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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

    Results information
    Results version number
    		 v1
    This version publication date
    03 Dec 2017
    First version publication date
    03 Dec 2017
    Other versions
    		 v2

    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
    Interim
    Date of interim/final analysis
    14 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2016
    Global end of trial reached?
    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 Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. 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 centres 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
    United States: 16
    Country: Number of subjects enrolled
    Japan: 5
    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
    		 -

    Pre-assignment
    Screening details
    		 Participants were screened at 1 visit or over multiple visits across a 4 week period. Following this, participants 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. Participants requiring dose reduction(s) were administered multiples of 25 mg tablets

    Number of subjects in period 1
    		Glasdegib Lead-in
    Started
    21
    Completed
    8
    Not completed
    13
         Adverse event, serious fatal
    1
         Ongoing in study
    3
         Unspecified
    4
         Subject refused further follow-up
    5

    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
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 4 4
        From 65-84 years
    		 17 17
        85 years and over
    		 0 0
    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 Participants 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 Participants 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: Statistical analysis of the primary endpoint was not done since the randomized part of the study was not enrolled so no data were available.
    End point values
    		 Glasdegib Lead-in
    Number of subjects analysed
    0 [2]
    Units: Percentage of Participants
    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

    Secondary: Percentage of Participants 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 Participants 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 participant 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 Participants
        number (not applicable)
    0
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Participants Achieving Anemia Response (Transfusion Dependent versus Independent) in the Lead-in Cohort
    End point description
    Anemia response was defined as transfusion-independent participants 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 participants
    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 Participants 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 Participants 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 [3]
    Units: Percentage of Participants
    Notes
    [3] - 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 [4]
    Units: Score on a scale
    Notes
    [4] - 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 Participants Achieving Anemia Response (Transfusion Dependent versus Independent) in the Randomized Cohort

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    End point title
    		 Percentage of Participants 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 [5]
    Units: Percentage of Participants
    Notes
    [5] - 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 [6]
    Units: Weeks
    Notes
    [6] - 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: Participant Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort

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    End point title
    		 Participant 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 [7]
    Units: Not applicable
    Notes
    [7] - 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 [8]
    Units: Months
    Notes
    [8] - The double blind, randomized, placebo controlled phase of the study was not enrolled.
    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 [9]
    Units: Not applicable
    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: 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 [10]
    Units: Not applicable
    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

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were assessed from informed consent up to at least 28 calendar days after last dose of investigational product. AEs were recorded from the time the subject has taken at least one dose of study treatment through last subject visit.
    Adverse event reporting additional description
    An event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    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
    4 / 21 (19.05%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    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
    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
    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
    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
    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
    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%)
    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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    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
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    Anaemia
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    5
    Thrombocytopenia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    4
    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
    Diarrhoea
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    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
    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
    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
    Infections and infestations
    Upper respiratory tract infection
         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
    Dehydration
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Hyperuricaemia
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4

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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. Participant 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 participant 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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