A Phase 2 interventional study of Glasdegib (PF-04449913) and Placebo in Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis, sponsored by Pfizer. Terminated at 19 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-01-17.
Sponsored by Pfizer · Phase 2, Interventional, and Treatment
A lead-in cohort of \~20 patients with primary or secondary myelofibrosis previously treated with 1 or more Janus kinase inhibitors enrolled to single-agent glasdegib to evaluate safety and tolerability. Following the lead-in, a phase 2, double blind, 2-arm study, randomized 2:1 to oral single-agent glasdegib versus placebo in 201 patients resistant or intolerant to ruxolitinib.
229 studies on the registry are indexed under Polycythemia Vera; 54 are open to participants now.
This study's enrollment of 21 is below the median of 55 across 174 interventional studies indexed under Polycythemia Vera.
Browse Polycythemia Vera studies →Pfizer is the lead sponsor of 3,244 studies on the registry; 139 are open to participants now.
Of its 582 completed or terminated interventional studies of FDA-regulated products, 381 (65%) have results posted.
Counted across the registry records on this site, refreshed daily.
Adequate organ function, demonstrated by the following laboratory values:
Exclusion criteria:
Oral daily dose of glasdegib (PF-04449913) 100 mg tablet in a continuous regimen of 28-day cycles.
Drug: Glasdegib (PF-04449913)
Oral daily dose of placebo 100 mg tablet in a continuous regimen of 28-day cycles.
Drug: Placebo
Oral daily dose of glasdegib (PF-04449913) 100 mg tablet in a continuous regimen of 28-day cycles.
Oral daily dose of placebo 100 mg tablet in a continuous regimen of 28-day cycles.
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
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.
Time frame: Week 24
Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort
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.
Time frame: Baseline up to Week 131
Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort
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.
Time frame: Baseline up to Week 131
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
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.
Time frame: Baseline up to Week 131
Number of Participants With Laboratory Abnormalities: Lead-in Cohort
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.
Time frame: Baseline up to Week 131
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
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).
Time frame: Baseline up to Week 131
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
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).
Time frame: Baseline up to Week 131
Percentage of Participants Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort
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.
Time frame: Week 24
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
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.
Time frame: Week 24
Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort
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.
Time frame: Weeks 12, 24, 36 and 48
Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Lead-in Cohort
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.
Time frame: Baseline to end of treatment
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 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.
Time frame: Cycle 1, Day 15
Area Under the Glasdegib Plasma Concentration Versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort
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.
Time frame: Cycle 1, Day 15
Time to Reach Cmax (Tmax) in the Lead-in Cohort
Tmax was the time of the first occurrence of Cmax observed directly from the plasma concentration data.
Time frame: Cycle 1, Day 15
Percentage of Participants Achieving SVR ≥50% as Measured by MRI/CT Scan at Week 24 in the Randomized Cohort
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.
Time frame: Week 24
Monthly Mean Change From Baseline in Overall TSS in the Randomized Cohort
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.
Time frame: Weeks 12, 24, 36 and 48
Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Randomized Cohort
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.
Time frame: Baseline to end of treatment
Participant Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort
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.
Time frame: Baseline to end of treatment
Median Duration of SVR in the Randomized Cohort
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.
Time frame: Baseline to end of treatment
Kaplan-Meier Estimate of Overall Survival in the Randomized Cohort
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.
Time frame: Baseline to end of treatment
Glasdegib PK Parameters in the Randomized Cohort
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.
Time frame: Cycle 1, Day 15
Psychometric Validation of the MPN-SAD in the Randomised Cohort
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.
Time frame: Baseline to end of treatment
Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort
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.
Time frame: Baseline up to Week 131
Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort
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.
Time frame: Baseline up to Week 131
Number of Participants With Treatment Emergent Adverse Events (AEs) According to Maximum Severity: Randomized Cohort
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.
Time frame: Baseline up to Week 131
Number of Participants With Laboratory Abnormalities: Randomized Cohort
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.
Time frame: Baseline up to Week 131
Number of Participants 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
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).
Time frame: Baseline up to Week 131
Number of Participants 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
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).
Time frame: Baseline up to Week 131
| Milestone | Glasdegib Lead-in |
|---|---|
| Started | 21 |
| Completed | 4 |
| Not completed | 17 |
| Withdrew: Participant refused further follow-up | 4 |
| Withdrew: Other | 5 |
| Withdrew: Death | 1 |
| Withdrew: Study terminated by sponsor | 1 |
| Withdrew: Adverse event | 6 |
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.
No measurements were reported for this outcome.
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.
| Participants | Glasdegib Lead-in |
|---|---|
| AEs | 21 |
| SAEs | 5 |
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.
| Participants | Glasdegib Lead-in |
|---|---|
| AEs | 19 |
| SAEs | 5 |
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.
| Participants | Glasdegib Lead-in |
|---|---|
| Grade 3 or 4 | 14 |
| Grade 5 | 1 |
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.
| Participants | Glasdegib Lead-in |
|---|---|
| Number of Participants With Laboratory Abnormalities: Lead-in Cohort | 21 |
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).
| Participants | Glasdegib Lead-in |
|---|---|
| Grade 3 | 3 |
| Grade 4 | 2 |
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.
| Percentage of participants | Glasdegib Lead-in |
|---|---|
| Percentage of Participants Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort | 0 |
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.
| Percentage of participants | Glasdegib Lead-in |
|---|---|
| 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 (1.2 to 30.4) |
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.
| Score on a scale | Glasdegib Lead-in |
|---|---|
| Monthly mean change at Week 12 | -2.74 ± 14.07 |
| Monthly mean change at Week 24 | -4.95 ± 5.78 |
| Monthly mean change at Week 36 | -4.11 ± NA |
| Monthly mean change at Week 48 | -8.39 ± 11.52 |
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.
| Percentage of participants | Glasdegib Lead-in |
|---|---|
| Transfusion independent ≥20 g/L Hb increase | 5.9 |
| Transfusion dependent | 0 |
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.
| nanograms per milliliter (ng/mL) | Glasdegib Lead-in |
|---|---|
| Cmax | 996.8 ± 45 |
| Cmin | 191.9 ± 68 |
| Cav | 548.0 ± 50 |
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.
| ng·hr/mL | Glasdegib Lead-in |
|---|---|
| Area Under the Glasdegib Plasma Concentration Versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort | 13150 ± 50 |
Tmax was the time of the first occurrence of Cmax observed directly from the plasma concentration data.
| Hours | Glasdegib Lead-in |
|---|---|
| Time to Reach Cmax (Tmax) in the Lead-in Cohort | 1.02 (0.483 to 4.00) |
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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).
| Participants | Glasdegib Lead-in |
|---|---|
| Grade 3 | 5 |
| Grade 4 | 1 |
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).
No measurements were reported for this outcome.
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).
No measurements were reported for this outcome.
Collected over Baseline up to Week 131. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Glasdegib Lead-in | 1/21 (4.8%) | 5/21 (23.8%) | 20/21 (95.2%) |
| Event | Glasdegib Lead-in |
|---|---|
| Gastric varices haemorrhageGastrointestinal disorders | 1/21 |
| Varices oesophagealGastrointestinal disorders | 1/21 |
| Disease progressionGeneral disorders | 1/21 |
| FatigueGeneral disorders | 1/21 |
| Portal hypertensionHepatobiliary disorders | 1/21 |
| Failure to thriveMetabolism and nutrition disorders | 1/21 |
| Memory impairmentNervous system disorders | 1/21 |
| Mental status changesPsychiatric disorders | 1/21 |
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 1/21 |
| Confusional statePsychiatric disorders | 1/21 |
| Event | Glasdegib Lead-in |
|---|---|
| DysgeusiaNervous system disorders | 13/21 |
| Muscle spasmsMusculoskeletal and connective tissue disorders | 12/21 |
| AlopeciaSkin and subcutaneous tissue disorders | 8/21 |
| FatigueGeneral disorders | 7/21 |
| Decreased appetiteMetabolism and nutrition disorders | 7/21 |
| Weight decreasedInvestigations | 6/21 |
| AnaemiaBlood and lymphatic system disorders | 5/21 |
| Lipase increasedInvestigations | 5/21 |
| NauseaGastrointestinal disorders | 4/21 |
| PyrexiaGeneral disorders | 4/21 |
| Age, Continuous(Years) | Glasdegib Lead-in |
|---|---|
| Mean | 69.3 ± 7.0 |
| Sex: Female, Male(Participants) | Glasdegib Lead-in |
|---|---|
| Female | 8 |
| Male | 13 |
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