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    Clinical Trial Results:
    A Phase 2, Double-Blind, Randomized Safety and Efficacy Study of Glasdegib (PF-04449913) versus Placebo in Patients with Myelofibrosis Previously Treated with Ruxolitinib

    Summary
    EudraCT number
    2014-001048-40
    Trial protocol
    GB   ES   AT   FR  
    Global end of trial date
    31 Jan 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Jan 2019
    First version publication date
    03 Dec 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    B1371013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02226172
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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
    01 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the lead-in cohort was to assess the safety and tolerability of glasdegib in patients with primary or secondary myelofibrosis (MF) who had been previously treated with 1 or more Janus kinase inhibitors (JAKis).
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects. The final protocol and any amendments were reviewed and approved by the Institutional Review Board(s) and/or Independent Ethics Committee(s) at each of the investigational centers participating in the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Oct 2014
    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
    Japan: 5
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    21
    EEA total number of subjects
    0
    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)
    4
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    In this study, 2 cohorts were involved lead-in and randomized cohort. Lead-in cohort was followed by randomized cohort. Though the drug was considered safe and tolerable in Myelofibrosis, but a key secondary efficacy end point was not met. Therefore, continuation into the randomized cohort did not proceed.

    Pre-assignment
    Screening details
    Subjects were screened at 1 visit or over multiple visits across a 4 week period. Following this, subjects entered the treatment phase of the study.

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

    Arms
    Arm title
    Glasdegib Lead-in
    Arm description
    Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Glasdegib
    Investigational medicinal product code
    PF-04449913
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glasdegib administered orally at a daily starting dose of 100 mg with approximately 8 ounces (240 mL) of water (in the morning, at the same time each day) on a continuous regimen of 28-day cycles. Subjects requiring dose reduction(s) were administered multiples of 25 mg tablets

    Number of subjects in period 1
    Glasdegib Lead-in
    Started
    21
    Completed
    4
    Not completed
    17
         Death
    1
         Study terminated by sponsor
    1
         Unspecified
    5
         Adverse Events
    6
         Lost to follow-up
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Glasdegib Lead-in
    Reporting group description
    Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.

    Reporting group values
    Glasdegib Lead-in Total
    Number of subjects
    21 21
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    69.3 ± 7.0 -
    Gender, Male/Female
    Units: Subjects
        Female
    8 8
        Male
    13 13

    End points

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    End points reporting groups
    Reporting group title
    Glasdegib Lead-in
    Reporting group description
    Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.

    Primary: Percentage of Subjects Achieving Spleen Volume Reduction (SVR) ≥35% as Measured by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) Scan at Week 24 in the Randomized Cohort

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    End point title
    Percentage of Subjects Achieving Spleen Volume Reduction (SVR) ≥35% as Measured by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) Scan at Week 24 in the Randomized Cohort [1]
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Primary
    End point timeframe
    Week 24
    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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [2]
    Units: percentage of subjects
    Notes
    [2] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment –Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort

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    End point title
    Number of Subjects With Treatment –Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort [3]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pretreatment state.AEs included both serious and non-serious adverse event.All subjects treated in the lead-in portion of the study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 131
    Notes
    [3] - 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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: subjects
        AEs
    21
        SAEs
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment Emergent Treatment –Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort

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    End point title
    Number of Subjects With Treatment Emergent Treatment –Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort [4]
    End point description
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator. AEs included both serious and non-serious adverse event. All subjects treated in the lead-in portion of the study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 131
    Notes
    [4] - 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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: subjects
        AEs
    19
        SAEs
    5
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment Emergent Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03: Lead-in Cohort

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03: Lead-in Cohort [5]
    End point description
    AE was untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. SAE was AE resulting in any outcomes or deemed significant for any other reason: death;initial or prolonged inpatient hospitalization;life-threatening experience; persistent or significant disability.Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pretreatment state.AE were assessed according to maximum severity grading based on NCI CTCAE Version 4.03.Grade 1=mild;Grade 2=moderate:within normal limits:Grade 3=severe or medically significant but not immediately life-threatening:Grade 4=life-threatening or disabling:urgent intervention indicated;Grade 5=death.Only categories with at least 1 subject with event were reported. All subjects treated in lead-in portion of the study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 131
    Notes
    [5] - 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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: subjects
        Grade 3 or 4
    14
        Grade 5
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Abnormalities: Lead-in Cohort

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    End point title
    Number of Subjects With Laboratory Abnormalities: Lead-in Cohort [6]
    End point description
    Abnormality:hematology:hemoglobin less than(<)0.8*lower limit of normal(LLN),platelets <0.5*LLN greater than(>)1.75*upper limit of normal(ULN),white blood cell count(WBC)<0.6* LLN>1.5*ULN,lymphocytes,total neutrophils<0.8* LLN>1.2* ULN,band Cells, basophils,eosinophils,monocytes>1.2*ULN,blast cells>1.0*ULN.Coagulation:activated partial thromboplastin time,prothrombin international ratio >1.1* ULN.Liver function: bilirubin >1.5*ULN, AST,ALT,lactate dehydrogenase,alkaline phosphatase>3.0*ULN,protein,albumin<0.8* LLN >1.2*ULN. Renal:blood urea nitrogen,creatinine >1.3*ULN,uric acid>1.2*ULN.Electrolytes: sodium<0.95*LLN >1.05*ULN,potassium,chloride,calcium,magnesium<0.9* LLN>1.1*ULN,phosphate<0.8*LLN >1.2*ULN.Chemistry:glucose<0.6*LLN >1.5*ULN,creatine kinase >2.0*ULN,amylase,lipase >1.5*ULN.Urinalysis:protein,blood >1.0*ULN,red blood cells,WBC>=20,epithelial cells >=6,casts,granular casts,hyaline >1,cellular casts,crystals>=1,bacteria>20.All subjects treated in lead-in portion of study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 131
    Notes
    [6] - 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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: subjects
    21
    No statistical analyses for this end point

    Primary: Number of Subjects with Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and above Hematological Test Abnormalities: Lead-in Cohort

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    End point title
    Number of Subjects with Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and above Hematological Test Abnormalities: Lead-in Cohort [7]
    End point description
    Anemia(grade[g]1:<LLNto10 gram per deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL, g4:lifethreatening);platelet (g1:<LLN to 75*10^3/millimeter[mm]^3, g2:<75*10^3/mm^3 to 50*10^3/mm^3, g3:<50*10^3/mm^3 to 25*10^3/mm^3, g4:<25*10^3/mm^3); lymphopenia (g1:<LLN to 8*10^2/mm^3, g2:<8*10^2 to 5*10^2/mm^3, g3:<5*10^2 to 2*10^2/mm^3, g4:<2*10^2/mm^3);neutrophil (Absolute) (g1:<LLN to 15*10^2/mm^3, g2:<15*10^2 to 10*10^2/mm^3, g3:<10*10^2 to 5*10^2/mm^3, g4:<5*10^2/mm^3); white blood cell count(g1:<LLN to 3*10^3/mm^3, g2:<3*10^3 to 2*10^3/mm^3, g3:<2*10^3 to 1*10^3/mm^3, g4:<1*10^3/mm^3); hemoglobin (g1:increase in hemoglobin level >0 to 2 g/dL above ULN or above baseline if baseline is above ULN, g2:increase in hemoglobin level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3: increase in hemoglobin level>4 g/dL above ULN or above baseline if baseline is above ULN). All subjects treated in lead-in portion of study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 131
    Notes
    [7] - 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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: subjects
        Grade 3
    3
        Grade 4
    2
    No statistical analyses for this end point

    Primary: Number of Subjects with Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and above Chemistry Test Abnormalities: Lead-in Cohort

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    End point title
    Number of Subjects with Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and above Chemistry Test Abnormalities: Lead-in Cohort [8]
    End point description
    ALT/AST g1:>ULN 3*ULN, g2:>3-5*ULN, g3:>5 20*ULN, g4:>20*ULN);Alkaline Phosphatase(g1:>ULN 2.5*ULN,g2:>2.5-5*ULN, g3:>5 20*ULN, g4:>20*ULN); Creatinine (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN, g3:>3 6*ULN, g4:>6*ULN);hyperglycemia(g1:>ULN-160,g2:>160 250, g3:>250 500, g4:>500mg/dL);bilirubin(total) (g1:>ULN-1.5*ULN, g2:>1.5-3*ULN, g3:>3 10*ULN,g4:>10*ULN);hypoglycaemia(g1:<LLN-55,g2:<55-40, g3:<40 30,g4:<30mg/dL); hyperkalemia (g1:>ULN-5.5,g2:>5.5-6, g3:>6 7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3, g3:<3 2.5, g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3 8, g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7, g3:<7-6, g4:<6mg/dL); hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5, g3:>12.5-13.5, g4:>13.5mg/dL); hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9,g3:<0.9-0.7, g4:<0.7mg/dL); hyponatremia (g1:<LLN-130,g3:<130-120, g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3 2,g3:<2, g4:lifethreatening);hypophosphatemia(g1:<LLN-2.5,g2:<2.5-2, g3:<2-1, g4:<1mg/dL).All subjects treated in lead-in portion of study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 131
    Notes
    [8] - 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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: subjects
        Grade 3
    5
        Grade 4
    1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort

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    End point title
    Percentage of Subjects Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort
    End point description
    MRI (CT scan may have been permitted if MRI was contraindicated) of the spleen and the liver was performed at baseline, then every 12 weeks while the subject was on treatment. The same method of assessment used at baseline was used for the duration of the trial to ensure consistency. Spleen volume was assessed by a central, independent blinded reader.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    6
    Units: percentage of subjects
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving ≥50% Reduction from Baseline in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Diary (MPN-SAD) at Week 24 in the Lead-in Cohort

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    End point title
    Percentage of Subjects Achieving ≥50% Reduction from Baseline in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Diary (MPN-SAD) at Week 24 in the Lead-in Cohort
    End point description
    The MPN-SAD assessed the impact of 9 MF symptoms, at their worst, over the past 7 days and over the past 24 hours on a scale of 0 (absent) to 10 (worst imaginable). The 9 symptoms are early satiety, abdominal discomfort, inactivity, night sweats, pruritus, bone pain, pain below the ribs on the left-hand side, fatigue and shortness of breath. The TSS is the sum of the individual scores, excluding inactivity and shortness of breath. The TSS at Week 24 is the average of the daily total scores from the last 28 days of symptom scores immediately prior to Week 24. A higher score indicates worse symptoms.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: percentage of subjects
        number (not applicable)
    4.8
    No statistical analyses for this end point

    Secondary: Monthly Mean Change from Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort

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    End point title
    Monthly Mean Change from Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort
    End point description
    The MPN-SAD assessed the impact of 9 MF symptoms, at their worst, over the past 7 days and over the past 24 hours on a scale of 0 (absent) to 10 (worst imaginable). The 9 symptoms are early satiety, abdominal discomfort, inactivity, night sweats, pruritus, bone pain, pain below the ribs on the left-hand side, fatigue and shortness of breath. The TSS is the sum of the individual scores, excluding inactivity and shortness of breath. The TSS at Week 24 is the average of the daily total scores from the last 28 days of symptom scores immediately prior to Week 24. A higher score indicates worse symptoms. 9999 = not applicable, no standard deviation was calculable since n=1.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 36 and 48
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Monthly mean change at Week 12 (n=13)
    -2.74 ± 14.07
        Monthly mean change at Week 24 (n=6)
    -4.95 ± 5.78
        Monthly mean change at Week 36 (n=1)
    -4.11 ± 9999
        Monthly mean change at Week 48 (n=2)
    -8.39 ± 11.52
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Anemia Response (Transfusion Dependent versus Independent) in the Lead-in Cohort

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    End point title
    Percentage of Subjects Achieving Anemia Response (Transfusion Dependent versus Independent) in the Lead-in Cohort
    End point description
    Anemia response was defined as transfusion-independent subjects with a ≥20 gram per liter (g/L) increase in hemoglobin (Hb) level where baseline Hb level was <100 g/L, or baseline transfusion-dependent patients becoming transfusion-independent post-baseline. Transfusion dependency before the start of study treatment was defined as transfusions of ≥6 units of packed red blood cells in the 12 weeks prior to start of study treatment, for a final pre-treatment Hb of <85 g/L. In addition, the most recent transfusion episode must have occurred in the 28 days prior to study enrollment. Response in transfusion-dependent patients required absence of any packed red blood cell transfusions during any consecutive rolling 12-week interval during the treatment phase, capped by a Hb level of ≥85 g/L.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    21
    Units: percentage of subjects
    number (not applicable)
        Transfusion independent ≥20 g/L Hb increase (n=17)
    5.9
        Transfusion dependent (n=4)
    0
    No statistical analyses for this end point

    Secondary: Maximum Observed Glasdegib Plasma Concentration (Cmax), Minimum Glasdegib Plasma Concentration Observed Prior to the Next Dose (Cmin), and Average Observed Glasdegib Plasma Concentration (Cavg) in the Lead-in Cohort

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    End point title
    Maximum Observed Glasdegib Plasma Concentration (Cmax), Minimum Glasdegib Plasma Concentration Observed Prior to the Next Dose (Cmin), and Average Observed Glasdegib Plasma Concentration (Cavg) in the Lead-in Cohort
    End point description
    Cmax was the highest plasma concentration of glasdegib observed directly from the plasma concentration data. Cmin was the lowest plasma concentration of glasdegib observed directly from the plasma concentration data. Cavg was the average concentration at steady state estimated using non-compartmental pharmacokinetic (PK) analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 15
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    19
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cmax (n=19)
    996.8 ± 45
        Cmin (n=19)
    191.9 ± 68
        Cav (n=17)
    548.0 ± 50
    No statistical analyses for this end point

    Secondary: Area Under the Glasdegib Plasma Concentration versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort

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    End point title
    Area Under the Glasdegib Plasma Concentration versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort
    End point description
    AUCtau was the area under the glasdegib plasma concentration-time profile from time zero to the end of the dosing interval (24 hours) estimated by non-compartmental PK analysis using the linear/log trapezoidal method.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 15
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    17
    Units: ng·hr/mL
        geometric mean (geometric coefficient of variation)
    13150 ± 50
    No statistical analyses for this end point

    Secondary: Time to reach Cmax (Tmax) in the Lead-in Cohort

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    End point title
    Time to reach Cmax (Tmax) in the Lead-in Cohort
    End point description
    Tmax was the time of the first occurrence of Cmax observed directly from the plasma concentration data.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 15
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    19
    Units: Hours
        median (full range (min-max))
    1.02 (0.483 to 4.00)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving SVR ≥50% as Measured by MRI/CT Scan at Week 24 in the Randomized Cohort

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    End point title
    Percentage of Subjects Achieving SVR ≥50% as Measured by MRI/CT Scan at Week 24 in the Randomized Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [9]
    Units: percentage of subjects
    Notes
    [9] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Monthly Mean Change from Baseline in Overall TSS in the Randomized Cohort

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    End point title
    Monthly Mean Change from Baseline in Overall TSS in the Randomized Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 36 and 48
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [10]
    Units: months
    Notes
    [10] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Anemia Response (Transfusion Dependent versus Independent) in the Randomized Cohort

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    End point title
    Percentage of Subjects Achieving Anemia Response (Transfusion Dependent versus Independent) in the Randomized Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [11]
    Units: percentage of subjects
    Notes
    [11] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Subject Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort

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    End point title
    Subject Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [12]
    Units: subjects
    Notes
    [12] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Median Duration of SVR in the Randomized Cohort

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    End point title
    Median Duration of SVR in the Randomized Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [13]
    Units: days
        number (not applicable)
    Notes
    [13] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of Overall Survival in the Randomized Cohort

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    End point title
    Kaplan-Meier Estimate of Overall Survival in the Randomized Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [14]
    Units: weeks
        number (not applicable)
    Notes
    [14] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Glasdegib PK Parameters in the Randomized Cohort

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    End point title
    Glasdegib PK Parameters in the Randomized Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 15
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [15]
    Units: nanogram per mililiter
        number (not applicable)
    Notes
    [15] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Psychometric validation of the MPN-SAD in the Randomised Cohort

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    End point title
    Psychometric validation of the MPN-SAD in the Randomised Cohort
    End point description
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [16]
    Units: scores on a scale
        number (not applicable)
    Notes
    [16] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment –Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort

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    End point title
    Number of Subjects With Treatment –Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. The double blind, randomized, placebo controlled phase of the study was not enrolled as the study was terminated early so, no data were collected to assess this end point.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 131
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [17]
    Units: subjects
    Notes
    [17] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Treatment –Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort

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    End point title
    Number of Subjects With Treatment Emergent Treatment –Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort
    End point description
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. Relatedness to study drug was assessed by the investigator. The double blind, randomized, placebo controlled phase of the study was not enrolled as the study was terminated early so, no data were collected to assess this end point.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 131
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [18]
    Units: subjects
    Notes
    [18] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) According to Maximum Severity: Randomized Cohort

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (AEs) According to Maximum Severity: Randomized Cohort
    End point description
    AE was untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship.SAE was AE resulting in any of following outcomes or deemed significant for any other reason:death; initial or prolonged inpatient hospitalization;life-threatening experience; persistent or significant disability/incapacity; congenital anomaly.A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment,or worsened during the treatment period relative to pretreatment state.AE were assessed according to maximum severity grading based on NCI CTCAE Version 4.03.G1=mild; G2=moderate; within normal limits.G3=severe or medically significant but not immediately life-threatening;G4=life-threatening or disabling; urgent intervention indicated; G5=death. Double blind, randomized, placebo controlled phase of study was not enrolled as study was terminated early so, no data were collected to assess this end point.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 131
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [19]
    Units: subjects
    Notes
    [19] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Laboratory Abnormalities in the Randomized Cohort

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    End point title
    Number of Subjects With Laboratory Abnormalities in the Randomized Cohort
    End point description
    Hematology:hemoglobin<0.8*LLN,platelets<0.5*LLN>1.75*ULN,WBC<0.6*LLN>1.5* ULN,lymphocytes,total neutrophils<0.8* LLN>1.2* ULN,band cells,basophils,eosinophils,monocytes >1.2*ULN, blast cells>1.0*ULN.Coagulation:activated partial thromboplastin time,prothrombin international ratio>1.1*ULN.Liver function:bilirubin>1.5*ULN, AST,ALT,lactate dehydrogenase,alkaline phosphatase>3.0*ULN,protein,albumin<0.8*LLN>1.2*ULN.Renal:blood urea nitrogen,creatinine >1.3* ULN,uric acid >1.2* ULN.Electrolytes:sodium<0.95*LLN>1.05*ULN, potassium,chloride,calcium, magnesium<0.9* LLN >1.1*ULN,phosphate<0.8* LLN >1.2*ULN.Chemistry: glucose<0.6*LLN >1.5*ULN,creatine kinase>2.0*ULN, amylase,lipase>1.5*ULN.Urinalysis:protein,blood>1.0*ULN,red blood cells,WBC>=20,epithelial cells>=6,casts,granular casts,hyaline >1,cellularcasts,crystals>=1,bacteria >20.The double blind,randomized,placebo controlled phase of study was not enrolled as study was terminated early so,no data were collected to assess this end point.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 131
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [20]
    Units: subjects
    Notes
    [20] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and above Hematological Test Abnormalities: Randomized Cohort

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    End point title
    Number of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and above Hematological Test Abnormalities: Randomized Cohort
    End point description
    Anemia g1:<LLN to10 g/dL, g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening);platelet (g1:<LLN to 75*10^3/mm^3, g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3);lymphopenia (g1:<LLN to 8*10^2/mm^3, g2:<8*10^2 to 5*10^2/mm^3, g3:<5*10^2 to 2*10^2/mm^3, g4:<2*10^2/mm^3);neutrophil (absolute) (g1:<LLN to 15*10^2/mm^3, g2:<15*10^2 to 10*10^2/mm^3, g3:<10*10^2 to 5*10^2/mm^3, g4:<5*10^2/mm^3);white blood cell count (g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3: <2*10^3 to 1*10^3/mm^3, g4:<1*10^3/mm^3);hemoglobin(g1:increase in hemoglobin level>0 to 2 g/dL above ULN or above baseline if baseline is above ULN, g2: increase in hemoglobin level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3:increase in hemoglobin level>4 g/dL above ULN or above baseline if baseline is above ULN). Double blind, randomized, placebo controlled phase of study was not enrolled as study was terminated early so,no data were collected to assess this end point.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 131
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [21]
    Units: subjects
    Notes
    [21] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and above Chemistry Test Abnormalities: Randomized Cohort

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    End point title
    Number of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and above Chemistry Test Abnormalities: Randomized Cohort
    End point description
    ALT/AST g1:>ULN 3*ULN, g2:>3-5*ULN, g3:>5 20*ULN,g4:>20*ULN);Alkaline Phosphatase (g1:>ULN 2.5*ULN, g2:>2.5-5*ULN, g3:>5 20*ULN,g4:>20*ULN);Creatinine (g1:>ULN-1.5*ULN, g2:>1.5-3*ULN, g3:>3 6*ULN, g4:>6*ULN);hyperglycemia (g1:>ULN-160,g2:>160 250, g3:>250 500,g4:>500mg/dL); bilirubin(total) (g1:>ULN-1.5*ULN, g2:>1.5-3*ULN, g3:>3 10*ULN,g4:>10*ULN); hypoglycaemia (g1:<LLN-55,g2:<55-40, g3:<40 30, g4:<30mg/dL);hyperkalemia (g1:>ULN-5.5,g2:>5.5-6, g3:>6 7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3,g3:<3 2.5, g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3 8,g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7, g3:<7-6, g4:<6mg/dL);hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5, g3:>12.5-13.5, g4:>13.5mg/dL);hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9, g3:<0.9-0.7,g4:<0.7mg/dL);hyponatremia (g1:<LLN-130,g3:<130-120, g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3-2, g3:<2, g4:lifethreatening);hypophosphatemia (g1:<LLN-2.5,g2:<2.5-2,g3:<2-1,g4:<1mg/dL). Study was terminated no data were collected.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 131
    End point values
    Glasdegib Lead-in
    Number of subjects analysed
    0 [22]
    Units: subjects
    Notes
    [22] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 131
    Adverse event reporting additional description
    Event appear as both an AE and SAE.However,what is presented are distinct events.Event may categorized as serious in 1 subject and non-serious in another subject,or 1 subject may have experienced both a serious and non-serious event.All subjects treated in lead-in portion of study.It was analysis population for analyses on lead-in portion of study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Glasdegib Lead-in
    Reporting group description
    Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.

    Serious adverse events
    Glasdegib Lead-in
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 21 (23.81%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Postoperative ileus
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Memory impairment
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastric varices haemorrhage
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Portal hypertension
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Glasdegib Lead-in
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 21 (95.24%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    5
    Lipase increased
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    10
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Weight decreased
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Dyspnoea exertional
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    5
    Neutropenia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    Thrombocytopenia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    Dysgeusia
         subjects affected / exposed
    13 / 21 (61.90%)
         occurrences all number
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    5
    Fatigue
         subjects affected / exposed
    7 / 21 (33.33%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Dry mouth
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 21 (38.10%)
         occurrences all number
    10
    Night sweats
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    Pruritus generalised
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Muscle spasms
         subjects affected / exposed
    12 / 21 (57.14%)
         occurrences all number
    20
    Myalgia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 21 (33.33%)
         occurrences all number
    7
    Hyperuricaemia
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Dehydration
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Hyperglycaemia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2014
    The requirement for 1 form of highly effective contraception was amended to 2 forms. The inclusion criterion concerning creatinine clearance and the exclusion criterion concerning corrected QT interval were clarified. A precaution was added for phototoxicity. The schedule of assessments was corrected to indicate ongoing collection of AEs during the study treatment period.
    19 Feb 2015
    The schedule of assessments was amended to clarify PK, electrocardiogram and bone marrow aspirate collection time points. The threshold for prolongation of QT interval corrected by the Fridericia formula (QTcF) was clarified in the exclusion criteria. Dosing modification guidelines for treatment related QTcF were revised. An administrative update to the AE reporting section was made. Communication of results by Pfizer was updated in line with Pfizer policy.
    26 May 2015
    Background information was updated, including estimated overall survival and preliminary data from B1371013 lead-in cohort. Pharmacodynamic data were added for the 50 mg glasdegib dose and details of the clinical development program were updated. Subject enrolment in the lead in cohort was revised; the potential to evaluate lower starting doses or intermittent dosing schedules for glasdegib was added, and overall survival was removed as an objective/endpoint for the lead in cohort. An inclusion criterion requiring documentation by the investigator that the subject had exhausted available therapies was added, and the exclusion criterion for prior anticancer therapy washout was revised. The inclusion criterion for MF symptom assessment to be based upon patient reported symptoms on the MPN-SAD screening form was revised. The inclusion criterion for pregnancy and contraception was updated to align with current guidelines, lifestyle guidelines were updated and a contraception check was added. The exclusion criteria for prior malignancies were revised. Protocol defined best supportive therapy was removed from the prohibited/permitted treatments section. Drug storage requirements were updated. Text emphasizing dosing compliance was added. Recommended dose modifications for muscle spasms/myalgia were added. The magnetic resonance imaging/computed tomography scan process was clarified and the requirement for a 5 day window for repeated imaging scans was removed. MPN-SAD collection was expanded. The follow up period was adjusted. Immunophenotyping and cytogenetics were removed.

    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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