23 months)
    		 1 0 4 5
        Children (2-11 years)
    		 42 83 9 134
        Adolescents (12-17 years)
    		 50 104 2 156
        Adults (18-64 years)
    		 19 74 1 94
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.45 ( 4.87 ) 15.79 ( 6.35 ) 5.32 ( 5.94 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 52 7 82
        Male
    		 89 209 14 312

    End points

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    End points reporting groups
    Reporting group title
    Mal. Non-Germinoma
    Reporting group description
    		 Study patients with a malignant non-germinoma GCT. In this diagnostic group, patients received the following treatment: - Patients with standard risk received standard chemotherapy consisting of four courses of cisplatin, etoposide and ifosfamide. High risk patients received 2 cycles of standard chemotherapy followed by two dose intensified courses of cisplatin, etoposide and ifosfamide with stem cell support. - After 3 courses of chemotherapy, resection of the residual tumor was performed (if indicated), If viable cells were found in the resected tumour specimen, the patients were transferred to the high risk arm. - Chemotherapy was followed by radiotherapy for both risk groups.

    Reporting group title
    Germinoma
    Reporting group description
    		 Study patients with a germinoma GCT. In this diagnostic group, patients received the following treatment: - Non-metastatic fully staged germinoma (± teratoma): Chemotherapy consisting of two courses (1 and 3) of carboplatin and etoposide, alternating with two courses (2 and 4) of ifosfamide and etoposide. Chemotherapy was followed by radiotherapy. - Metastatic or incompletely staged germinomas (± teratoma): Received only radiotherapy.

    Reporting group title
    Teratoma
    Reporting group description
    		 Study patients with intracranial teratomas were registered in order to obtain better information regarding the epidemiology and biology of this rare disease. Teratoma were treated by surgery as main treatment option and additional treatment according to histology and resection status. Treatment for mature and immature teratoma had to be individualised, based on the age of the patient, clinical status, tumour stage and histology. Thus, no overall therapeutic strategy was outlined in the protocol but recommendations were given on an individual basis.

    Primary: 3-year Event Free Survival probability - ITT

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    End point title
    		 3-year Event Free Survival probability - ITT
    End point description
    The probability of Event Free Survival (pEFS) at 3 years was estimated according to the Kaplan-Meier method. The analysis was performed using the “intention to treat” (ITT) principle for all study patients of the respective diagnostic groups (Germinoma, Non-Germinoma and Teratoma).
    End point type
    Primary
    End point timeframe
    From date of diagnosis to first event (death from any cause, relapse, progressive disease on therapy or second malignancy).
    End point values
    		 Mal. Non-Germinoma Germinoma Teratoma
    Number of subjects analysed
    112
    261
    21
    Units: percent
        number (confidence interval 95%)
    69.7 (59.6 to 77.7)
    96.2 (92.9 to 98.0)
    80.7 (56.3 to 92.3)
    Statistical analysis title
    		 Final analysis (Intention to treat)
    Statistical analysis description
    The log-rank test was used to compare the groups.
    Comparison groups
    Germinoma v Teratoma v Mal. Non-Germinoma
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Confidence interval

    Primary: 3-year Event Free Survival probability - PP

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    End point title
    		 3-year Event Free Survival probability - PP
    End point description
    The probability of event-free survival (pEFS) at 3 years was estimated according to the Kaplan-Meier method. The analysis was performed using the “per protocol” (PP) principle for all study patients of the respective diagnostic groups (Germinoma, Non-Germinoma and Teratoma). Patients for the PP analysis were all patients with complete diagnostic procedures, administration of all blocks of chemotherapy required by the protocol and radiotherapy delivered according to the protocol with dosage deviations less than 10%. Patients, who died during treatment were analysed in the PP analysis.
    End point type
    Primary
    End point timeframe
    From date of diagnosis to first event (death from any cause, relapse, progressive disease on therapy or second malignancy).
    End point values
    		 Mal. Non-Germinoma Germinoma Teratoma
    Number of subjects analysed
    71
    215
    20
    Units: percent
        number (confidence interval 95%)
    67.6 (54.0 to 78.0)
    97.0 (93.3 to 98.6)
    85.0 (60.4 to 94.9)
    Statistical analysis title
    		 Final analysis (Per Protocol)
    Statistical analysis description
    The log-rank test was used to compare the groups.
    Comparison groups
    Mal. Non-Germinoma v Germinoma v Teratoma
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Confidence interval

    Secondary: 3-year Survival probability - ITT

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    End point title
    		 3-year Survival probability - ITT
    End point description
    The probability of Survival at 3 years was estimated according to the Kaplan-Meier method. The analysis was performed according to the “intention to treat” (ITT) principle for all study patients of the respective diagnostic groups (Germinoma, Non-Germinoma and Teratoma).
    End point type
    Secondary
    End point timeframe
    From date of diagnosis to death from any cause.
    End point values
    		 Mal. Non-Germinoma Germinoma Teratoma
    Number of subjects analysed
    112
    261
    21
    Units: percent
        number (confidence interval 95%)
    81.0 (71.5 to 87.6)
    99.6 (97.1 to 99.9)
    95.2 (70.7 to 99.3)
    Statistical analysis title
    		 Final analysis (Intention to treat)
    Statistical analysis description
    The log-rank test was used to compare the groups.
    Comparison groups
    Mal. Non-Germinoma v Germinoma v Teratoma
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Confidence interval

    Secondary: 3-year Survival probability - PP

    		 Close Top of page
    End point title
    		 3-year Survival probability - PP
    End point description
    The probability of Survival (pEFS) at 3 years was estimated according to the Kaplan-Meier method. The analysis was performed according to the “per protocol” (PP) principle for all study patients of the respective diagnostic groups (Germinoma, Non-Germinoma and Teratoma). Patients for the PP analysis were all patients with complete diagnostic procedures, administration of all blocks of chemotherapy required by the protocol and radiotherapy delivered according to the protocol with dosage deviations less than 10%. Patients, who died during treatment were analysed in the PP analysis.
    End point type
    Secondary
    End point timeframe
    From date of diagnosis to death from any cause.
    End point values
    		 Mal. Non-Germinoma Germinoma Teratoma
    Number of subjects analysed
    71
    215
    20
    Units: percent
        number (confidence interval 95%)
    84.4 (72.4 to 91.4)
    99.5 (96.6 to 99.9)
    95.0 (69.5 to 99.3)
    Statistical analysis title
    		 Final analysis (Per Protocol)
    Statistical analysis description
    The log-rank test was used to compare the groups.
    Comparison groups
    Mal. Non-Germinoma v Germinoma v Teratoma
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first day of study treatment until end of study follow-up (2 years after treatment initiation).
    Adverse event reporting additional description
    SAEs were reported in compliance with the law. In the eCRF, however, only toxicities according to CTCAE were documented without information on whether they were serious. Therefore, severe toxicities (CTC grade >=3, hematologic: CTC grade 4) were reported here as SAE and non-severe toxicities (CTC grade 1-2, hematologic: CTC grade 1-3) as non-SAE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Mal. Non-Germinoma
    Reporting group description
    		 All study patients with a malignant non-germinoma GCT who received study treatment. In this reporting group, 15 tumor-related deaths occurred. Because the causal relationship between treatment and the occurrence of toxicity was not recorded in the eCRF, 0 is entered here under „Serious adverse events“ for „Occurrences causally related to treatment“.

    Reporting group title
    Germinoma
    Reporting group description
    		 All study patients with a germinoma GCT who received study treatment. In this reporting group, one tumor-related death occurred. Because the causal relationship between treatment and the occurrence of toxicity was not recorded in the eCRF, 0 is entered here under „Serious adverse events“ for „Occurrences causally related to treatment“.

    Serious adverse events
    		 Mal. Non-Germinoma Germinoma
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 112 (88.39%)
    170 / 261 (65.13%)
         number of deaths (all causes)
    15
    1
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Hemoglobin
         subjects affected / exposed
    24 / 112 (21.43%)
    15 / 261 (5.75%)
         occurrences causally related to treatment / all
    0 / 34
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WBC
         subjects affected / exposed
    89 / 112 (79.46%)
    110 / 261 (42.15%)
         occurrences causally related to treatment / all
    0 / 256
    0 / 203
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophils
         subjects affected / exposed
    90 / 112 (80.36%)
    149 / 261 (57.09%)
         occurrences causally related to treatment / all
    0 / 271
    0 / 405
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelets
         subjects affected / exposed
    66 / 112 (58.93%)
    56 / 261 (21.46%)
         occurrences causally related to treatment / all
    0 / 129
    0 / 80
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerular filtration
         subjects affected / exposed
    1 / 112 (0.89%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubular phosphate r.
         subjects affected / exposed
    3 / 112 (2.68%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatremia
         subjects affected / exposed
    14 / 112 (12.50%)
    11 / 261 (4.21%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    28 / 112 (25.00%)
    34 / 261 (13.03%)
         occurrences causally related to treatment / all
    0 / 55
    0 / 44
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalemia
         subjects affected / exposed
    10 / 112 (8.93%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalemia
         subjects affected / exposed
    18 / 112 (16.07%)
    10 / 261 (3.83%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphatemia
         subjects affected / exposed
    19 / 112 (16.96%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 31
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypermagnesemia
         subjects affected / exposed
    22 / 112 (19.64%)
    11 / 261 (4.21%)
         occurrences causally related to treatment / all
    0 / 42
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesemia
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcemia
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcemia
         subjects affected / exposed
    7 / 112 (6.25%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    12 / 112 (10.71%)
    6 / 261 (2.30%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 112 (5.36%)
    6 / 261 (2.30%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral neurotox.
         subjects affected / exposed
    8 / 112 (7.14%)
    6 / 261 (2.30%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central neurotox.
         subjects affected / exposed
    5 / 112 (4.46%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hemorrhage
         subjects affected / exposed
    4 / 112 (3.57%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    6 / 112 (5.36%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    23 / 112 (20.54%)
    10 / 261 (3.83%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    13 / 112 (11.61%)
    12 / 261 (4.60%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    10 / 112 (8.93%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    3 / 112 (2.68%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hearing
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Audiometry
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction/hypersensitivity
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver
         subjects affected / exposed
    4 / 112 (3.57%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Changes in the skin
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiform.
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    24 / 112 (21.43%)
    21 / 261 (8.05%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Mal. Non-Germinoma Germinoma
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    110 / 112 (98.21%)
    255 / 261 (97.70%)
    Investigations
    Hemoglobin
         subjects affected / exposed
    82 / 112 (73.21%)
    201 / 261 (77.01%)
         occurrences all number
    387
    726
    WBC
         subjects affected / exposed
    16 / 112 (14.29%)
    119 / 261 (45.59%)
         occurrences all number
    174
    553
    Neutrophils
         subjects affected / exposed
    13 / 112 (11.61%)
    64 / 261 (24.52%)
         occurrences all number
    107
    265
    Platelets
         subjects affected / exposed
    32 / 112 (28.57%)
    138 / 261 (52.87%)
         occurrences all number
    197
    316
    Creatinine
         subjects affected / exposed
    35 / 112 (31.25%)
    33 / 261 (12.64%)
         occurrences all number
    68
    65
    Glomerular filtration
         subjects affected / exposed
    23 / 112 (20.54%)
    18 / 261 (6.90%)
         occurrences all number
    39
    32
    Tubular phosphate r.
         subjects affected / exposed
    5 / 112 (4.46%)
    9 / 261 (3.45%)
         occurrences all number
    5
    10
    Hypernatremia
         subjects affected / exposed
    32 / 112 (28.57%)
    42 / 261 (16.09%)
         occurrences all number
    78
    90
    Hyponatremia
         subjects affected / exposed
    33 / 112 (29.46%)
    46 / 261 (17.62%)
         occurrences all number
    96
    115
    Hyperkalemia
         subjects affected / exposed
    29 / 112 (25.89%)
    39 / 261 (14.94%)
         occurrences all number
    54
    59
    Hypokalemia
         subjects affected / exposed
    36 / 112 (32.14%)
    47 / 261 (18.01%)
         occurrences all number
    93
    79
    Hypophosphatemia
         subjects affected / exposed
    37 / 112 (33.04%)
    53 / 261 (20.31%)
         occurrences all number
    98
    94
    Hypermagnesemia
         subjects affected / exposed
    33 / 112 (29.46%)
    27 / 261 (10.34%)
         occurrences all number
    82
    51
    Hypomagnesemia
         subjects affected / exposed
    28 / 112 (25.00%)
    29 / 261 (11.11%)
         occurrences all number
    49
    53
    Hypercalcemia
         subjects affected / exposed
    13 / 112 (11.61%)
    17 / 261 (6.51%)
         occurrences all number
    26
    33
    Hypocalcemia
         subjects affected / exposed
    51 / 112 (45.54%)
    51 / 261 (19.54%)
         occurrences all number
    132
    93
    Acidosis
         subjects affected / exposed
    17 / 112 (15.18%)
    19 / 261 (7.28%)
         occurrences all number
    33
    34
    Cardiac disorders
    Cardiac function
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 261 (1.15%)
         occurrences all number
    4
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    64 / 112 (57.14%)
    122 / 261 (46.74%)
         occurrences all number
    132
    186
    Peripheral neurotox.
         subjects affected / exposed
    22 / 112 (19.64%)
    23 / 261 (8.81%)
         occurrences all number
    31
    30
    Central neurotox.
         subjects affected / exposed
    35 / 112 (31.25%)
    40 / 261 (15.33%)
         occurrences all number
    59
    52
    General disorders and administration site conditions
    Hemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
    8 / 261 (3.07%)
         occurrences all number
    3
    10
    Fever
         subjects affected / exposed
    69 / 112 (61.61%)
    97 / 261 (37.16%)
         occurrences all number
    158
    165
    Nausea
         subjects affected / exposed
    68 / 112 (60.71%)
    182 / 261 (69.73%)
         occurrences all number
    254
    471
    Vomiting
         subjects affected / exposed
    84 / 112 (75.00%)
    133 / 261 (50.96%)
         occurrences all number
    254
    292
    Stomatitis
         subjects affected / exposed
    22 / 112 (19.64%)
    28 / 261 (10.73%)
         occurrences all number
    37
    38
    Diarrhea
         subjects affected / exposed
    35 / 112 (31.25%)
    40 / 261 (15.33%)
         occurrences all number
    63
    59
    Pain
         subjects affected / exposed
    4 / 112 (3.57%)
    13 / 261 (4.98%)
         occurrences all number
    9
    15
    Ear and labyrinth disorders
    Hearing
         subjects affected / exposed
    29 / 112 (25.89%)
    13 / 261 (4.98%)
         occurrences all number
    60
    23
    Audiometry
         subjects affected / exposed
    26 / 112 (23.21%)
    9 / 261 (3.45%)
         occurrences all number
    49
    15
    Hepatobiliary disorders
    Liver
         subjects affected / exposed
    11 / 112 (9.82%)
    19 / 261 (7.28%)
         occurrences all number
    24
    35
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    78 / 112 (69.64%)
    192 / 261 (73.56%)
         occurrences all number
    228
    490
    Changes in the skin
         subjects affected / exposed
    46 / 112 (41.07%)
    82 / 261 (31.42%)
         occurrences all number
    68
    94
    Erythema multiform.
         subjects affected / exposed
    12 / 112 (10.71%)
    18 / 261 (6.90%)
         occurrences all number
    16
    19
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    19 / 112 (16.96%)
    19 / 261 (7.28%)
         occurrences all number
    31
    31
    Hematuria
         subjects affected / exposed
    33 / 112 (29.46%)
    21 / 261 (8.05%)
         occurrences all number
    54
    30
    Endocrine disorders
    Endocrine
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 261 (1.15%)
         occurrences all number
    4
    6
    Infections and infestations
    Infection
         subjects affected / exposed
    47 / 112 (41.96%)
    66 / 261 (25.29%)
         occurrences all number
    101
    103

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2015
    - Additional information on the management of certain toxicities has been added. - Evaluation time points were adapted. - Further details on the administration of chemotherapy were provided. - The SAE chapter has been amended. - New side effects of the study therapy were added and explained.
    26 Apr 2018
    - Additional information about replacement of cisplatin with carboplatin were added (Chemotherapy in malignant non-germinoma). - Information on time management in case of SAE were amended. - The extension of the recruitment period for the study by two years was added.

    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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