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    Clinical Trial Results:
    An international phase II trial assessing tolerability and efficacy of sequential Methotrexate-Aracytin-based combination and R-ICE combination, followed by high-dose chemotherapy supported by autologous stem cell transplant, in patients with systemic B-cell lymphoma with central nervous system involvement at diagnosis or relapse (MARIETTA regimen)

    Summary
    EudraCT number
    		 2014-003031-19
    Trial protocol
    		 IT   NL  
    Global end of trial date
    22 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2025
    First version publication date
    06 Jun 2025
    Other versions
    Summary report(s)
    		 IELSG42 Results - Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    IELSG42
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02329080
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    International Extranodal Lymphoma Study Group (IELSG)
    Sponsor organisation address
    Via Vincenzo Vela 6, Bellinzona, Switzerland, 6500
    Public contact
    IELSG Operations Office, International Extranodal Lymphoma Study Group (IELSG) , 0041 58 666 7321, ielsg@ior.usi.ch
    Scientific contact
    IELSG Operations Office, International Extranodal Lymphoma Study Group (IELSG) , 0041 58 666 7321, ielsg@ior.usi.ch
    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
    12 May 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Mar 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a new sequential combination of high-dose methotrexate (HD-MTX)-AraC-based chemoimmunotherapy, followed by R-ICE regimen, and by high-dose chemotherapy supported by Autologous Stem Cell Transplantation (ASCT).
    Protection of trial subjects
    Guidelines for dose modifications and dose delays were included in the study protocol, in order to minimize any possible risks for the patients. The following supportive therapies could be delivered: antiemetics, analgesics, antibiotics, anticonvulsants, sedatives, anti-hyperuricemic agents as well as other therapies to control metabolic and malnutrition disturbances. Antimicrobial prophylaxis should follow Institutional guidelines since the variability in endemic or epidemic distribution of infectious agents. However, oral antiviral (Acyclovir 400 mg bid), antifungine (Fluconazole 200 mg/d) and antipneumocystic (Trimethoprim 160 mg and sulfamethoxazole 800 mg, thrice per week) prophylaxis was suggested. Conventional doses of G-CSF from day 6th to 12th of every course associated with antibiotic prophylaxis as per local practice (same period) were also suggested. Platelet transfusion were performed when counts was <10 x 109/L, or <20 x 109/L in case of fever or active bleeding. RBC transfusion were performed with haemoglobin <8.0 g/dL or in selected patients with higher levels according to physician’s preference
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Mar 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
    Switzerland: 1
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Italy: 54
    Worldwide total number of subjects
    79
    EEA total number of subjects
    58
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    52
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment lasted from 30 March 2015 to 03 August 2018

    Pre-assignment
    Screening details
    		 During the recrutment period 79 patients were enrolled and 75 of them were treated

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

    Arms
    Arm title
    		 Arm 1
    Arm description
    		 Experimental treatment was started within 3 weeks of baseline assessment of target lesions. Treatment included 6 cycles of chemoimmunotherapy, the first 3 cycles with an HDMTX- based combination followed by other 3 cycles of R-ICE combination and finally a BCNU-thiotepa containing conditioning and subsequent ASCT. The interval between the first day of 2 consecutive cycles was 3 weeks. The interval between the last chemoimmunotherapy cycle and conditioning was 4-6 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Intrathecal use
    Dosage and administration details
    3.5 mg/m2 on day 1 of HDMTX combination for 3 cycles of 3 weeks If liposomal cytarabine is not available, standard intrathecal chemotherapy with 50 mg Hydrocortisone + methotrexate 10-12 mg + cytarabine 40-50 mg is administered on Day 4 of each cycle of HDMTX and R-ICE combination

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 on Day 0 of HDMTX combination for 3 cycles lasting 3 weeks 375 mg/m2 on Day 1 of R-ICE combination for 3 cycles lasting 3 weeks

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use, Intravenous use
    Dosage and administration details
    4g/m2 on Day 2 and 3 of HDMTX combination for 3 cycles lasting 3 weeks If liposomal cytarabine is not available, standard intrathecal chemotherapy with 50 mg Hydrocortisone + methotrexate 10-12 mg + cytarabine 40-50 mg is administered on Day 4 of each cycle of HDMTX and R-ICE combination

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/m2 on Day 2 of R-ICE combination for 3 cycles lasting 3 weeks

    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
    800 mg on Day 2 of R-ICE combination for 3 cycles lasting 3 weeks

    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
    100 mg/m2 on Day 1,2 and 3 of R-ICE combination for 3 cycles lasting 3 weeks

    Investigational medicinal product name
    Thiotepa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m2 on day 4 of HDMTX combination for 3 cycles lasting 3 weeks 5 mg/Kg on days -6 and -5 of conditioning regimen

    Investigational medicinal product name
    Carmustine
    Investigational medicinal product code
    Other name
    BCNU
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m2 on Day - 6 of the conditioning regimen

    Investigational medicinal product name
    Liposomal Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    50 mg on Day 5 of HDMTX combination for 3 cycles lasting 3 weeks 50 mg on Day 4 of R-ICE combination for 3 cycles lasting 3 weeks

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In case of BCNU unavailability, 3.2 mg/kg on days -4, -3 and -2 of the conditioning regimen

    Investigational medicinal product name
    Hydrocortisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intrathecal use
    Dosage and administration details
    If liposomal cytarabine is not available, standard intrathecal combination with 50 mg Hydrocortisone + methotrexate 10-12 mg + cytarabine 40-50 mg is administered on on Day 4 of each cycle of HDMTX and R-ICE combination.

    Number of subjects in period 1 [1]
    		Arm 1
    Started
    75
    Completed
    37
    Not completed
    38
         Adverse event, serious fatal
    4
         Physician decision
    2
         Adverse event, non-fatal
    1
         Partial response
    4
         Complete response
    4
         Lost to follow-up
    1
         Lack of efficacy
    22
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Four patients were excluded after enrolment before the start of study treatment because of unrelated laboratory abnormalities (two patients), disease only at flow cytometry examination of the cerebrospinal fluid (one), and death at the same time as registration (one).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (Overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (Overall period) Total
    Number of subjects
    		 75 75
    Age categorical
    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)
    		 50 50
        From 65-84 years
    		 25 25
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 58 (23 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 37 37
        Male
    		 38 38
    CNS involvement at presentation
    Units: Subjects
        CNS involvement at presentation
    		 32 32
        No CNS involvement at presentation
    		 43 43
    Isolated CNS relapse
    Units: Subjects
        Isolated CNS relapse
    		 15 15
        No Isolated CNS relapse
    		 60 60
    Concomitant CNS-systemic localisation
    Units: Subjects
        Concomitant CNS-systemic localisation
    		 28 28
        No Concomitant CNS-systemic localisation
    		 47 47
    HBV or HCV seropositivity
    Units: Subjects
        HBV or HCV seropositivity
    		 2 2
        No HBV or HCV seropositivity
    		 73 73
    CNS site of disease - Brain parenchima
    Units: Subjects
        Brain parenchima
    		 34 34
        No brain parenchima
    		 41 41
    CNS site of disease - Cerebrospinal fluid or meninges
    Units: Subjects
        Cerebrospinal fluid or meninges
    		 8 8
        No Cerebrospinal fluid or meninges
    		 67 67
    CNS sites of disease - Spinal cord
    Units: Subjects
        Spinal cord
    		 2 2
        No Spinal cord
    		 73 73
    CNS sites of disease - Eyes
    Units: Subjects
        Eyes
    		 2 2
        No eyes
    		 73 73
    CNS sites of disease - Brain and cerebrospinal fluid or meninges
    Units: Subjects
        Brain and cerebrospinal fluid or meninges
    		 13 13
        No brain and cerebrospinal fluid or meninges
    		 62 62
    CNS sites of disease - Brain and eyes
    Units: Subjects
        Brain and eyes
    		 10 10
        No brain and eyes
    		 65 65
    CNS sites of disease - Brain, cerebrospinal fluid and eyes
    Units: Subjects
        Brain, cerebrospinal fluid and eyes
    		 6 6
        No Brain, cerebrospinal fluid and eyes
    		 69 69
    ECOG-PS
    Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
    Units: Subjects
        ECOG-PS > 1
    		 28 28
        ECOG-PS </= 1
    		 47 47
    Number of extranodal organs involved (other than CNS)
    Units: Subjects
        Number of extranodal organs involved >1
    		 23 23
        Number of extranodal organs involved </=1
    		 52 52
    High LDH serum concentration
    Units: Subjects
        High LDH serum concentration
    		 37 37
        No High LDH serum concentration
    		 38 38
    Advanced stage
    Units: Subjects
        Advanced stage
    		 60 60
        No advanced stage
    		 15 15
    International Prognostic Index (IPI)
    Units: Subjects
        Low IPI risk
    		 14 14
        Low-intermediate IPI risk
    		 18 18
        High-intermediate IPI risk
    		 26 26
        High IPI risk
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 Experimental treatment was started within 3 weeks of baseline assessment of target lesions. Treatment included 6 cycles of chemoimmunotherapy, the first 3 cycles with an HDMTX- based combination followed by other 3 cycles of R-ICE combination and finally a BCNU-thiotepa containing conditioning and subsequent ASCT. The interval between the first day of 2 consecutive cycles was 3 weeks. The interval between the last chemoimmunotherapy cycle and conditioning was 4-6 weeks

    Primary: 1 year progression free survival (PFS)

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    End point title
    		 1 year progression free survival (PFS) [1]
    End point description
    End point type
    Primary
    End point timeframe
    At 1 year from enrolment
    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: Single arm trial
    End point values
    		 Arm 1
    Number of subjects analysed
    75
    Units: Percentage
        number (confidence interval 95%)
    58 (55 to 61)
    No statistical analyses for this end point

    Secondary: 2-year progression-free survival (PFS)

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    End point title
    		 2-year progression-free survival (PFS)
    End point description
    End point type
    Secondary
    End point timeframe
    At 2 years after trial entry
    End point values
    		 Arm 1
    Number of subjects analysed
    75
    Units: Percentage
        number (confidence interval 95%)
    46 (39 to 53)
    No statistical analyses for this end point

    Secondary: 2 year overall survival (OS)

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    End point title
    		 2 year overall survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    At 2 years from treatment starts
    End point values
    		 Arm 1
    Number of subjects analysed
    75
    Units: Percentage
        number (confidence interval 95%)
    46 (39 to 53)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From trial inclusion until 30 days after end of treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Safety evaluable population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety evaluable population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 75 (61.33%)
         number of deaths (all causes)
    50
         number of deaths resulting from adverse events
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatremia
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Poorly differentiated adenocarcinoma
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Bleeding
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Neurological toxicity
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain ischemic stroke
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bleeding brain lesion
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    16 / 75 (21.33%)
         occurrences causally related to treatment / all
    23 / 23
         deaths causally related to treatment / all
    0 / 0
    Neutropenic fever
         subjects affected / exposed
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bicytopenia
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal bleeding
         subjects affected / exposed
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Vomiting and diarrhea
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Microperforation of the bowel
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bowel perforation
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute renal failure
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Septic arthritis
         subjects affected / exposed
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    Interstitial pneumonia
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    13 / 75 (17.33%)
         occurrences causally related to treatment / all
    12 / 15
         deaths causally related to treatment / all
    1 / 3
    Pneumonia
         subjects affected / exposed
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus reactivation
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fungal chest infection
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 75 (1.33%)
         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
    		 Safety evaluable population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 75 (96.00%)
    Vascular disorders
    Vascular Disorders
         subjects affected / exposed
    15 / 75 (20.00%)
         occurrences all number
    23
    Cardiac disorders
    Cardiac Disorders
         subjects affected / exposed
    8 / 75 (10.67%)
         occurrences all number
    16
    Nervous system disorders
    Nervous System Disorders
         subjects affected / exposed
    24 / 75 (32.00%)
         occurrences all number
    67
    Blood and lymphatic system disorders
    Blood and Lymphatic System Disorders G3-4
         subjects affected / exposed
    51 / 75 (68.00%)
         occurrences all number
    327
    General disorders and administration site conditions
    General Disorders and Administration Site Conditions
         subjects affected / exposed
    55 / 75 (73.33%)
         occurrences all number
    121
    Eye disorders
    Eye Disorders
         subjects affected / exposed
    5 / 75 (6.67%)
         occurrences all number
    6
    Gastrointestinal disorders
    Gastrointestinal Disorders
         subjects affected / exposed
    35 / 75 (46.67%)
         occurrences all number
    116
    Respiratory, thoracic and mediastinal disorders
    Respiratory Thoracic and Mediastinal Disorders
         subjects affected / exposed
    9 / 75 (12.00%)
         occurrences all number
    13
    Skin and subcutaneous tissue disorders
    Skin and Subcutaneous Tissue Disorders
         subjects affected / exposed
    15 / 75 (20.00%)
         occurrences all number
    15
    Renal and urinary disorders
    Renal and Urinary Disorders
         subjects affected / exposed
    7 / 75 (9.33%)
         occurrences all number
    12
    Infections and infestations
    Infections and Infestations
         subjects affected / exposed
    28 / 75 (37.33%)
         occurrences all number
    65

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2017
    Amendment No. 3 (protocol version 4.0 ) This amendment was implemented in all four countries. The reasons of the amendment were to correct the infusion duration of cytarabine, and to clarify the dose of folinic acid and the capped dose of carboplatin. In addition, it was suggested a radiotherapy treatment in case of progressive disease and the schedule and methods for disease evaluation was clarified.

    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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