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    Clinical Trial Results:
    A Multicenter, open, randomized, controlled phase IIb trial evaluating efficacy and tolerability of GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) plus low-dose cytarabine versus low-dose cytarabine alone, in treatment of newly diagnosed acute myeloid leukemia (AML) elderly patients, unfit for intensive chemotherapy. ENFORCE 1 study.

    Summary
    EudraCT number
    		 2012-002026-78
    Trial protocol
    		 IT   FI   DE   ES  
    Global end of trial date
    10 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2020
    First version publication date
    21 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GRASPA-AML 2012-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01810705
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Erytech Pharma
    Sponsor organisation address
    60 avenue Rockefeller, Bâtiment Adenine, Lyon, France, 69008
    Public contact
    Clinical Operations. Jean Baptiste Bertrand, ERYTECH Pharma, 33 4 78 74 44 38, jb.bertrand@erytech.com
    Scientific contact
    Jason Cain, ERYTECH Pharma, +1 857 285 24 15, ason.cain@erytech.com
    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
    19 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate Overall Survival (OS) in AML patients who were 65-85 years old and unfit for intensive chemotherapy, when treated with GRASPA (L-asparaginase encapsulated in erythrocytes) plus low-dose cytarabine compared to low-dose cytarabine alone
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements related to safety of trial subjects were also followed during the conduct of the trial. An independant DSMB reviewed the interim results from the study as well as safety and futility on a regular basis. The DSMB had the potential to stop the study for overwhelming evidence of benefit or futility.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Mar 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 110
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    123
    EEA total number of subjects
    123
    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)
    0
    From 65 to 84 years
    121
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient in: 11MAR2013 Last patient in: 02AUG2016 Territories: Europe (France, Italy, Spain, Finland, Norway, Germany)

    Pre-assignment
    Screening details
    		 • Patient >= 65 years old and ≤ 85 years old • Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrome diagnosed within 6 months prior to study enrollment • Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death) • ECOG performance status ≤ 2

    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
    Yes

    Arm title
    		 low-dose cytarabine + GRASPA
    Arm description
    		 In the experimental group, the patients will receive one administration of GRASPA (100 IU/kg) at Day 11 in combination with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GRASPA
    Investigational medicinal product code
    Other name
    Eryaspase
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the experimental group, the patients will receive one administration of GRASPA (100 IU/kg) at Day 11 in combination with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months.

    Arm title
    		 low-dose cytarabine alone
    Arm description
    		 In the control arm, patients will be treated with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months. Each period of 28 days constitute a cycle of chemotherapy.
    Arm type
    		 Standard polychemotherapy with low dose cytarabine

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		low-dose cytarabine + GRASPA low-dose cytarabine alone
    Started
    83
    40
    Completed
    10
    5
    Not completed
    73
    35
         Consent withdrawn by subject
    1
    1
         Exclusion criteria (randomized in error)
    2
    -
         Death (all causes)
    70
    34

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    low-dose cytarabine + GRASPA
    Reporting group description
    		 In the experimental group, the patients will receive one administration of GRASPA (100 IU/kg) at Day 11 in combination with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months.

    Reporting group title
    low-dose cytarabine alone
    Reporting group description
    		 In the control arm, patients will be treated with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months. Each period of 28 days constitute a cycle of chemotherapy.

    Reporting group values
    		 low-dose cytarabine + GRASPA low-dose cytarabine alone Total
    Number of subjects
    		 83 40 123
    Age categorical
    Units: Subjects
        65-85 years
    		 83 40 123
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 77.2 ± 4.17 76.0 ± 4.54 -
    Gender categorical
    Units: Subjects
        Female
    		 37 16 53
        Male
    		 46 24 70

    End points

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    End points reporting groups
    Reporting group title
    low-dose cytarabine + GRASPA
    Reporting group description
    		 In the experimental group, the patients will receive one administration of GRASPA (100 IU/kg) at Day 11 in combination with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months.

    Reporting group title
    low-dose cytarabine alone
    Reporting group description
    		 In the control arm, patients will be treated with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months. Each period of 28 days constitute a cycle of chemotherapy.

    Subject analysis set title
    Intention-to-Treat efficacy population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) efficacy population comprised of all randomised patients in the groups to which they were randomly assigned, regardless of their adherence to the entry criteria, the treatment they actually received, or subsequent withdrawal from treatment or deviation from the protocol.

    Subject analysis set title
    Per Protocol efficacy population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol (PP) efficacy population comprised all patients from the ITT population without major protocol deviations who received trial product and completed at least one course of treatment

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population comprised all patients who received at least one administration of trial products. Data analysis for the Safety population will be according to treatment received. All evaluations of safety will be undertaken based on this population.

    Primary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was to be assessed by measuring time elapsed between randomisation and death for any cause. Any patient not known to have died at the time of analysis is censored based on the last recorded date on which the patient was known to be alive
    End point type
    Primary
    End point timeframe
    Whole trial period
    End point values
    		 low-dose cytarabine + GRASPA low-dose cytarabine alone
    Number of subjects analysed
    83
    40
    Units: months
        median (confidence interval 95%)
    4.8 (3.1 to 7.0)
    6.4 (3.6 to 10.7)
    Statistical analysis title
    		 Analysis of OS
    Statistical analysis description
    The p-value for the time to event analysis is associated with the stratified log-rank statistic. The stratification factor is performance status (0-1, 2). Hazard ratio and 95% confidence interval are estimated from the stratified Cox model. The stratification factor is performance status (0-1, 2).
    Comparison groups
    low-dose cytarabine + GRASPA v low-dose cytarabine alone
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.827 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.59
    Notes
    [1] - Not statistically significant. No evidence to support treatment differences for OS

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from signature of the informed consent from first patient and until 4 months after last GRASPA/ low-dose cytarabine administration of last patient.
    Adverse event reporting additional description
    Serious adverse events reported in this report (details of serious adverse events table) are treatment emergent serious adverse events with threshold 5.0 %.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    low-dose cytarabine alone
    Reporting group description
    		 -

    Reporting group title
    low-dose cytarabine + GRASPA
    Reporting group description
    		 -

    Serious adverse events
    		 low-dose cytarabine alone low-dose cytarabine + GRASPA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 39 (82.05%)
    74 / 81 (91.36%)
         number of deaths (all causes)
    34
    70
         number of deaths resulting from adverse events
    16
    35
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    3 / 39 (7.69%)
    10 / 81 (12.35%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 12
         deaths causally related to treatment / all
    1 / 3
    0 / 7
    Pyrexia
         subjects affected / exposed
    2 / 39 (5.13%)
    7 / 81 (8.64%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile bone marrow aplasia
         subjects affected / exposed
    2 / 39 (5.13%)
    8 / 81 (9.88%)
         occurrences causally related to treatment / all
    0 / 2
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 39 (7.69%)
    7 / 81 (8.64%)
         occurrences causally related to treatment / all
    2 / 5
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anaemia
         subjects affected / exposed
    1 / 39 (2.56%)
    7 / 81 (8.64%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhagic Events
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 81 (7.41%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Pancytopenia
         subjects affected / exposed
    1 / 39 (2.56%)
    5 / 81 (6.17%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 39 (0.00%)
    6 / 81 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    3 / 39 (7.69%)
    6 / 81 (7.41%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    6 / 39 (15.38%)
    12 / 81 (14.81%)
         occurrences causally related to treatment / all
    1 / 6
    5 / 13
         deaths causally related to treatment / all
    1 / 3
    2 / 6
    Septic shock
         subjects affected / exposed
    6 / 39 (15.38%)
    7 / 81 (8.64%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 7
         deaths causally related to treatment / all
    2 / 6
    1 / 7
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 81 (4.94%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Lung infection
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 low-dose cytarabine alone low-dose cytarabine + GRASPA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    80 / 81 (98.77%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    6 / 39 (15.38%)
    10 / 81 (12.35%)
         occurrences all number
    6
    12
    Hypertension
         subjects affected / exposed
    4 / 39 (10.26%)
    10 / 81 (12.35%)
         occurrences all number
    5
    12
    Purpura
         subjects affected / exposed
    2 / 39 (5.13%)
    5 / 81 (6.17%)
         occurrences all number
    2
    5
    Haematoma
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 81 (4.94%)
         occurrences all number
    2
    4
    Petechiae
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 81 (3.70%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    asthenia
         subjects affected / exposed
    18 / 39 (46.15%)
    28 / 81 (34.57%)
         occurrences all number
    20
    34
    Oedema peripheral
         subjects affected / exposed
    9 / 39 (23.08%)
    13 / 81 (16.05%)
         occurrences all number
    10
    17
    Pain
         subjects affected / exposed
    2 / 39 (5.13%)
    8 / 81 (9.88%)
         occurrences all number
    2
    8
    Injection site haematoma
         subjects affected / exposed
    2 / 39 (5.13%)
    5 / 81 (6.17%)
         occurrences all number
    2
    5
    Pyrexia
         subjects affected / exposed
    13 / 39 (33.33%)
    26 / 81 (32.10%)
         occurrences all number
    27
    50
    General physical health deterioration
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 81 (4.94%)
         occurrences all number
    3
    4
    Immune system disorders
    Alloimmunisation
         subjects affected / exposed
    1 / 39 (2.56%)
    16 / 81 (19.75%)
         occurrences all number
    1
    16
    Allergic transfusion reaction
         subjects affected / exposed
    2 / 39 (5.13%)
    5 / 81 (6.17%)
         occurrences all number
    2
    5
    Hypersensitivity
         subjects affected / exposed
    0 / 39 (0.00%)
    8 / 81 (9.88%)
         occurrences all number
    0
    14
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 39 (20.51%)
    11 / 81 (13.58%)
         occurrences all number
    9
    14
    Cough
         subjects affected / exposed
    7 / 39 (17.95%)
    9 / 81 (11.11%)
         occurrences all number
    7
    10
    Acute pulmonary oedema
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Lung disorder
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 81 (3.70%)
         occurrences all number
    3
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 39 (10.26%)
    11 / 81 (13.58%)
         occurrences all number
    4
    12
    Depression
         subjects affected / exposed
    3 / 39 (7.69%)
    5 / 81 (6.17%)
         occurrences all number
    3
    5
    Confusional state
         subjects affected / exposed
    0 / 39 (0.00%)
    4 / 81 (4.94%)
         occurrences all number
    0
    5
    Investigations
    Blood albumin decreased
         subjects affected / exposed
    6 / 39 (15.38%)
    24 / 81 (29.63%)
         occurrences all number
    8
    29
    Pancreatic enzymes abnormal
         subjects affected / exposed
    5 / 39 (12.82%)
    20 / 81 (24.69%)
         occurrences all number
    5
    31
    Transaminases increased
         subjects affected / exposed
    6 / 39 (15.38%)
    15 / 81 (18.52%)
         occurrences all number
    10
    40
    Antithrombin III decreased
         subjects affected / exposed
    3 / 39 (7.69%)
    17 / 81 (20.99%)
         occurrences all number
    3
    22
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 39 (12.82%)
    15 / 81 (18.52%)
         occurrences all number
    5
    18
    Weight decreased
         subjects affected / exposed
    7 / 39 (17.95%)
    9 / 81 (11.11%)
         occurrences all number
    7
    9
    Blood Creatinine increased
         subjects affected / exposed
    3 / 39 (7.69%)
    12 / 81 (14.81%)
         occurrences all number
    3
    15
    Blood chloride increased
         subjects affected / exposed
    2 / 39 (5.13%)
    11 / 81 (13.58%)
         occurrences all number
    3
    15
    Blood urea increased
         subjects affected / exposed
    4 / 39 (10.26%)
    9 / 81 (11.11%)
         occurrences all number
    6
    9
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 39 (5.13%)
    7 / 81 (8.64%)
         occurrences all number
    2
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 39 (7.69%)
    5 / 81 (6.17%)
         occurrences all number
    3
    5
    Blood chloride decreased
         subjects affected / exposed
    3 / 39 (7.69%)
    5 / 81 (6.17%)
         occurrences all number
    3
    6
    Prothrombin time ratio decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    8 / 81 (9.88%)
         occurrences all number
    0
    10
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 81 (7.41%)
         occurrences all number
    1
    7
    Injury, poisoning and procedural complications
    fall
         subjects affected / exposed
    3 / 39 (7.69%)
    10 / 81 (12.35%)
         occurrences all number
    3
    12
    Transfusion reaction
         subjects affected / exposed
    1 / 39 (2.56%)
    7 / 81 (8.64%)
         occurrences all number
    1
    8
    Traumatic haematoma
         subjects affected / exposed
    3 / 39 (7.69%)
    2 / 81 (2.47%)
         occurrences all number
    3
    2
    Food poisoning
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    5 / 39 (12.82%)
    2 / 81 (2.47%)
         occurrences all number
    5
    2
    Cardiac failure
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 81 (4.94%)
         occurrences all number
    1
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 39 (15.38%)
    12 / 81 (14.81%)
         occurrences all number
    6
    13
    Blood and lymphatic system disorders
    thrombocytopenia
         subjects affected / exposed
    32 / 39 (82.05%)
    59 / 81 (72.84%)
         occurrences all number
    84
    149
    Leukopenia
         subjects affected / exposed
    19 / 39 (48.72%)
    41 / 81 (50.62%)
         occurrences all number
    31
    87
    Neutropenia
         subjects affected / exposed
    18 / 39 (46.15%)
    35 / 81 (43.21%)
         occurrences all number
    34
    98
    Lymphopenia
         subjects affected / exposed
    6 / 39 (15.38%)
    8 / 81 (9.88%)
         occurrences all number
    6
    9
    Leukocytosis
         subjects affected / exposed
    2 / 39 (5.13%)
    8 / 81 (9.88%)
         occurrences all number
    2
    8
    Bone marrow failure
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 81 (2.47%)
         occurrences all number
    2
    2
    Leukostasis syndrome
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Anaemia
         subjects affected / exposed
    34 / 39 (87.18%)
    62 / 81 (76.54%)
         occurrences all number
    74
    170
    Hemorrhagic Events
         subjects affected / exposed
    9 / 39 (23.08%)
    21 / 81 (25.93%)
         occurrences all number
    11
    23
    Febrile neutropenia
         subjects affected / exposed
    1 / 39 (2.56%)
    7 / 81 (8.64%)
         occurrences all number
    1
    8
    Febrile bone marrow aplasia
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 81 (4.94%)
         occurrences all number
    2
    4
    Pancytopenia
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 81 (3.70%)
         occurrences all number
    0
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 81 (4.94%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    15 / 39 (38.46%)
    24 / 81 (29.63%)
         occurrences all number
    21
    57
    Diarrhoea
         subjects affected / exposed
    10 / 39 (25.64%)
    24 / 81 (29.63%)
         occurrences all number
    12
    32
    Constipation
         subjects affected / exposed
    10 / 39 (25.64%)
    18 / 81 (22.22%)
         occurrences all number
    11
    22
    Vomiting
         subjects affected / exposed
    5 / 39 (12.82%)
    14 / 81 (17.28%)
         occurrences all number
    14
    27
    Stomatitis
         subjects affected / exposed
    3 / 39 (7.69%)
    7 / 81 (8.64%)
         occurrences all number
    4
    7
    Aphthous ulcer
         subjects affected / exposed
    1 / 39 (2.56%)
    9 / 81 (11.11%)
         occurrences all number
    1
    11
    Abdominal pain
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 81 (4.94%)
         occurrences all number
    2
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 81 (4.94%)
         occurrences all number
    4
    4
    Haemorrhoids
         subjects affected / exposed
    2 / 39 (5.13%)
    5 / 81 (6.17%)
         occurrences all number
    2
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 39 (10.26%)
    1 / 81 (1.23%)
         occurrences all number
    4
    1
    Odynophagia
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 81 (1.23%)
         occurrences all number
    2
    1
    Gingival pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    5 / 39 (12.82%)
    15 / 81 (18.52%)
         occurrences all number
    5
    25
    Hepatocellular injury
         subjects affected / exposed
    1 / 39 (2.56%)
    5 / 81 (6.17%)
         occurrences all number
    2
    5
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    3 / 39 (7.69%)
    8 / 81 (9.88%)
         occurrences all number
    3
    10
    Pruritus
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 81 (4.94%)
         occurrences all number
    3
    4
    Rash
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 81 (4.94%)
         occurrences all number
    1
    4
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    5 / 39 (12.82%)
    12 / 81 (14.81%)
         occurrences all number
    5
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 39 (10.26%)
    5 / 81 (6.17%)
         occurrences all number
    5
    7
    Pain in extremity
         subjects affected / exposed
    2 / 39 (5.13%)
    8 / 81 (9.88%)
         occurrences all number
    2
    10
    Back pain
         subjects affected / exposed
    3 / 39 (7.69%)
    5 / 81 (6.17%)
         occurrences all number
    3
    6
    Musculoskeletal pain
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 81 (4.94%)
         occurrences all number
    1
    4
    Myalgia
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 81 (4.94%)
         occurrences all number
    2
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 39 (10.26%)
    12 / 81 (14.81%)
         occurrences all number
    6
    13
    Bronchitis
         subjects affected / exposed
    3 / 39 (7.69%)
    6 / 81 (7.41%)
         occurrences all number
    5
    6
    Conjunctivitis
         subjects affected / exposed
    0 / 39 (0.00%)
    7 / 81 (8.64%)
         occurrences all number
    0
    7
    Oral candidiasis
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 81 (7.41%)
         occurrences all number
    1
    6
    Fungal infection
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 81 (2.47%)
         occurrences all number
    2
    2
    Rhinitis
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 81 (2.47%)
         occurrences all number
    2
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Sepsis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 39 (2.56%)
    2 / 81 (2.47%)
         occurrences all number
    1
    2
    Lung infection
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Infection
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 81 (3.70%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    9 / 39 (23.08%)
    16 / 81 (19.75%)
         occurrences all number
    13
    19
    Decreased appetite
         subjects affected / exposed
    6 / 39 (15.38%)
    5 / 81 (6.17%)
         occurrences all number
    8
    5
    Hyperglycaemia
         subjects affected / exposed
    3 / 39 (7.69%)
    8 / 81 (9.88%)
         occurrences all number
    4
    10
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 39 (5.13%)
    8 / 81 (9.88%)
         occurrences all number
    2
    9
    Hyperkalaemia
         subjects affected / exposed
    3 / 39 (7.69%)
    6 / 81 (7.41%)
         occurrences all number
    3
    8
    Hypophosphataemia
         subjects affected / exposed
    0 / 39 (0.00%)
    7 / 81 (8.64%)
         occurrences all number
    0
    8
    Hyperuricaemia
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 81 (4.94%)
         occurrences all number
    2
    4
    Dehydration
         subjects affected / exposed
    3 / 39 (7.69%)
    2 / 81 (2.47%)
         occurrences all number
    3
    2
    Hyperphosphataemia
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 81 (3.70%)
         occurrences all number
    2
    3
    Vitamin D deficiency
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 81 (1.23%)
         occurrences all number
    2
    1
    Hypokalaemia
         subjects affected / exposed
    8 / 39 (20.51%)
    25 / 81 (30.86%)
         occurrences all number
    11
    31
    Hyponatraemia
         subjects affected / exposed
    5 / 39 (12.82%)
    17 / 81 (20.99%)
         occurrences all number
    16
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2013
    Clarification of secondary endpoints. Correction of Pharmacokinetic and pharmacodynamic parameters procedures, and immunogenicity time points.
    22 Jan 2014
    Clarification inclusion/exclusion criteria. Clarification of study treatment administration.
    21 Jul 2014
    Addition of exclusion criteria to comply with BFArM demand. Clarification of inclusion criteria.
    11 Dec 2015
    Based on strong recommendation from several discussions with our coordinator PI as well as statistics experts, primary objective was changed to OS as considered more relevant for the pathology. PFS is now part of secondary objectives. Exploratory objectives were moved as secondary endpoints. Clarification of inclusion/exclusion criteria

    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.
    The study is not powered explicitly for OS, and statistical significance in favor of GRASPA plus low-dose cytarabine is not anticipated.
    For support, Contact us.
    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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