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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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. 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).