Trial Outcomes & Findings for Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib (NCT NCT02226172)

NCT ID: NCT02226172

Last Updated: 2019-01-17

Results Overview

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.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 21 participants
• Primary outcome timeframe: Week 24
• Results posted on: 2019-01-17

Participant Flow

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 outcome measure was not met. Therefore, continuation into the randomized cohort did not proceed.

Participant milestones

Measure	Glasdegib Lead-in Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Overall Study STARTED	21
Overall Study COMPLETED	4
Overall Study NOT COMPLETED	17

Reasons for withdrawal

Measure	Glasdegib Lead-in Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Overall Study Participant refused further follow-up	4
Overall Study Other	5
Overall Study Death	1
Overall Study Study terminated by sponsor	1
Overall Study Adverse Event	6

Baseline Characteristics

Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib

Baseline characteristics by cohort

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Age, Continuous	69.3 Years STANDARD_DEVIATION 7.0 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 24

Population: FAS included all participants in the randomized Phase 2 component of the study who were randomized with study drug assignment designated according to initial randomization.

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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline up to Week 131

Population: All participants treated in the lead-in portion of the study.

An AE was any untoward medical occurrence in a participant 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 events.

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort AEs	21 Participants
Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort SAEs	5 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 131

Population: All participants treated in the lead-in portion of the study.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant 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 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 pre-treatment state. Relatedness to study drug was assessed by the investigator. AEs included both serious and non-serious adverse event.

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort AEs	19 Participants
Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort SAEs	5 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 131

Population: All participants treated in the lead-in portion of the study.

AE was untoward medical occurrence in participant 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; 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.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 participant with event were reported.

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Number of Participants 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 Grade 3 or 4	14 Participants
Number of Participants 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 Grade 5	1 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 131

Population: All participants treated in the lead-in portion of the study.

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.

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Number of Participants With Laboratory Abnormalities: Lead-in Cohort	21 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 131

Population: All participants treated in the lead-in portion of the study.

Anemia (grade [g]1:< LLN to 10 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).

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Number of Participants 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 Grade 3	3 Participants
Number of Participants 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 Grade 4	2 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 131

Population: All participants treated in the lead-in portion of the study.

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).

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Number of Participants 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 Grade 3	5 Participants
Number of Participants 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 Grade 4	1 Participants

SECONDARY outcome

Timeframe: Week 24

Population: Lead-in Analysis Set - included all participants treated in the lead-in portion of the study. Only participants who remained on treatment at Week 24 underwent MRI/CT scan.

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.

Outcome measures

Measure	Glasdegib Lead-in n=6 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Percentage of Participants Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort	0 Percentage of participants

SECONDARY outcome

Timeframe: Week 24

Population: Lead-in Analysis Set

The MPN-SAD assessed the impact of 9 myelofibrosis 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.

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
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	4.8 Percentage of participants Interval 1.2 to 30.4

SECONDARY outcome

Timeframe: Weeks 12, 24, 36 and 48

Population: Lead-in Analysis Set

The MPN-SAD assessed the impact of 9 myelofibrosis 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.

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort Monthly mean change at Week 36	-4.11 Score on a scale Standard Deviation NA No standard deviation was calculable since n=1.
Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort Monthly mean change at Week 12	-2.74 Score on a scale Standard Deviation 14.07
Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort Monthly mean change at Week 24	-4.95 Score on a scale Standard Deviation 5.78
Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort Monthly mean change at Week 48	-8.39 Score on a scale Standard Deviation 11.52

SECONDARY outcome

Timeframe: Baseline to end of treatment

Population: Lead-in Analysis Set

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.

Outcome measures

Measure	Glasdegib Lead-in n=21 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Lead-in Cohort Transfusion independent ≥20 g/L Hb increase	5.9 Percentage of participants
Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Lead-in Cohort Transfusion dependent	0 Percentage of participants

SECONDARY outcome

Timeframe: Cycle 1, Day 15

Population: PK Parameter Analysis Population - included all enrolled participants treated who had at least 1 of the PK parameters of interest and were dose compliant (at steady state for glasdegib ).

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.

Outcome measures

Measure	Glasdegib Lead-in n=19 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
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 Cmax	996.8 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 45
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 Cmin	191.9 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 68
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 Cav	548.0 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 50

SECONDARY outcome

Timeframe: Cycle 1, Day 15

Population: PK Parameter Analysis Population

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.

Outcome measures

Measure	Glasdegib Lead-in n=17 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Area Under the Glasdegib Plasma Concentration Versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort	13150 ng·hr/mL Geometric Coefficient of Variation 50

SECONDARY outcome

Timeframe: Cycle 1, Day 15

Population: PK Parameter Analysis Population

Tmax was the time of the first occurrence of Cmax observed directly from the plasma concentration data.

Outcome measures

Measure	Glasdegib Lead-in n=19 Participants Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Time to Reach Cmax (Tmax) in the Lead-in Cohort	1.02 Hours Interval 0.483 to 4.0

SECONDARY outcome

Timeframe: Week 24

Population: FAS

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Weeks 12, 24, 36 and 48

Population: FAS

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to end of treatment

Population: FAS

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to end of treatment

Population: FAS

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to end of treatment

Population: FAS

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to end of treatment

Population: FAS

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1, Day 15

Population: PK Parameter Analysis Population

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to end of treatment

Population: FAS

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline up to Week 131

Population: 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 outcome measure.

An AE was any untoward medical occurrence in a participant 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline up to Week 131

Population: 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 outcome measure.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline up to Week 131

Population: 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 outcome measure.

AE was untoward medical occurrence in participant 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 (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. 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline up to Week 131

Population: 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 outcome measure.

Abnormality: hematology: hemoglobin less than (<)0.8*lower limit of normal(LLN), platelets <0.5*LLN >1.75*upper limit of normal(ULN), white blood cell count(WBC) <0.6* LLN greater than (>)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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline up to Week 131

Population: 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 outcome measure.

Anemia g1:< LLN to 10 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).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline up to Week 131

Population: 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 outcome measure.

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).

Outcome measures

Outcome data not reported

Adverse Events

Glasdegib Lead-in

Serious events: 5 serious events

Other events: 20 other events

Deaths: 1 deaths

Serious adverse events

Measure	Glasdegib Lead-in n=21 participants at risk Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Gastrointestinal disorders Gastric varices haemorrhage	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Gastrointestinal disorders Varices oesophageal	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
General disorders Disease progression	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
General disorders Fatigue	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Hepatobiliary disorders Portal hypertension	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Metabolism and nutrition disorders Failure to thrive	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Nervous system disorders Memory impairment	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Psychiatric disorders Mental status changes	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Respiratory, thoracic and mediastinal disorders Respiratory failure	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Psychiatric disorders Confusional state	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Cardiac disorders Sinus tachycardia	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Respiratory, thoracic and mediastinal disorders Hypoxia	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Infections and infestations Bronchitis	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Injury, poisoning and procedural complications Postoperative ileus	4.8% 1/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.

Other adverse events

Measure	Glasdegib Lead-in n=21 participants at risk Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.
Blood and lymphatic system disorders Anaemia	23.8% 5/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Blood and lymphatic system disorders Neutropenia	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Blood and lymphatic system disorders Thrombocytopenia	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Gastrointestinal disorders Abdominal pain	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Gastrointestinal disorders Abdominal pain upper	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Gastrointestinal disorders Constipation	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Gastrointestinal disorders Diarrhoea	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Gastrointestinal disorders Dry mouth	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
General disorders Asthenia	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
General disorders Fatigue	33.3% 7/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Gastrointestinal disorders Nausea	19.0% 4/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
General disorders Pyrexia	19.0% 4/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Infections and infestations Upper respiratory tract infection	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Injury, poisoning and procedural complications Fall	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Investigations Electrocardiogram QT prolonged	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Investigations Lipase increased	23.8% 5/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Investigations Lymphocyte count decreased	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Investigations Weight decreased	28.6% 6/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Metabolism and nutrition disorders Decreased appetite	33.3% 7/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Metabolism and nutrition disorders Dehydration	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Metabolism and nutrition disorders Hyperuricaemia	19.0% 4/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Musculoskeletal and connective tissue disorders Back pain	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Musculoskeletal and connective tissue disorders Muscle spasms	57.1% 12/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Musculoskeletal and connective tissue disorders Myalgia	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Musculoskeletal and connective tissue disorders Pain in extremity	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Nervous system disorders Dizziness	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Nervous system disorders Dysgeusia	61.9% 13/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Respiratory, thoracic and mediastinal disorders Cough	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Skin and subcutaneous tissue disorders Alopecia	38.1% 8/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Skin and subcutaneous tissue disorders Night sweats	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Skin and subcutaneous tissue disorders Pruritus	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Skin and subcutaneous tissue disorders Pruritus generalised	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Skin and subcutaneous tissue disorders Rash	14.3% 3/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.
Metabolism and nutrition disorders Hyperglycaemia	9.5% 2/21 • Baseline up to Week 131 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. All participants treated in the lead-in portion of the study. It was the analysis population for all analyses on the lead-in portion of the study.

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: ClinicalTrials.gov_Inquiries@pfizer.com

Results disclosure agreements

• Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. Investigators will, on request, remove any previously undisclosed Confidential Information (other than the Study results themselves) before disclosure.
• Publication restrictions are in place

Restriction type: OTHER