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    Clinical Trial Results:
    A Phase 2 Trial of MLN8237, an Oral Aurora A Kinase Inhibitor, in Adult Patients with Acute Myelogenous Leukemia and High-Grade Myelodysplastic Syndrome

    Summary
    EudraCT number
    		 2008-006977-34
    Trial protocol
    		 FR  
    Global end of trial date
    04 Jul 2011

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 Jul 2018
    First version publication date
    30 Dec 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    SAE revision.
    Summary report(s)
    		 Summary Results

    Trial information

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    Trial identification
    Sponsor protocol code
    C14005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00830518
    WHO universal trial number (UTN)
    		 U1111-1187-6616
    Sponsors
    Sponsor organisation name
    Takeda Oncology
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, USA 02139
    Public contact
    Medical Director,Clinical Science, Takeda Oncology, +1 844-662-8532, GlobalOncologyMedinfo@takeda.com
    Scientific contact
    Medical Director,Clinical Science, Takeda Oncology, +1 844-662-8532, GlobalOncologyMedinfo@takeda.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
    04 Jul 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jul 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate antitumor activity of MLN8237 as measured by response rate in participants with Acute Myelogenous Leukemia (AML) and High-Grade Myelodysplastic Syndrome (MDS)
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Feb 2009
    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 States: 42
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    France: 13
    Worldwide total number of subjects
    57
    EEA total number of subjects
    13
    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)
    7
    From 65 to 84 years
    49
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 19 investigative sites in France, Canada and the United States from 10 February 2009 to 04 July 2011.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of acute myelogenous leukemia or myelodysplastic syndrome received 50 mg alisertib twice daily for 7 days in 21 day cycles. Results are reported according to lymphoma disease subtypes: acute myelogenous leukemia and myelodysplastic syndrome.

    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
    		 Alisertib 50 mg (Acute myeloid leukemia)
    Arm description
    		 Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alisertib
    Investigational medicinal product code
    Other name
    MLN8237
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles).

    Arm title
    		 Alisertib 50 mg (Myelodysplastic syndrome)
    Arm description
    		 Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alisertib
    Investigational medicinal product code
    Other name
    MLN8237
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles).

    Number of subjects in period 1
    		Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome)
    Started
    46
    11
    Completed
    0
    0
    Not completed
    46
    11
         Adverse event, non-fatal
    14
    1
         Progressive Disease
    18
    8
         Withdrawal by Patient
    2
    -
         Symptomatic Deterioration
    4
    1
         Reason not Specified
    8
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alisertib 50 mg (Acute myeloid leukemia)
    Reporting group description
    		 Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles).

    Reporting group title
    Alisertib 50 mg (Myelodysplastic syndrome)
    Reporting group description
    		 Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles).

    Reporting group values
    		 Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome) Total
    Number of subjects
    		 46 11 57
    Age Categorical
    Units: Subjects
        <60 years
    		 4 2 6
        ≥60 years
    		 42 9 51
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.9 ( 7.41 ) 69.5 ( 12.50 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 22 3 25
        Male
    		 24 8 32
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 2 0 2
        Not Hispanic or Latino
    		 34 9 43
        Not Reported
    		 10 2 12
    Region of Enrollment
    Units: Subjects
        United States
    		 33 9 42
        France
    		 11 2 13
        Canada
    		 2 0 2
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 36 10 46
        Black or African American
    		 3 0 3
        Asian
    		 1 0 1
        Not Reported
    		 6 1 7
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG performance is defined as: 0=Normal activity (fully active, able to carry on all predisease performance without restriction); 1=Symptoms but ambulatory (restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature); 2=In bed <50% of the time (ambulatory and capable of all self-care, but unable to carry out any work activities.
    Units: Subjects
        ECOG Performance Status=0
    		 9 3 12
        ECOG Performance Status=1
    		 29 8 37
        ECOG Performance Status=2
    		 8 0 8
    Study Specific Characteristic | Height
    Baseline height data is available for n=36,10, respectively.
    Units: cm
        arithmetic mean (standard deviation)
    		 165.8 ( 8.35 ) 171.4 ( 9.98 ) -
    Study Specific Characteristic | Weight
    Baseline weight data is available for n=45,11, respectively.
    Units: kg
        arithmetic mean (standard deviation)
    		 73.7 ( 13.80 ) 80.4 ( 17.27 ) -
    Study Specific Characteristic | Baseline Body Surface Area (BSA)
    Baseline BSA data is available for n=36,10, respectively.
    Units: m^2
        arithmetic mean (standard deviation)
    		 1.83 ( 0.203 ) 1.94 ( 0.262 ) -
    Study Specific Characteristic | Years Since Initial Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 0.65 ( 0.793 ) 0.82 ( 0.780 ) -

    End points

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    End points reporting groups
    Reporting group title
    Alisertib 50 mg (Acute myeloid leukemia)
    Reporting group description
    		 Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles).

    Reporting group title
    Alisertib 50 mg (Myelodysplastic syndrome)
    Reporting group description
    		 Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles).

    Primary: Best Overall Response Rate (ORR) Based on Investigator’s Assessment

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    End point title
    		 Best Overall Response Rate (ORR) Based on Investigator’s Assessment [1]
    End point description
    Best ORR:number of participants with complete remission(CR)/partial remission(PR) assessed by Investigator using modified AML/MDS International Working Group Criteria.AML:CR=neutrophils>1*10^9/L,platelets>100*10^9/L,bone marrow blasts(BMB)<5%,transfusion independent,no extramedullary disease(EMD);CRi=BMB<5%,transfusion independent,no EMD;PR=neutrophils>1*10^9/L,platelets>100*10^9/L, BMB>50% decrease(dec.)and 5% to 25%,blasts<5% with Auer rods;PRi=BMB>50%dec.and 5%-25%.MDS:CR=bone marrow:≤5%myeloblasts with normal maturation,peripheral blood:hemoglobin ≥11g/dL,platelets ≥100*10^9/L,neutrophils≥1.0*10^9/L,blasts0%;PR=all CR criteria if abnormal before treatment except:BMB dec.by ≥50% over pretreatment but still>5%;PRi=BMB dec.by ≥50% over pretreatment but still >5%;Marrow CR=bone marrow:≤5% myeloblasts and dec.by ≥50% over pretreatment,peripheral blood hematologic improvement responses noted. (Response-Evaluable Population)
    End point type
    Primary
    End point timeframe
    Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)
    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: No statistical analyses are reported for this endpoint.
    End point values
    		 Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome)
    Number of subjects analysed
    35
    10
    Units: participants
        CR + PR
    6
    0
        Complete Remission (CR + CRi + Marrow CRi)
    1
    0
        Partial Remission (PR + PRi)
    5
    0
        Stable Disease as Best Response
    17
    2
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS is defined as the time from the date of first study drug administration to the date of first documented progressive disease (PD) or death.Response-Evaluable Population included all participants who received at least 1 dose of alisertib and had at least 1 post-baseline response assessment. For a participant that has not progressed and has not died, PFS is censored at the last response assessment that is SD or better.
    End point type
    Secondary
    End point timeframe
    Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)
    End point values
    		 Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome)
    Number of subjects analysed
    35
    10
    Units: days
        median (confidence interval 95%)
    55.0 (47.0 to 67.0)
    38.0 (35.0 to 113.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of response is defined as the time from the date of first documentation of a response to the date of first documented PD. Response-­Evaluable Population included all participants who had measurable disease, received at least 1 dose of alisertib, and had at least 1 post baseline response assessment. All responders were evaluated in this outcome measure. For a participant that has not progressed, DOR is censored at the last response assessment that is SD or better.
    End point type
    Secondary
    End point timeframe
    Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)
    End point values
    		 Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome)
    Number of subjects analysed
    6
    0 [2]
    Units: days
        median (confidence interval 95%)
    409.0 (57.0 to 596.0)
    ( to )
    Notes
    [2] - No participants with response.
    No statistical analyses for this end point

    Secondary: Best Overall Hematologic Improvement (HI) Response for Myelodysplastic Syndrome Based on Investigator Assessment

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    End point title
    		 Best Overall Hematologic Improvement (HI) Response for Myelodysplastic Syndrome Based on Investigator Assessment [3]
    End point description
    Best overall HI response:percentage of participants with response as assessed by Investigator based on IWG criteria:1)Erythroid response (pretreatment,<11 g/dL):hemoglobin(Hgb) increase(inc.) by ≥1.5 g/dL,relevant reduction of units of red blood cell (RBC) transfusions by absolute number of at least 4 RBC transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks.Only RBC transfusions given for Hgb of ≤9.0 g/dL pretreatment will count in RBC transfusion response evaluation.2)Platelet response(pretreatment<100*10^9/L):Absolute inc. of ≥30*10^9/L for participants starting:>20*10^9/L platelets, inc.<20*10^9/L to >20*10^9/L by at least 100%.3)Neutrophil response(pretreatment,<1.0*10^9/L):At least 100% inc. and an absolute inc. >0.5*10^9/L.4)Progression or relapse after HI:At least 1 of following: 50% decrement from maximum response levels in granulocytes or platelets, or reduction in Hgb by ≥1.5g/dL,or transfusion dependence. (Safety Population)
    End point type
    Secondary
    End point timeframe
    Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    		 Alisertib 50 mg (Myelodysplastic syndrome)
    Number of subjects analysed
    11
    Units: percentage of participants
        Erythroid Response
    0
        Platelet Response
    0
        Neutrophil Response
    0
        Progression or Relapse
    0
        Not Available
    91
        Unable to Assess
    9
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths

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    End point title
    		 Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.Safety population was defined as all participants who received any amount of alisertib.
    End point type
    Secondary
    End point timeframe
    First dose of study drug to 30 days after last dose (Up to 18.9 months)
    End point values
    		 Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome)
    Number of subjects analysed
    46
    11
    Units: participants
        AE
    46
    11
        SAE
    36
    8
        Deaths
    20
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events

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    End point title
    		 Number of Participants with Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events
    End point description
    Vital signs measurements (blood pressure, heart rate, and oral temperature) were obtained throughout the study. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.Safety population was defined as all participants who received any amount of alisertib.
    End point type
    Secondary
    End point timeframe
    First dose of study drug to 30 days after last dose (Up to 18.9 months)
    End point values
    		 Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome)
    Number of subjects analysed
    46
    11
    Units: participants
        Dyspnoea
    12
    2
        Pyrexia
    10
    2
        Hypotension
    8
    0
        Atrial fibrillation
    4
    1
        Tachycardia
    3
    0
        Dyspnoea exertional
    2
    1
        Hypertension
    1
    1
        Supraventricular tachycardia
    2
    0
        Weight decreased
    2
    0
        Tachypnoea
    1
    0
        Hyperthermia
    1
    0
        Hypothermia
    1
    0
        Bradycardia
    0
    1
        Ventricular tachycardia
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Laboratory Values reported as Treatment-Emergent Adverse Events

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    End point title
    		 Number of Participants with Abnormal Laboratory Values reported as Treatment-Emergent Adverse Events
    End point description
    Abnormal Laboratory Values for Chemistry or Hematology tests that were assessed by the investigator to be Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. A treatment­-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.Safety population was defined as all participants who received any amount of alisertib.
    End point type
    Secondary
    End point timeframe
    First dose of study drug to 30 days after last dose (Up to 18.9 months)
    End point values
    		 Alisertib 50 mg (Acute myeloid leukemia) Alisertib 50 mg (Myelodysplastic syndrome)
    Number of subjects analysed
    46
    11
    Units: participants
        Febrile neutropenia
    17
    4
        Anaemia
    14
    3
        Thrombocytopenia
    9
    2
        Neutropenia
    5
    3
        Leukopenia
    3
    2
        Hypoalbuminaemia
    4
    0
        Leukocytosis
    3
    0
        Hypokalaemia
    3
    0
        Hyponatraemia
    3
    0
        Neutrophil count decreased
    3
    0
        Hypocalcaemia
    2
    0
        Clostridium difficile colitis
    2
    0
        Febrile bone marrow aplasia
    1
    0
        Hypoxia
    1
    0
        Hyperkalaemia
    1
    0
        Hypernatraemia
    1
    0
        Hyperglycaemia
    1
    0
        Hypoglycaemia
    1
    0
        Hypomagnesaemia
    0
    1
        Hypophospataemia
    1
    0
        Alanine aminotransferase increased
    0
    1
        Blood bilirubin increased
    1
    0
        Oxygen saturation decreased
    1
    0
        Blood culture positive
    1
    0
        Blood magnesium decreased
    1
    0
        Blood creatinine increased
    1
    0
        White blood cell count decreased
    1
    0
        Gilbert’s syndrome
    1
    0
        Lymphoedema
    1
    0
        Platelet count decreased
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to 30 days after last dose (Up to 18.9 Months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Alisertib 50 mg (Myelodysplastic syndrome)
    Reporting group description
    		 Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles).

    Reporting group title
    Alisertib 50 mg (Acute myeloid leukemia)
    Reporting group description
    		 Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles).

    Serious adverse events
    		 Alisertib 50 mg (Myelodysplastic syndrome) Alisertib 50 mg (Acute myeloid leukemia)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 11 (72.73%)
    36 / 46 (78.26%)
         number of deaths (all causes)
    2
    22
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    5 / 46 (10.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Fatigue
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hip fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depressed level of consciousness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 11 (36.36%)
    13 / 46 (28.26%)
         occurrences causally related to treatment / all
    1 / 4
    5 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck mass
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 11 (18.18%)
    5 / 46 (10.87%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serratia bacteraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Alisertib 50 mg (Myelodysplastic syndrome) Alisertib 50 mg (Acute myeloid leukemia)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    45 / 46 (97.83%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    7 / 46 (15.22%)
         occurrences all number
    0
    8
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 11 (45.45%)
    15 / 46 (32.61%)
         occurrences all number
    6
    16
    Oedema peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    12 / 46 (26.09%)
         occurrences all number
    0
    14
    Asthenia
         subjects affected / exposed
    1 / 11 (9.09%)
    8 / 46 (17.39%)
         occurrences all number
    1
    8
    Pyrexia
         subjects affected / exposed
    2 / 11 (18.18%)
    9 / 46 (19.57%)
         occurrences all number
    3
    15
    Axillary pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Chills
         subjects affected / exposed
    1 / 11 (9.09%)
    6 / 46 (13.04%)
         occurrences all number
    1
    7
    Catheter site erythema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 11 (27.27%)
    9 / 46 (19.57%)
         occurrences all number
    3
    10
    Epistaxis
         subjects affected / exposed
    3 / 11 (27.27%)
    5 / 46 (10.87%)
         occurrences all number
    3
    6
    Oropharyngeal pain
         subjects affected / exposed
    3 / 11 (27.27%)
    3 / 46 (6.52%)
         occurrences all number
    3
    4
    Pleural effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    4
    Sneezing
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences all number
    1
    2
    Dyspnoea
         subjects affected / exposed
    2 / 11 (18.18%)
    10 / 46 (21.74%)
         occurrences all number
    2
    10
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    5
    Mental status changes
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences all number
    1
    2
    Psychotic disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    5
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 11 (27.27%)
    2 / 46 (4.35%)
         occurrences all number
    4
    2
    Excoriation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    4
    Tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Bradycardia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    2 / 11 (18.18%)
    11 / 46 (23.91%)
         occurrences all number
    2
    11
    Headache
         subjects affected / exposed
    2 / 11 (18.18%)
    5 / 46 (10.87%)
         occurrences all number
    2
    5
    Balance disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Burning sensation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Subdural hygroma
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 46 (8.70%)
         occurrences all number
    2
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 11 (27.27%)
    10 / 46 (21.74%)
         occurrences all number
    5
    12
    Thrombocytopenia
         subjects affected / exposed
    2 / 11 (18.18%)
    8 / 46 (17.39%)
         occurrences all number
    4
    9
    Neutropenia
         subjects affected / exposed
    3 / 11 (27.27%)
    5 / 46 (10.87%)
         occurrences all number
    5
    6
    Leukopenia
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 46 (6.52%)
         occurrences all number
    3
    3
    Febrile neutropenia
         subjects affected / exposed
    0 / 11 (0.00%)
    6 / 46 (13.04%)
         occurrences all number
    0
    7
    Leukocytosis
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    5
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 11 (18.18%)
    21 / 46 (45.65%)
         occurrences all number
    4
    29
    Stomatitis
         subjects affected / exposed
    4 / 11 (36.36%)
    13 / 46 (28.26%)
         occurrences all number
    5
    15
    Nausea
         subjects affected / exposed
    3 / 11 (27.27%)
    19 / 46 (41.30%)
         occurrences all number
    3
    24
    Vomiting
         subjects affected / exposed
    2 / 11 (18.18%)
    8 / 46 (17.39%)
         occurrences all number
    2
    10
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    4
    Dysphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    6 / 46 (13.04%)
         occurrences all number
    0
    7
    Constipation
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Gingival bleeding
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    5
    Haemorrhoids
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences all number
    2
    2
    Oral pain
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    4
    Proctalgia
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences all number
    1
    2
    Abdominal distension
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Dyspepsia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Tongue ulceration
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Anal fissure
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Oral disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    2 / 11 (18.18%)
    11 / 46 (23.91%)
         occurrences all number
    2
    12
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 11 (36.36%)
    7 / 46 (15.22%)
         occurrences all number
    4
    7
    Pruritus
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 46 (4.35%)
         occurrences all number
    2
    2
    Petechiae
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    4
    Blood blister
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 46 (2.17%)
         occurrences all number
    2
    1
    Ecchymosis
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Night sweats
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Rash
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences all number
    3
    2
    Rash pruritic
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
         occurrences all number
    1
    4
    Urticaria
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    4
    Rash macular
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Back pain
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 46 (6.52%)
         occurrences all number
    2
    3
    Pain in extremity
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    4
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Gouty arthritis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 46 (6.52%)
         occurrences all number
    1
    5
    Oral herpes
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
         occurrences all number
    1
    4
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Bronchitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Anal abscess
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Aspergillosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 11 (0.00%)
    8 / 46 (17.39%)
         occurrences all number
    0
    9
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    4
    Hypokalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    4
    Hyponatraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    4
    Hypomagnesaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2009
    Amendment 1 -Clarify eligibility of patients with high-grade (eg, high-risk) MDS, relevant to IPSS categories and relevant to prior treatment, including demethylating agents which were approved for MDS. -Remove the requirement for follow-up bone marrow biopsies after the baseline biopsy and aspirate, since the Standard of Care among participating investigators did not require serial biopsies for follow-up of disease control. - Clarify that glucose and albumin should be obtained at screening, not baseline.
    26 Mar 2009
    Amendment 2 -Due to the nature of the disease under study in this protocol, the specific requirement for repeat testing of CBC with differential in the setting of ANC < 500/mm^3 or a platelet count < 25,000/mm^3 was removed. - clarification that additional laboratory safety testing could be done on existing blood volume, if required locally.
    27 Aug 2009
    Amendment 3 1.Update to definitions for disease response and progression -Clarify/update the response criteria for MDS patients based on recent literature. -Update the AML response criteria as per revised IWG AML criteria -Add a secondary endpoint for patients with MDS: Evaluation of Hematologic Improvement (HI) that generally aligns with IWG criteria in myelodysplasia 2.Modify the criteria for resuming treatment with alisertib after drug has been held due to an adverse event 3.Enrollment of a minimum number of patients with AML and MDS. To assure balance in clinical experience from this study, this amendment specified that a minimum of 8 patients were to be enrolled in each disease group (ie, 8 patients with AML and 8 patients with MDS) in the first stage of the protocol. 4. Reduce the frequency and clarify reasons for bone marrow testing.
    27 Oct 2010
    Amendment 4 To provide opportunity for continued treatment with study drug alisertib beyond 12 months for patients who tolerated alisertib and experienced objective response or disease control -To provide a reduced Schedule of Events for patients who had been on the study for more than 12 months and who were tolerating treatment with evidence of disease control -To add restrictions for concomitant medications that are known potent UGT/CYP inducers -To confirm that the interim analysis would not be conducted -To update the current clinical experience section -To update the current risk section -To clarify language around completion of treatment and withdrawal from study -To update product complaint language for consistency with Millennium’s administrative requirements -To update and move contact information for the medical monitor to the study manual.

    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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