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    Clinical Trial Results:
    A Phase 1/2, Dose and Schedule Finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Oral Azacitidine (CC-486) in Subjects with Acute Myeloid Leukemia or Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation.

    Summary
    EudraCT number
    		 2012-005805-36
    Trial protocol
    		 GB  
    Global end of trial date
    26 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jun 2018
    First version publication date
    10 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-486-AML-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01835587
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Barry Skikne, MD, Celgene Corporation, 01 913-266-0334, BSkikne@Celgene.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
    14 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the maximum tolerated dose (MTD) of oral azacitidine in subjects with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after allogeneic hematopoietic stem cell transplantation (HSCT)
    Protection of trial subjects
    Patient Confidentiality and Personal Data Protection. This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Oct 2013
    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
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    30
    EEA total number of subjects
    2
    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)
    15
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The multicenter study was conducted in the United States and the United Kingdom. Participants were enrolled at 5 study sites.

    Pre-assignment
    Screening details
    		 Participants with a confirmed diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received an allogeneic hematopoietic stem cell transplant (HSCT) were eligible to participate and begin study drug between 42 and 84 days post HSCT. One participant was enrolled into the study but discontinued before being treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CC-486 200 mg Days 1-7 (Cohort 1)
    Arm description
    		 Participants received CC-486 200 mg by mouth (PO) once daily (QD) on Days 1 to 7 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event (AE), disease recurrence or relapse, progressive disease (PD), development of Grade III/IV acute graft versus host disease (GVHD), withdrawal of consent, lost to follow-up, protocol violation or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-486
    Investigational medicinal product code
    Other name
    Oral Azacitidine
    Pharmaceutical forms
    Coated tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    CC-486 200 mg on days 1-7 of each 28-day cycle.

    Arm title
    		 CC-486 300 mg Days 1-7 (Cohort 2)
    Arm description
    		 Participants received CC-486 300 mg by mouth once daily on Days 1 to 7 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-486
    Investigational medicinal product code
    Other name
    Oral Azacitidine
    Pharmaceutical forms
    Coated tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    CC-486 300 mg on days 1-7 of each 28-day cycle.

    Arm title
    		 CC-486 150 mg Days 1-14 (Cohort 3A)
    Arm description
    		 Participants received CC-486 150 mg by mouth once daily on Days 1 to 14 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-486
    Investigational medicinal product code
    Other name
    Oral Azacitidine
    Pharmaceutical forms
    Coated tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    CC-486 150 mg on days 1-14 of each 28-day cycle.

    Arm title
    		 CC-486 200 mg Days 1-14 (Cohort 3)
    Arm description
    		 Participants received CC-486 200 mg by mouth once daily on Days 1 to 14 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease (GVHD), withdrawal of consent, lost to follow-up, protocol violation or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-486
    Investigational medicinal product code
    Other name
    Oral Azacitidine
    Pharmaceutical forms
    Coated tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    CC-486 200 mg on days 1-14 of each 28-day cycle.

    Number of subjects in period 1
    		CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Started
    3
    4
    4
    19
    Completed
    1
    0
    2
    10
    Not completed
    2
    4
    2
    9
         Adverse event, serious fatal
    -
    -
    -
    1
         Consent withdrawn by subject
    2
    -
    -
    3
         Adverse event, non-fatal
    -
    -
    2
    2
         Miscellaneous
    -
    1
    -
    -
         Disease Recurrence or Relapse
    -
    3
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CC-486 200 mg Days 1-7 (Cohort 1)
    Reporting group description
    		 Participants received CC-486 200 mg by mouth (PO) once daily (QD) on Days 1 to 7 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event (AE), disease recurrence or relapse, progressive disease (PD), development of Grade III/IV acute graft versus host disease (GVHD), withdrawal of consent, lost to follow-up, protocol violation or death.

    Reporting group title
    CC-486 300 mg Days 1-7 (Cohort 2)
    Reporting group description
    		 Participants received CC-486 300 mg by mouth once daily on Days 1 to 7 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.

    Reporting group title
    CC-486 150 mg Days 1-14 (Cohort 3A)
    Reporting group description
    		 Participants received CC-486 150 mg by mouth once daily on Days 1 to 14 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.

    Reporting group title
    CC-486 200 mg Days 1-14 (Cohort 3)
    Reporting group description
    		 Participants received CC-486 200 mg by mouth once daily on Days 1 to 14 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease (GVHD), withdrawal of consent, lost to follow-up, protocol violation or death.

    Reporting group values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3) Total
    Number of subjects
    		 3 4 4 19 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 0 3 3 9 15
        From 65-84 years
    		 3 1 1 10 15
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 68.3 ( 5.77 ) 47.8 ( 18.26 ) 61.8 ( 8.73 ) 60.8 ( 12.60 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 1 0 0 4 5
        Male
    		 2 4 4 15 25
    Diagnosis at Study Entry
    Diagnosis of AML or MDS
    Units: Subjects
        Acute Myeloid Leukemia
    		 2 4 4 16 26
        Myelodysplastic Syndrome
    		 1 0 0 3 4
    AML World Health Organization (WHO) Classification
    AML is classified using the WHO classification system based upon a combination of morphology, immunophenotype, genetics, and clinical features. There are several broad groups and include: 1. AML with genetic abnormalities; 2. AML with multilineage dysplasia 3. AML related to previous chemotherapy or radiation 4. Unspecified AML - do not fall into the above groups
    Units: Subjects
        AML With Recurrent Genetic Abnormalities
    		 0 2 0 7 9
        AML With Myelodysplasia Related Changes
    		 0 0 1 2 3
        Therapy Related Myeloid Neoplasms
    		 0 0 1 0 1
        AML Not Otherwise Specified
    		 2 2 2 7 13
        Diagnosis of MDS
    		 1 0 0 3 4
    MDS International Prognostic Scoring System (IPSS) Risk Classification
    The MDS IPSS score assesses the severity of MDS based on 3 prognostic factors each assigned a score: the percentage of bone marrow blasts, chromosome changes in the marrow cells (karyotype) and the presence of one or more low blood cell counts (cytopenias). The IPSS score is the sum of the bone marrow blast + karyotype + cytopenia score and ranges from 0 (low risk) to 3.5 (high risk). Prognosis is categorized as Low risk (score = 0), Intermediate-1 (score 0.5 to 1.0), Intermediate-2 (score 1.5 to 2.0) or High risk (score ≥ 2.5).
    Units: Subjects
        INT-1
    		 0 0 0 1 1
        INT-2
    		 1 0 0 1 2
        High
    		 0 0 0 1 1
        Diagnosis of AML
    		 2 4 4 16 26
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG performance status is used by doctors and researchers to assess how a subject's disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
    Units: Subjects
        0 = Fully Active
    		 1 1 1 8 11
        1 = Restrictive but ambulatory
    		 2 3 3 11 19
        2 = Ambulatory but unable to work
    		 0 0 0 0 0
    Race
    Units: Subjects
        Asian
    		 0 1 0 0 1
        White
    		 3 3 4 18 28
        Not Collected or Reported
    		 0 0 0 1 1
    Time from MDS or AML Diagnosis to Allogeneic HSCT
    Units: months
        arithmetic mean (standard deviation)
    		 8.6 ( 6.79 ) 6.4 ( 4.35 ) 3.5 ( 1.71 ) 10.6 ( 16.72 ) -

    End points

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    End points reporting groups
    Reporting group title
    CC-486 200 mg Days 1-7 (Cohort 1)
    Reporting group description
    		 Participants received CC-486 200 mg by mouth (PO) once daily (QD) on Days 1 to 7 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event (AE), disease recurrence or relapse, progressive disease (PD), development of Grade III/IV acute graft versus host disease (GVHD), withdrawal of consent, lost to follow-up, protocol violation or death.

    Reporting group title
    CC-486 300 mg Days 1-7 (Cohort 2)
    Reporting group description
    		 Participants received CC-486 300 mg by mouth once daily on Days 1 to 7 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.

    Reporting group title
    CC-486 150 mg Days 1-14 (Cohort 3A)
    Reporting group description
    		 Participants received CC-486 150 mg by mouth once daily on Days 1 to 14 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.

    Reporting group title
    CC-486 200 mg Days 1-14 (Cohort 3)
    Reporting group description
    		 Participants received CC-486 200 mg by mouth once daily on Days 1 to 14 of each 28-day cycle for a maximum duration of 12 months or until they experienced an adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease (GVHD), withdrawal of consent, lost to follow-up, protocol violation or death.

    Subject analysis set title
    CC-486 200 mg Days 1-7 and Days 1-14
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic (PK) data from participants who received CC-486 200 mg by mouth daily were combined because the wash-out period between the PK sample collection and previous CC-486 dose was greater than 7-fold the half-life elimination of the drug, and CC 486 does not accumulate following multiple administrations.

    Subject analysis set title
    CC-486 300 mg Days 1-7
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK data for participants who received CC-486 300 mg by mouth once daily on Days 1 to 7 of each 28 day cycle for a maximum duration of 12 months or until they experienced, adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.

    Subject analysis set title
    CC-486 150 mg Days 1-14
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PD data for participants who received CC-486 150 mg by mouth once daily on Days 1 to 14 of each 28-day cycle for a maximum duration of 12 months or until they experienced, adverse event, disease recurrence or relapse, progressive disease, development of Grade III/IV acute graft versus host disease, withdrawal of consent, lost to follow-up, protocol violation or death.

    Primary: The Number of Dose Limiting Toxicities (DLT)

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    End point title
    		 The Number of Dose Limiting Toxicities (DLT) [1]
    End point description
    A DLT included events that started within 28 days of the first dose of CC-486 in a 28-day cycle, constituted a change from baseline irrespective of outcome, as decided by the investigator to be related to CC-486 including: • ≥ Grade (GR) 3 nausea, diarrhea, or vomiting despite the use of medical support • Other significant nonhematologic toxicity of ≥ GR 3 considered not related to the disease or intercurrent illness • Absolute neutrophil count (ANC) < 0.5 x 10^9/L for > 1 week despite growth factor support • Platelets < 25 x 10^9/L for > 1 week despite transfusion support • Failure of recovery to an ANC ≥ 1.0 x 10^9/L and/or platelets ≥ 50 x 10^9/L with a hypocellular marrow by 56 days after the start of a cycle of CC-486 not due to relapse or progressive disease. The maximum tolerated dose is defined as the cohort delivering the highest dose in which no more than 33% of the evaluable subjects had a DLT The safety population included subjects who received ≥ 1 dose of CC-486
    End point type
    Primary
    End point timeframe
    2 months (Cycles 1 and 2)
    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: The primary endpoint of finding the maximum tolerated dose did not require statistical analysis be conducted.
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3
    4
    4
    19
    Units: Participants
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAE)
    End point description
    A TEAE was defined as any AE with an onset date on or after the first dose of IP or any event already present that worsened in severity or increased in frequency after exposure to IP up to 28 days after the last dose. In addition, an AE that occurred beyond the timeframe and was assessed by the doctor as possibly related to IP was considered to be treatment-emergent. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for AEs (NCI CTCAE) version 4.0, where 1= Mild; 2= Moderate; 3= Severe; 4= Life-threatening; 5= Death related to AE. Serious AEs resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in a medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes above. The safety population includes subjects who received at least one dose of CC-486.
    End point type
    Secondary
    End point timeframe
    From the first dose of IP up to 28 days after the last dose of IP. The median duration of exposure was 252.5 days overall; up to the final data cut-off date of 14 July 2017.
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3
    4
    4
    19
    Units: participants
        Any TEAE
    3
    4
    4
    19
        Any TEAE With A Grade 3 or 4
    2
    3
    3
    14
        Any TEAE Related to IP
    3
    3
    4
    17
        TEAE With A Grade 3 or 4 Related to IP
    1
    1
    3
    8
        Serious TEAE
    1
    3
    2
    6
        Serious TEAE Related to IP
    1
    0
    1
    2
        TEAE With Outcome of Death
    0
    0
    0
    1
        TEAE Leading to Discontinuation of IP
    0
    0
    2
    6
        TEAE Related to IP and Leading to Stopping IP
    0
    0
    1
    3
        TEAE Leading to Dose Reduction
    0
    0
    0
    1
        TEAE Leading to Dose Interruption
    1
    0
    1
    6
        TEAE Leading to Dose Drug Interruption/Reduction
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Kaplan Meier Estimate of Time to Discontinuation from Treatment

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    End point title
    		 Kaplan Meier Estimate of Time to Discontinuation from Treatment
    End point description
    The time to discontinuation from treatment was assessed as an estimate of treatment tolerability and was defined as the interval from the date of the first IP dose to the date of discontinuation from IP as indicated on the discontinuation from treatment case report form (CRF) page. Time to discontinuation from study treatment was analyzed using the Kaplan-Meier method where participants who did not discontinue were censored at the date of last visit. The safety population includes subjects who received at least one dose of CC-486.
    End point type
    Secondary
    End point timeframe
    From the time of randomization until the end of treatment; the median duration of exposure was 252.5 days overall.
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3 [2]
    4 [3]
    4 [4]
    19 [5]
    Units: days
    number (not applicable)
        25th Percentile
    184.0
    104.5
    228.5
    58.0
        Median
    189.0
    177.0
    99999
    389.0
        75th Percentile
    99999
    189.0
    99999
    99999
    Notes
    [2] - 99999= indicates time was not reached due to subjects remaining in study until study closure.
    [3] - 99999= indicates time was not reached due to subjects remaining in study until study closure.
    [4] - 99999= indicates time was not reached due to subjects remaining in study until study closure.
    [5] - 99999= indicates time was not reached due to subjects remaining in study until study closure.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Graft Versus Host Disease During the Entire Course of the Study

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    End point title
    		 Percentage of Participants With Graft Versus Host Disease During the Entire Course of the Study
    End point description
    Acute graft versus host disease generally occurs after allogeneic hematopoietic stem cell transplantation. It is a reaction of donor immune cells against host tissues. The 3 main tissues that acute GVHD affects are the skin, liver, and gastrointestinal tract. Chronic GVHD is scored per the National Institute of Health consensus conference grading system. Clinical manifestations of chronic GVHD include skin involvement resembling lichen planus or the cutaneous manifestations of scleroderma; dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract; and a rising serum bilirubin concentration. The safety population includes subjects who received at least one dose of CC-486.
    End point type
    Secondary
    End point timeframe
    From the first dose of CC-486 up to study discontinuation or death. Up to final data cut off date of 14 July 2017; up to 186 weeks and 4 days
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3
    4
    4
    19
    Units: percentage of participants
        number (confidence interval 95%)
    66.7 (9.43 to 99.16)
    0.0 (0.00 to 60.24)
    75.0 (19.41 to 99.37)
    63.2 (38.36 to 83.71)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve from Time 0 to the Time of the Last Quantifiable Concentration Of CC-486 (AUC-t).

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    End point title
    		 Area Under the Plasma Concentration-time Curve from Time 0 to the Time of the Last Quantifiable Concentration Of CC-486 (AUC-t).
    End point description
    Area under the plasma concentration-time curve from Time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. The pharmacokinetic population included subjects with evaluable CC-486 plasma PK profiles.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1 and 2 stay until 6 hours after CC-486 administration.
    End point values
    		 CC-486 200 mg Days 1-7 and Days 1-14 CC-486 300 mg Days 1-7 CC-486 150 mg Days 1-14
    Number of subjects analysed
    20 [6]
    5 [7]
    2 [8]
    Units: ng*h/mL
    geometric mean (geometric coefficient of variation)
        Without Concomitant Meds|
    204.6 ( 63.0 )
    253.3 ( 26.6 )
    99999 ( 99999 )
        With Concomitant Meds|
    176.8 ( 69.0 )
    226.7 ( 54.5 )
    187.2 ( 34.1 )
    Notes
    [6] - 4 Without Concomitant Meds N = 20 With Concomitant Meds
    [7] - N = 2 Without Concomitant Meds N = 5 With Concomitant Meds
    [8] - N = 0 Without Concomitant Meds; 99999= not applicable due to 0 subjects N = 2 With Concomitant Me
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve from Time 0 to Extrapolated to Infinity (AUC-inf AUC0-∞) Of CC-486

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    End point title
    		 Area Under the Plasma Concentration-Time Curve from Time 0 to Extrapolated to Infinity (AUC-inf AUC0-∞) Of CC-486
    End point description
    Area under the plasma concentration-time curve from Time 0 extrapolated to infinity, calculated as [AUCt + Ct/ λz]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC %Extrap was ≥25%, AUC inf was not reported. The pharmacokinetic population included subjects with evaluable CC-486 plasma PK profiles.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1 and 2 stay until 6 hours after the CC-486 administration
    End point values
    		 CC-486 200 mg Days 1-7 and Days 1-14 CC-486 300 mg Days 1-7 CC-486 150 mg Days 1-14
    Number of subjects analysed
    18 [9]
    5 [10]
    2 [11]
    Units: ng*h/mL
    geometric mean (geometric coefficient of variation)
        Without Concomitant Meds
    206.0 ( 62.8 )
    218.4 ( 99999 )
    99999 ( 99999 )
        With Concomitant Meds
    187.5 ( 70.1 )
    232.5 ( 51.7 )
    188.6 ( 33.5 )
    Notes
    [9] - N = 4 Without Concomitant Meds N = 18 With Concomitant Meds
    [10] - N= 1 Without Concomitant Meds N= 5 With Concomitant Meds 99999=sample size could not be calculated
    [11] - N = 0 Without Concomitant Meds N = 2 With Concomitant Meds 99999= not applicable due to 0 subjects
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) Of CC-486

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    End point title
    		 Maximum Observed Concentration (Cmax) Of CC-486
    End point description
    Maximum observed plasma concentration, obtained directly from the observed concentration versus time data. The pharmacokinetic population included subjects with evaluable CC-486 plasma PK profiles.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1 and 2 stay until 6 hours after oral azacitidine administration
    End point values
    		 CC-486 200 mg Days 1-7 and Days 1-14 CC-486 300 mg Days 1-7 CC-486 150 mg Days 1-14
    Number of subjects analysed
    20 [12]
    5 [13]
    2 [14]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Without Concomitant Meds
    151.9 ( 43.5 )
    149.8 ( 7.6 )
    99999 ( 99999 )
        With Concomitant Meds
    114.3 ( 73.4 )
    137.8 ( 65.7 )
    91.49 ( 25.1 )
    Notes
    [12] - N = 4 Without Concomitant Meds N = 20 With Concomitant Meds
    [13] - N = 2 Without Concomitant Meds N = 5 With Concomitant Meds
    [14] - N = 0 Without Concomitant Meds N = 2 With Concomitant Meds 99999= not applicable due to 0 subjects
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Concentration (Tmax) of CC-486

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    End point title
    		 Time to Reach Maximum Concentration (Tmax) of CC-486
    End point description
    Time to Cmax, obtained directly from the observed concentration versus time data. The pharmacokinetic population included subjects with evaluable CC-486 plasma PK profiles.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1 and 2 stay until 6 hours after oral CC-486 administration
    End point values
    		 CC-486 200 mg Days 1-7 and Days 1-14 CC-486 300 mg Days 1-7 CC-486 150 mg Days 1-14
    Number of subjects analysed
    20 [15]
    5 [16]
    2 [17]
    Units: hours
    median (full range (min-max))
        Without Concomitant Meds
    0.77 (0.50 to 1.5)
    2.3 (1.5 to 3.1)
    99999 (99999 to 99999)
        With Concomitant Meds
    144 (24.3 to 252)
    2.0 (1.5 to 2.5)
    2.0 (2.0 to 2.0)
    Notes
    [15] - N = 4 Without Concomitant Meds N = 20 With Concomitant Meds
    [16] - 2 Without Concomitant Meds N = 5 With Concomitant Meds
    [17] - N = 0 Without Concomitant Meds N = 2 With Concomitant Meds 99999= not applicable due to 0 subjects
    No statistical analyses for this end point

    Secondary: Terminal Half-Life (T1/2) of CC-486

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    End point title
    		 Terminal Half-Life (T1/2) of CC-486
    End point description
    Terminal phase half-life in plasma, calculated as [(ln 2)/λz]. t1/2 was only calculated when a reliable estimate for λz could be obtained. The pharmacokinetic population included subjects with evaluable CC-486 plasma PK profiles.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1 and 2 stay until 6 hours after oral CC-486 administration
    End point values
    		 CC-486 200 mg Days 1-7 and Days 1-14 CC-486 300 mg Days 1-7 CC-486 150 mg Days 1-14
    Number of subjects analysed
    18 [18]
    5 [19]
    2 [20]
    Units: hours
    geometric mean (geometric coefficient of variation)
        Without Concomitant Meds
    0.528 ( 6.8 )
    0.575 ( 99999 )
    99999 ( 99999 )
        With Concomitant Meds
    0.553 ( 24.5 )
    0.565 ( 44.3 )
    0.446 ( 20.6 )
    Notes
    [18] - N = 4 Without Concomitant Meds N = 18 With Concomitant Meds
    [19] - N = 1 Without Concomitant Meds N = 5 With Concomitant Meds 99999-sample size to small to calculate
    [20] - N = 0 Without Concomitant Meds N = 2 With Concomitant Meds 99999= not applicable due to 0 subjects
    No statistical analyses for this end point

    Secondary: Apparent Total Clearance (CL/F) of CC-486

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    End point title
    		 Apparent Total Clearance (CL/F) of CC-486
    End point description
    Apparent total clearance, calculated as [Dose/AUCinf]. The pharmacokinetic population included subjects with evaluable CC-486 plasma PK profiles.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1 and 2 stay until 6 hours after oral CC-486 administration
    End point values
    		 CC-486 200 mg Days 1-7 and Days 1-14 CC-486 300 mg Days 1-7 CC-486 150 mg Days 1-14
    Number of subjects analysed
    18 [21]
    5 [22]
    2 [23]
    Units: L/h
    geometric mean (geometric coefficient of variation)
        Without Concomitant Meds
    971.1 ( 62.8 )
    1374 ( 99999 )
    99999 ( 99999 )
        With Concomitant Meds
    1067 ( 70.1 )
    1290 ( 51.7 )
    795.4 ( 33.5 )
    Notes
    [21] - N = 4 Without Concomitant Meds N = 18 With Concomitant Meds
    [22] - N = 1 Without Concomitant Meds N = 5 With Concomitant Meds
    [23] - N = 0 Without Concomitant Meds N = 2 With Concomitant Meds 99999= not applicable due to 0 subjects
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution (Vz/F) of CC-486

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    End point title
    		 Apparent Volume of Distribution (Vz/F) of CC-486
    End point description
    Apparent volume of distribution, calculated as [(CL/F)/λz].Apparent volume of distribution, calculated as [(CL/F)/λz]. The pharmacokinetic population included subjects with evaluable CC-486 plasma PK profiles.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1 and 2 stay until 6 hours after oral CC-486 administration
    End point values
    		 CC-486 200 mg Days 1-7 and Days 1-14 CC-486 300 mg Days 1-7 CC-486 150 mg Days 1-14
    Number of subjects analysed
    18 [24]
    5 [25]
    2 [26]
    Units: Liters
    geometric mean (geometric coefficient of variation)
        Without Concomitant Meds
    739.9 ( 58.7 )
    1139 ( 99999 )
    99999 ( 99999 )
        With Concomitant Meds
    851.3 ( 77.6 )
    1052 ( 100.0 )
    511.8 ( 12.3 )
    Notes
    [24] - N = 4 Without Concomitant Meds N = 18 With Concomitant Meds
    [25] - N = 1 Without Concomitant Meds N = 5 With Concomitant Meds 99999-sample size to small to calculate
    [26] - N = 0 Without Concomitant Meds N =2 With Concomitant Meds 99999= not applicable due to 0 subjects
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease Relapse or Progression

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    End point title
    		 Percentage of Participants With Disease Relapse or Progression
    End point description
    Disease relapse was defined as the reappearance of > 5% blasts in the bone marrow that persisted for at least 4 weeks. Disease progression was defined as the reappearance of > 10% of blasts in the bone marrow that persisted for at least 4 weeks. The preliminary efficacy population included all subjects who received at least one dose of IP and had at least one post-baseline efficacy assessment performed.
    End point type
    Secondary
    End point timeframe
    Date of first dose of IP to disease relapse or progression; up to data cut-off date of 14 July 2017.
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3
    4
    4
    19
    Units: Percentage of Participants
        number (not applicable)
    33.3
    75.0
    0
    15.8
    No statistical analyses for this end point

    Secondary: Time to Disease Recurrence/Progression

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    End point title
    		 Time to Disease Recurrence/Progression
    End point description
    Time to disease relapse/progression was defined as the interval from the date of allogeneic HSCT to the date of treatment discontinuation or study discontinuation where reason for discontinuation is disease relapse or disease progression, or the date of disease progression recorded on the survival electronic Case Report Form page, whichever occurred first. Time to disease relapse/progression was analyzed using competing risk methods where death without documented relapse/progression was treated as a competing risk for relapse/progression. relapse/progression. The preliminary efficacy population included all subjects who received at least one dose of IP and had at least one post-baseline efficacy assessment performed.
    End point type
    Secondary
    End point timeframe
    Date of allogenic HSCT to disease progression or discontinuation. Median number of days from first dose to disease relapse or progression was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 657.5 days for Cohort 3A and 559.0 days for Cohort 3.
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3
    4
    4
    19
    Units: days
        arithmetic mean (standard deviation)
    691.7 ( 436.10 )
    452.5 ( 493.50 )
    660.8 ( 218.12 )
    521.7 ( 310.53 )
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival was defined as the time from the date of allogeneic hematopoietic stem cell transplantation to death from any cause. The preliminary efficacy population included all subjects who received at least one dose of IP and had at least one post-baseline efficacy assessment performed.
    End point type
    Secondary
    End point timeframe
    Date of the allogeneic HSCT to death from any cause. Median number of days participants were assessed from first dose to last contact was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3 [27]
    4 [28]
    4 [29]
    19 [30]
    Units: Days
    number (not applicable)
        25th Percentile
    741.0
    304
    99999
    547
        Median
    99999
    99999
    99999
    99999
        75th Percentile
    99999
    99999
    99999
    99999
    Notes
    [27] - 99999=median OS not reached due to long survival of subjects relative to study duration
    [28] - 99999=median OS not reached due to long survival of subjects relative to study duration
    [29] - 99999=median OS not reached due to long survival of subjects relative to study duration
    [30] - 99999=median OS not reached due to long survival of subjects relative to study duration
    No statistical analyses for this end point

    Secondary: Kaplan Meier Estimate of Relapse-Free Survival (RFS)

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    End point title
    		 Kaplan Meier Estimate of Relapse-Free Survival (RFS)
    End point description
    Relapse-free survival was defined as the interval from the date of allogeneic HSCT to the date of first documented > 5% blasts in the bone marrow or death from any cause, whichever occurred first. Participants who were still alive and continued to have less than or equal to 5% blasts in the bone marrow or who were lost to follow-up were censored at the date of their last response assessment. The preliminary efficacy population included all subjects who received at least one dose of IP and had at least one post-baseline efficacy assessment performed.
    End point type
    Secondary
    End point timeframe
    Date of allogeneic HSCT to date of progression or death from any cause; median number of days subjects were assessed from first dose to last contact was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3
    End point values
    		 CC-486 200 mg Days 1-7 (Cohort 1) CC-486 300 mg Days 1-7 (Cohort 2) CC-486 150 mg Days 1-14 (Cohort 3A) CC-486 200 mg Days 1-14 (Cohort 3)
    Number of subjects analysed
    3
    4 [31]
    4 [32]
    19 [33]
    Units: Days
        25th Percentile
    741
    183
    99999
    397
        Median
    921
    255
    99999
    99999
        75th Percentile
    1101
    99999
    99999
    99999
    Notes
    [31] - 99999=median PFS not reached due to long progression free in subjects relative to study duration.
    [32] - 99999=median PFS not reached due to long progression free in subjects relative to study duration.
    [33] - 99999=median PFS not reached due to long progression free in subjects relative to study duration.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of IP up to 28 days after the last dose of IP. The median duration of exposure was 252.5 days overall.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    200 mg x 7 days
    Reporting group description
    		 -

    Reporting group title
    300 mg x 7 days
    Reporting group description
    		 -

    Reporting group title
    150mg x 14 days
    Reporting group description
    		 -

    Reporting group title
    200 mg x 14 days
    Reporting group description
    		 -

    Serious adverse events
    		 200 mg x 7 days 300 mg x 7 days 150mg x 14 days 200 mg x 14 days
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
    6 / 19 (31.58%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 200 mg x 7 days 300 mg x 7 days 150mg x 14 days 200 mg x 14 days
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    18 / 19 (94.74%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    2
    0
    3
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    7 / 19 (36.84%)
         occurrences all number
    2
    3
    4
    8
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    1
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Immune system disorders
    Chronic graft versus host disease in skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Graft versus host disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    2
    Graft versus host disease in liver
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Graft versus host disease in skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    1
    3
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Obliterative bronchiolitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    3
    Sneezing
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    3
    3
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    6
    5
    Blood potassium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Blood uric acid increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    5
    5
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    3
    Post-traumatic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    0
    2
    Dysgeusia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Radial nerve palsy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    8 / 19 (42.11%)
         occurrences all number
    2
    3
    5
    12
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    3
    7
    Lymphopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    5
    7
    Neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    4 / 19 (21.05%)
         occurrences all number
    1
    1
    1
    6
    Thrombocytopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    6 / 19 (31.58%)
         occurrences all number
    1
    1
    2
    10
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Keratitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Photophobia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Retinal detachment
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    3
    2
    0
    6
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    0
    4
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    11 / 19 (57.89%)
         occurrences all number
    5
    4
    3
    16
    Dry mouth
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    0
    3
    Gastrointestinal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
    4 / 4 (100.00%)
    12 / 19 (63.16%)
         occurrences all number
    7
    3
    6
    16
    Oesophagitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    8 / 19 (42.11%)
         occurrences all number
    3
    1
    2
    13
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    3
    Rosacea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Skin ulcer
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Bladder spasm
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Chronic kidney disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Joint range of motion decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    2
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Osteopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Osteoporosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Pain in jaw
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Catheter site cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Clostridium difficile infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Corneal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Nail infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin candida
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    1
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    1
    Diabetes mellitus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gout
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    6
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    4
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    6
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    5
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    2
    3
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    2
    Vitamin D deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2015
    • Hematologic toxicities that did not meet the definition of DLT were observed early in Cohort 3 (200 mg QD for 14 days), which prompted the following changes: - Incorporation of an alternative cohort with azacitidine total exposure lower than Cohort 3, specifically 150 mg QD for 14 days - Increase in the minimal platelet count required for study entry from 25 x 10^9/L to 75 x 10^9/L - Removal of the 21-day treatment schedules - Increase in the lower limit for platelet count in the definition of DLT - Change to the neutropenia and thrombocytopenia criteria for interrupting or resuming IP • Other changes included the following: - Cohort 1 (200 mg QD for 7 days) was safe and well tolerated without DLT. Therefore, lower dose cohorts (100 mg QD for Days 1 to 7 and 150 mg QD for Days 1 to 7) were removed. - Pregnancy testing was added on Cycle 5 Day 1 and beyond. A change was also made to require serum pregnancy test at screening, instead of a serum or urine pregnancy test. - The reference section was updated. - New protocol template language related to safety and the end of study definition was added. - Minor typographical corrections were made. - Which subjects should undergo standard PK sampling and sparse PK sampling was clarified. - The timing for bone marrow aspirate or biopsy during screening was clarified. - The definition of overdose added and AE reporting procedures for overdose were clarified to conform to template updates. - The stepwise reduction of dose or treatment duration 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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