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    Clinical Trial Results:
    Randomized Phase III Study of Low-Dose Cytarabine and Etoposide with or without All-Trans Retinoic Acid in Older Patients not Eligible for Intensive Chemotherapy with Acute Myeloid Leukemia and NPM1 Mutation

    Summary
    EudraCT number
    		 2010-023409-37
    Trial protocol
    		 DE   AT  
    Global end of trial date
    13 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jul 2019
    First version publication date
    26 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AMLSG_15-10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01237808
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital of Ulm
    Sponsor organisation address
    Albert-Einstein-Allee 23, Ulm, Germany, 89081
    Public contact
    AMLSG Clinical Trials Office, University Hospital Ulm, +49 731500 56072, aml.sekretariat@uniklinik-ulm.de
    Scientific contact
    AMLSG Clinical Trials Office, University Hospital Ulm, +49 731500 56072, aml.sekretariat@uniklinik-ulm.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
    21 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Efficacy Objective - Evaluation of overall survival after treatment with low-dose cytarabine and etoposide with or without all-trans retinoic acid (ATRA) in patients with acute myeloid leukemia (AML) and nucleophosmin-1 (NPM1) mutation ineligible for intensive treatment Secondary Efficacy Objectives -Evaluation of efficacy based on complete remission (CR) rates, event-free survival (EFS), and cumulative incidences of relapse and deaths in CR Safety Objectives and QOL Objectives - Evaluation of safety based on toxicity - Evaluation of safety based on duration of neutropenia and leukopenia after each treatment cycle, incidence of infections, duration of hospitalization -Assessment of quality of life
    Protection of trial subjects
    In this study, safety was assessed by evaluating the following: reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, chest X-ray, echo scan, physical examination findings, monitoring of concomitant therapy. For each safety parameter, all findings (whether normal or abnormal) were recorded in the CRF.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 May 2011
    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
    Austria: 10
    Country: Number of subjects enrolled
    Germany: 134
    Worldwide total number of subjects
    144
    EEA total number of subjects
    144
    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)
    2
    From 65 to 84 years
    136
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 First Patient in: 11.05.2011 Last Patient in: 14.09.2016 Recruitment was not interrupted during the course of the trial.

    Pre-assignment
    Screening details
    		 Molecular genetic analysis (central AMLSG reference lab) of blood and bone marrow was performed at baseline within 48 hours to make an enrollment possible.

    Pre-assignment period milestones
    Number of subjects started
    		 144
    Number of subjects completed
    		 144 [1]

    Notes
    [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: Two Analysis data sets were defined: 1. ITT (Intention to treat): included all randomized patients with signed informed consent. They were analyzed according to randomisation arm. (control: n=72, ATRA: n=72) 2. Safety: Analyses were performed according to the Treatment the patients actually received. Therefore, 6 patients did not receive the IMP in the ATRA arm and were analyzed for safety within the control arm. (control: n=78, ATRA: n=66)
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm A: Control
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During six repetitive treatment cycles: Cytarabine 20 mg/day, s.c., bid, days 1-7; (total dose 280 mg).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection, Capsule
    Routes of administration
    Intravenous use, Intravenous bolus use , Oral use
    Dosage and administration details
    First Treatment cycle: 50 mg/m²/day, continuously i.v., days 1-3; (total dose 150 mg/m2). Treatment cycle 2 to 6: 100 mg/day, p.o. or i.v. (over 1 hour), days 1-3; (total dose 300 mg).

    Arm title
    		 Arm B: ATRA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During six repetitive treatment cycles: Cytarabine 20 mg/day, s.c., bid, days 1-7; (total dose 280 mg).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use , Intravenous use, Oral use
    Dosage and administration details
    First Treatment cycle: 50 mg/m²/day, continuously i.v., days 1-3; (total dose 150 mg/m2). Treatment cycle 2 to 6: 100 mg/day, p.o. or i.v. (over 1 hour), days 1-3; (total dose 300 mg).

    Investigational medicinal product name
    All-trans retinoic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    During six Treatment cycles: 45 mg/m²/day p.o., days 8-10; 15 mg/m²/day p.o., days 11-28 with or shortly after meals distributed on 3 doses per day

    Number of subjects in period 1 [2]
    		Arm A: Control Arm B: ATRA
    Started
    72
    72
    Completed
    32
    11
    Not completed
    46
    61
         Adverse event, non-fatal
    1
    2
         Other
    5
    6
         Death
    6
    16
         Patient wish
    5
    7
         Lack of efficacy
    29
    30
    Joined
    6
    0
         Transferred in from other group/arm
    6
    -
    Notes
    [2] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Two Analysis data sets were defined: 1. ITT (Intention to treat): included all randomized patients with signed informed consent. They were analyzed according to randomisation arm. (control: n=72, ATRA: n=72) 2. Safety: Analyses were performed according to the Treatment the patients actually received. Therefore, 6 patients did not receive the IMP in the ATRA arm and were analyzed for safety within the control arm. (control: n=78, ATRA: n=66)

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two Analysis data sets were defined: 1. ITT (Intention to treat): included all randomized patients with signed informed consent. They were analyzed according to randomisation arm. (control: n=72, ATRA: n=72) 2. Safety: Analyses were performed according to the Treatment the patients actually received. Therefore, 6 patients did not receive the IMP in the ATRA arm and were analyzed for safety within the control arm. (control: n=78, ATRA: n=66)
    Reporting group values
    		 overall trial Total
    Number of subjects
    		 144 144
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 76.8 (63.8 to 91.8) -
    Gender categorical
    Units: Subjects
        Female
    		 70 70
        Male
    		 74 74
    FLT3 ITD
    Units: Subjects
        negative
    		 105 105
        positive
    		 39 39
    ECOG performance status
    Units: Subjects
        level 0
    		 21 21
        level 1
    		 68 68
        level 2
    		 41 41
        level 3
    		 14 14
        level 4
    		 0 0
    HCT-CI score
    Units: Subjects
        Score <=1
    		 47 47
        Score 2
    		 25 25
        Score 3
    		 35 35
        Score >=4
    		 37 37
    Type of AML
    Units: Subjects
        deNovo
    		 126 126
        sAML
    		 5 5
        tAML
    		 13 13
    White blood count (WBC)
    Units: G/l
        median (full range (min-max))
    		 -
    Platelets
    Units: G/l
        median (full range (min-max))
    		 -
    Hemoglobin
    Units: g/dl
        median (full range (min-max))
    		 -
    Blasts in peripheral blood
    Units: % (percent)
        median (full range (min-max))
    		 28.5 (0 to 98) -
    Blasts in bone marrow
    Units: % (percent)
        median (full range (min-max))
    		 -
    LDH
    Units: G/l
        median (full range (min-max))
    		 -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention to treat (ITT) population was defined according to the intent-to-treat principle and consists of all randomized patients with a signed informed consent. Patients in this population were analyzed according to the treatment arm assigned at randomization.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included patients from the ITT population who actually received at least one dose or part of a dose of the study treatments (low-dose cytarabine and etoposide/etoposidphosphate with or without all-trans retinoic acid (ATRA)) during the considered treatment phase. The safety population was the primary population for the analysis of safety parameters. All analyses using this population were based on the treatment actually received.

    Subject analysis sets values
    		 ITT population Safety Population
    Number of subjects
    144
    144
    Age categorical
    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)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    76.8 (63.8 to 91.8)
    76.8 (63.8 to 91.8)
    Gender categorical
    Units: Subjects
        Female
    70
    70
        Male
    74
    74
    FLT3 ITD
    Units: Subjects
        negative
    105
    105
        positive
    39
    39
    ECOG performance status
    Units: Subjects
        level 0
    21
    21
        level 1
    68
    68
        level 2
    41
    41
        level 3
    14
    14
        level 4
    0
    0
    HCT-CI score
    Units: Subjects
        Score <=1
    47
    47
        Score 2
    25
    25
        Score 3
    35
    35
        Score >=4
    37
    37
    Type of AML
    Units: Subjects
        deNovo
    126
    126
        sAML
    5
    5
        tAML
    13
    13
    White blood count (WBC)
    Units: G/l
        median (full range (min-max))
    20.4 (0.4 to 335.0)
    Platelets
    Units: G/l
        median (full range (min-max))
    66 (4 to 494)
    Hemoglobin
    Units: g/dl
        median (full range (min-max))
    9.1 (5.2 to 13.2)
    Blasts in peripheral blood
    Units: % (percent)
        median (full range (min-max))
    28.5 (0 to 98)
    28.5 (0 to 98)
    Blasts in bone marrow
    Units: % (percent)
        median (full range (min-max))
    80 (5 to 100)
    LDH
    Units: G/l
        median (full range (min-max))
    397.5 (155 to 2111)

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Control
    Reporting group description
    		 -

    Reporting group title
    Arm B: ATRA
    Reporting group description
    		 -

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention to treat (ITT) population was defined according to the intent-to-treat principle and consists of all randomized patients with a signed informed consent. Patients in this population were analyzed according to the treatment arm assigned at randomization.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included patients from the ITT population who actually received at least one dose or part of a dose of the study treatments (low-dose cytarabine and etoposide/etoposidphosphate with or without all-trans retinoic acid (ATRA)) during the considered treatment phase. The safety population was the primary population for the analysis of safety parameters. All analyses using this population were based on the treatment actually received.

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    The primary efficacy endpoint was OS, which was defined as the time from the date of randomization to the date of death due to any cause. For patients who are still alive and patients who are lost to follow up, OS was be censored at the date they were last known to be alive.
    End point type
    Primary
    End point timeframe
    after two years
    End point values
    		 Arm A: Control Arm B: ATRA ITT population
    Number of subjects analysed
    72
    72
    144
    Units: Median overall survival
        median (confidence interval 95%)
    9.15 (7.38 to 12.52)
    5.02 (3.61 to 7.61)
    6.56 (5.15 to 9.31)
    Attachments
    		 Overall survival
    Statistical analysis title
    		 Log rank test
    Comparison groups
    Arm B: ATRA v Arm A: Control
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023 [1]
    Method
    		 Logrank
    Confidence interval
    Notes
    [1] - There were significant differences between the treatment groups with the ATRA group performing worse than the control group: chisq=5.15 on 1 degrees of freedom, p=0.023.

    Secondary: Rate of complete Remission (CR/CRi)

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    End point title
    		 Rate of complete Remission (CR/CRi)
    End point description
    A patient was said to have achieved CR/CRi during the overall study treatment if his/her best response during or at completion of the study treatment was a CR/CRi; all other patients who did not meet this criterion were considered not to have achieved CR/CRi during treatment and regarded as having events at Day 1 after start of treatment.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Arm A: Control Arm B: ATRA ITT population
    Number of subjects analysed
    72
    72
    72
    Units: Subjects with complete remission
    26
    24
    50
    No statistical analyses for this end point

    Secondary: Cumulative incidence of relapse

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    End point title
    		 Cumulative incidence of relapse
    End point description
    The analyses of CIR and CID were restricted to patients who achieved CR/CRi during study treatment. For patients not experiencing relapse or death during the study, CIR and CID were censored at the date of last response evaluation. The incidence of relapse was estimated using the cumulative incidence function, treating death in first CR/CRi as a competing risk. Non-relapse mortality was analyzed in the same way, treating relapse in first CR/CRi as a competing risk.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Arm A: Control Arm B: ATRA ITT population
    Number of subjects analysed
    26
    24
    50
    Units: CIR after two years
        number (confidence interval 95%)
    0.92 (0.82 to 1.00)
    0.88 (0.74 to 1.00)
    0.90 (0.83 to 0.98)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of death

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    End point title
    		 Cumulative incidence of death
    End point description
    The analyses of CIR and CID were restricted to patients who achieved CR/CRi during study treatment. For patients not experiencing relapse or death during the study, CIR and CID were censored at the date of last response evaluation. The incidence of relapse was estimated using the cumulative incidence function, treating death in first CR/CRi as a competing risk. Non-relapse mortality was analyzed in the same way, treating relapse in first CR/CRi as a competing risk.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Arm A: Control Arm B: ATRA ITT population
    Number of subjects analysed
    26
    24
    50
    Units: CID after 2 years
        number (confidence interval 95%)
    0.00 (0.00 to 0.00)
    0.08 (0.00 to 0.19)
    0.04 (0.00 to 0.09)
    No statistical analyses for this end point

    Secondary: Event-free survival

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    End point title
    		 Event-free survival
    End point description
    Event-free survival (EFS) was defined as the time from the date of entry into the trial to the date of either primary refractory disease, relapse from CR/CRi or death from any cause. Refractory disease described the failure to achieve CR/CRi within study
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Arm A: Control Arm B: ATRA ITT population
    Number of subjects analysed
    72
    72
    144
    Units: months
        median (confidence interval 95%)
    0.13 (0.07 to 1.08)
    0.16 (0.10 to 1.02)
    0.16 (0.10 to 0.62)
    No statistical analyses for this end point

    Other pre-specified: Quality of life (global health status)

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    End point title
    		 Quality of life (global health status)
    End point description
    After evaluation of EORTC (European Organisation for Research and Treatment of Cancer) Quality of Life Core Questionnaire (QLQ-C30), scores were derived. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Changes in score values between diagnosis and end of Treatment were analyzed.
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Arm A: Control Arm B: ATRA ITT population
    Number of subjects analysed
    7
    7
    14
    Units: Changes in score value %
        median (full range (min-max))
    16.7 (-16.7 to 58.3)
    16.7 (-33.3 to 66.7)
    16.7 (-33.3 to 66.7)
    No statistical analyses for this end point

    Other pre-specified: Rate of Early/Hypoplastic Deaths (ED/HD)

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    End point title
    		 Rate of Early/Hypoplastic Deaths (ED/HD)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Arm A: Control Arm B: ATRA ITT population
    Number of subjects analysed
    78
    66
    144
    Units: Number of ED/HD
    10
    9
    19
    No statistical analyses for this end point

    Other pre-specified: Incidence of infection after each treatment cycle

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    End point title
    		 Incidence of infection after each treatment cycle
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Arm A: Control Arm B: ATRA Safety Population
    Number of subjects analysed
    78
    66
    144
    Units: Incidence, %
    number (confidence interval 95%)
        Cycle 1
    57.7 (46.6 to 68.0)
    60.6 (48.5 to 71.5)
    59.0 (50.9 to 66.7)
        Cycle 2
    31.9 (20.4 to 46.2)
    58.5 (43.4 to 72.2)
    44.3 (34.4 to 54.7)
        Cycle 3
    23.1 (12.6 to 38.3)
    33.3 (18.0 to 53.3)
    27.0 (17.6 to 39.0)
        Cycle 4
    11.7 (4.7 to 26.7)
    22.2 (9.0 to 45.2)
    15.4 (8.0 to 27.5)
        Cycle 5
    16.1 (7.1 to 32.6)
    18.8 (6.6 to 43.0)
    17.0 (8.9 to 30.1)
        Cycle 6
    7.7 (2.1 to 24.1)
    16.7 (4.7 to 44.8)
    10.5 (4.2 to 24.1)
    No statistical analyses for this end point

    Other pre-specified: Duration of neutropenia

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    End point title
    		 Duration of neutropenia
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Arm A: Control Arm B: ATRA
    Number of subjects analysed
    78
    66
    Units: Days
    median (confidence interval 95%)
        Cycle 1
    28 (26 to 38)
    29 (24 to 34)
        Cycle 2
    27 (25 to 34)
    30 (22 to 36)
        Cycle 3
    25 (17 to 30)
    32 (28 to 32)
        Cycle 4
    27 (27 to 27)
    24 (21 to 24)
        Cycle 5
    28 (27 to 28)
    34 (27 to 34)
        Cycle 6
    27 (22 to 27)
    40 (40 to 40)
    No statistical analyses for this end point

    Other pre-specified: Duration of thrombopenia

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    End point title
    		 Duration of thrombopenia
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Arm A: Control Arm B: ATRA
    Number of subjects analysed
    78
    66
    Units: Days
    median (confidence interval 95%)
        Cycle 1
    18 (17 to 21)
    24 (20 to 33)
        Cycle 2
    16 (15 to 21)
    20 (18 to 35)
        Cycle 3
    16 (12 to 16)
    28 (17 to 28)
        Cycle 4
    24 (17 to 24)
    32 (23 to 32)
        Cycle 5
    18 (12 to 18)
    18 (18 to 18)
        Cycle 6
    17 (4 to 17)
    40 (40 to 40)
    No statistical analyses for this end point

    Other pre-specified: Number of nights in hospital (initial stay)

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    End point title
    		 Number of nights in hospital (initial stay)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Arm A: Control Arm B: ATRA
    Number of subjects analysed
    78
    66
    Units: Nights
    median (full range (min-max))
        Cycle 1
    21 (1 to 43)
    21 (0 to 53)
        Cycle 2
    8 (0 to 34)
    9 (0 to 39)
        Cycle 3
    7 (0 to 34)
    7 (0 to 13)
        Cycle 4
    6 (0 to 29)
    7 (0 to 13)
        Cycle 5
    6 (0 to 10)
    7 (0 to 11)
        Cycle 6
    4 (0 to 16)
    6 (0 to 9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were reported from Inform Consent signature up to 28 days after last study drug administration or until all drug-related toxicities had been resolved, whichever was late.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Arm A: Control
    Reporting group description
    		 -

    Reporting group title
    Arm B: ATRA
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A: Control Arm B: ATRA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 78 (57.69%)
    40 / 66 (60.61%)
         number of deaths (all causes)
    12
    16
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary malignancy
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    CNS Hemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Intra-operative injury: Retina
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Constitutional symptoms - other
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Fever
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 3
    1 / 1
    Pain -other
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hemorrhage pulmonary
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARDS
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnea
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary -other
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Cardiac disorders
    Cardiac Arrhythmia - Other
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular arrhythmia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac general - other
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Cardiac ischemia/infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CNS ischemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood alteration
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurology - Other
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope (fainting)
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head/Headache
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hemoglobin
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    7 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytes
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophils
         subjects affected / exposed
    3 / 78 (3.85%)
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelets
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumor lysis syndrome
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GI -other
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nausea
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Stomach pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatology -Other
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hemorrhage, GU
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal - other
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 66 (7.58%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Stricture anastomotic, GU
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal - Other
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Febrile neutroopenia
         subjects affected / exposed
    6 / 78 (7.69%)
    11 / 66 (16.67%)
         occurrences causally related to treatment / all
    5 / 6
    10 / 14
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Gastrointestinal: Esophagus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection - other
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 66 (6.06%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
         deaths causally related to treatment / all
    1 / 1
    2 / 3
    Infection with grade 3 or 4 neutrophils
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal: joint
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal: Soft tissue
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung (pneumonia)
         subjects affected / exposed
    11 / 78 (14.10%)
    5 / 66 (7.58%)
         occurrences causally related to treatment / all
    6 / 11
    2 / 6
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    Urinary tract NOS
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Control Arm B: ATRA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 78 (98.72%)
    64 / 66 (96.97%)
    Vascular disorders
    Hemorrhage - other
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 66 (7.58%)
         occurrences all number
    6
    8
    Edema: limb
         subjects affected / exposed
    12 / 78 (15.38%)
    15 / 66 (22.73%)
         occurrences all number
    19
    21
    Phlebitis
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 66 (6.06%)
         occurrences all number
    5
    5
    Cardiac disorders
    Cardiac general - other
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 66 (6.06%)
         occurrences all number
    8
    6
    Hypertension
         subjects affected / exposed
    18 / 78 (23.08%)
    10 / 66 (15.15%)
         occurrences all number
    36
    14
    Hypotension
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 66 (4.55%)
         occurrences all number
    4
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 66 (7.58%)
         occurrences all number
    7
    5
    Mood alteration
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 66 (3.03%)
         occurrences all number
    13
    3
    Mood alteration: agitation
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 66 (3.03%)
         occurrences all number
    7
    2
    Mood alteration: Depression
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 66 (7.58%)
         occurrences all number
    2
    6
    Head/Headache
         subjects affected / exposed
    5 / 78 (6.41%)
    8 / 66 (12.12%)
         occurrences all number
    5
    11
    Blood and lymphatic system disorders
    Blood - other
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 66 (6.06%)
         occurrences all number
    4
    4
    Hemoglobin
         subjects affected / exposed
    63 / 78 (80.77%)
    54 / 66 (81.82%)
         occurrences all number
    170
    135
    Leukocytes
         subjects affected / exposed
    52 / 78 (66.67%)
    48 / 66 (72.73%)
         occurrences all number
    161
    115
    Neutrophils
         subjects affected / exposed
    39 / 78 (50.00%)
    31 / 66 (46.97%)
         occurrences all number
    99
    69
    Platelets
         subjects affected / exposed
    65 / 78 (83.33%)
    61 / 66 (92.42%)
         occurrences all number
    171
    140
    General disorders and administration site conditions
    Constitutional symptoms - other
         subjects affected / exposed
    9 / 78 (11.54%)
    2 / 66 (3.03%)
         occurrences all number
    15
    5
    Fatigue
         subjects affected / exposed
    13 / 78 (16.67%)
    14 / 66 (21.21%)
         occurrences all number
    33
    22
    Fever
         subjects affected / exposed
    26 / 78 (33.33%)
    15 / 66 (22.73%)
         occurrences all number
    39
    17
    Insomnia
         subjects affected / exposed
    25 / 78 (32.05%)
    18 / 66 (27.27%)
         occurrences all number
    41
    23
    Weight gain
         subjects affected / exposed
    9 / 78 (11.54%)
    7 / 66 (10.61%)
         occurrences all number
    10
    11
    Weight loss
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 66 (3.03%)
         occurrences all number
    6
    2
    Pain NOS
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 66 (6.06%)
         occurrences all number
    8
    4
    Pain
         subjects affected / exposed
    14 / 78 (17.95%)
    10 / 66 (15.15%)
         occurrences all number
    19
    16
    Pain -other
         subjects affected / exposed
    7 / 78 (8.97%)
    8 / 66 (12.12%)
         occurrences all number
    12
    11
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    5 / 78 (6.41%)
    7 / 66 (10.61%)
         occurrences all number
    10
    7
    Constipation
         subjects affected / exposed
    29 / 78 (37.18%)
    17 / 66 (25.76%)
         occurrences all number
    51
    19
    Diarrhea
         subjects affected / exposed
    16 / 78 (20.51%)
    9 / 66 (13.64%)
         occurrences all number
    21
    12
    Hemorrhoids
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 66 (3.03%)
         occurrences all number
    8
    3
    Mucositis (clinical exam)
         subjects affected / exposed
    15 / 78 (19.23%)
    9 / 66 (13.64%)
         occurrences all number
    21
    9
    Mucositis (functional/symptomatic)
         subjects affected / exposed
    6 / 78 (7.69%)
    5 / 66 (7.58%)
         occurrences all number
    12
    5
    Nausea
         subjects affected / exposed
    29 / 78 (37.18%)
    17 / 66 (25.76%)
         occurrences all number
    69
    41
    Vomiting
         subjects affected / exposed
    6 / 78 (7.69%)
    9 / 66 (13.64%)
         occurrences all number
    6
    10
    Abdomen NOS pain
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 66 (7.58%)
         occurrences all number
    8
    7
    Stomach pain
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 66 (6.06%)
         occurrences all number
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Hemorrhage pulmonary
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 66 (9.09%)
         occurrences all number
    5
    7
    Cough
         subjects affected / exposed
    11 / 78 (14.10%)
    11 / 66 (16.67%)
         occurrences all number
    12
    13
    Dyspnea
         subjects affected / exposed
    11 / 78 (14.10%)
    11 / 66 (16.67%)
         occurrences all number
    15
    14
    Pleural effusion
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 66 (7.58%)
         occurrences all number
    4
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 66 (4.55%)
         occurrences all number
    13
    8
    Dermatology -other
         subjects affected / exposed
    10 / 78 (12.82%)
    7 / 66 (10.61%)
         occurrences all number
    15
    11
    Injection site reaction
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 66 (9.09%)
         occurrences all number
    4
    7
    Rash
         subjects affected / exposed
    13 / 78 (16.67%)
    9 / 66 (13.64%)
         occurrences all number
    16
    12
    Hematoma
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 66 (4.55%)
         occurrences all number
    7
    3
    Petechiae
         subjects affected / exposed
    4 / 78 (5.13%)
    8 / 66 (12.12%)
         occurrences all number
    7
    8
    Renal and urinary disorders
    Renal - other
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 66 (1.52%)
         occurrences all number
    8
    1
    Fluid retention/edema
         subjects affected / exposed
    16 / 78 (20.51%)
    10 / 66 (15.15%)
         occurrences all number
    29
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 66 (4.55%)
         occurrences all number
    8
    3
    Extremity-limb pain
         subjects affected / exposed
    6 / 78 (7.69%)
    6 / 66 (9.09%)
         occurrences all number
    9
    14
    Joint pain
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 66 (3.03%)
         occurrences all number
    13
    2
    Infections and infestations
    Febrile neutropenia
         subjects affected / exposed
    11 / 78 (14.10%)
    10 / 66 (15.15%)
         occurrences all number
    16
    17
    Infection - other
         subjects affected / exposed
    13 / 78 (16.67%)
    11 / 66 (16.67%)
         occurrences all number
    23
    21
    Infection with grade 3 or 4 neutrophils
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 66 (9.09%)
         occurrences all number
    7
    12
    Lung (pneumonia)
         subjects affected / exposed
    11 / 78 (14.10%)
    17 / 66 (25.76%)
         occurrences all number
    14
    30
    Urinary tract NOS
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 66 (6.06%)
         occurrences all number
    6
    4
    Metabolism and nutrition disorders
    Creatinine
         subjects affected / exposed
    10 / 78 (12.82%)
    4 / 66 (6.06%)
         occurrences all number
    18
    6
    GGT
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 66 (9.09%)
         occurrences all number
    4
    7
    Hyperuricemia
         subjects affected / exposed
    11 / 78 (14.10%)
    3 / 66 (4.55%)
         occurrences all number
    22
    4
    Hypocalcemia
         subjects affected / exposed
    8 / 78 (10.26%)
    6 / 66 (9.09%)
         occurrences all number
    10
    9
    Hypokalemia
         subjects affected / exposed
    24 / 78 (30.77%)
    19 / 66 (28.79%)
         occurrences all number
    39
    32
    Metabolic: Other
         subjects affected / exposed
    11 / 78 (14.10%)
    10 / 66 (15.15%)
         occurrences all number
    19
    14
    CRP increase
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 66 (4.55%)
         occurrences all number
    10
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2014
    Amendment 1 (dated 17 June 2014) was issued after enrolment of n=86 patients. The following major procedural changes were made to the protocol: • Dose reduction of ATRA: Administration of 45mg/m² from day 8 until day 10, thereafter from day 11 until day 28 reduction of ATRA dose to 15mg/m² (Integration of urgent amendment due to increased frequency of toxicities, in particular infections, and deaths observed in the ATRA arm compared to the control arm (Interim safety analysis, March 2014). • Changes in the personal responsibility
    08 Nov 2016
    Amendment 2 (dated 08 November 2016) to the protocol was issued after end of enrolment. The following major procedural changes were made to the protocol: • Integration of optional intravenous administration of Etoposide (cycles 2 to 6) due to a supply bottleneck of oral Etoposid (Vepesid K) and Etoposidphosphat (Etopophos). • Changes in the personal responsibility (coordinating investigator)

    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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