Neoplasms

Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Heart and Blood Diseases

Rare Diseases

Neoplasm Metastasis

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Essential Thrombocythemia

Chronic Myeloproliferative Disorders

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.

Glasdegib (PF-04449913)

Placebo

Pfizer CT.gov Call Center

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.

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

A Phase 2, Double-blind, Randomized Safety And Efficacy Study Of Glasdegib (Pf-04449913) Versus Placebo In Patients With Myelofibrosis Previously Treated With Ruxolitinib

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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).

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).

Pfizer

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.

Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles.

Glasdegib Lead-in

Age, Continuous

Sex: Female, Male

Pfizer ClinicalTrials.gov Call Center

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.

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

SAEs

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

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

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

Grade 3 or 4

Grade 5

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

Number of Participants With Laboratory Abnormalities: Lead-in Cohort

Grade 3

Grade 4

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

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.

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

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

Monthly mean change at Week 12

Monthly mean change at Week 24

Monthly mean change at Week 36

Monthly mean change at Week 48

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

Transfusion independent ≥20 g/L Hb increase

Transfusion dependent

Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Lead-in Cohort

Cmax

Cmin

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 ).

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

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

Time to Reach Cmax (Tmax) in the Lead-in Cohort

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

Monthly Mean Change From Baseline in Overall TSS in the Randomized Cohort

Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Randomized Cohort

Participant Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort

Median Duration of SVR in the Randomized Cohort

Kaplan-Meier Estimate of Overall Survival in the Randomized Cohort

Glasdegib PK Parameters in the Randomized Cohort

Psychometric Validation of the MPN-SAD in the Randomised Cohort

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.

Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort

Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort

Number of Participants With Treatment Emergent Adverse Events (AEs) According to Maximum Severity: Randomized Cohort

Number of Participants With Laboratory Abnormalities: Randomized Cohort

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

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

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

Spots Global Cancer Trial Database for Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib

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