Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis Clinical Trial
Official title:
A Phase 2, Double-blind, Randomized Safety And Efficacy Study Of Glasdegib (Pf-04449913) Versus Placebo In Patients With Myelofibrosis Previously Treated With Ruxolitinib
| Verified date | December 2018 |
| Source | Pfizer |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 21 |
| Est. completion date | January 31, 2018 |
| Est. primary completion date | December 14, 2016 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility |
Inclusion criteria: - Diagnosis of primary MF (PMF) or secondary MF (PET-MF and PPV-MF) as per WHO 2008 criteria. - Lead-in cohort: resistant or intolerant to 1 or more Janus kinase inhibitors (licensed or experimental). - Randomized cohort: resistant or intolerant to prior ruxolitinib therapy. Documentation by the Investigator that the patient has exhausted available treatment options (eg, resistant or intolerant to hydroxyurea, etc). - Spleen 5 cm below the inferior left costal margin as measured by manual palpation. - Active symptomatic MF as defined by the screening MPN-SAD patient-reported instrument requiring a severity score of at least 5 on one symptom, or a severity score of = 3 on at least two of the symptoms (on a 0 to 10 scale). - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3. - Adequate organ function, demonstrated by the following laboratory values: 1. Absolute Neutrophil Count 75 x 10(9)/L; 2. Platelet count >50 x 10(9)/L with no evidence of bleeding and not requiring platelet transfusions; 3. Serum creatinine <1.5 x upper limit of normal (ULN) or estimated creatinine clearance 60 mL/min (as calculated using the standard method of the institution); 4. Serum amylase or lipase <1.5 x ULN; 5. Aspartate aminotransferase and alanine aminotransferase values 3.0 x ULN (or 5x ULN in the case of patients with MF accompanied by hepatic extramedullary hematopoiesis, as manifested by any degree of hepatomegaly). 6. Total bilirubin values <1.5 x ULN unless the bilirubin is principally unconjugated (in the context of hemolysis) or there is documented Gilbert's disease. 7. Serum electrolyte values < Grade 2 (sodium, potassium, calcium, phosphorous and magnesium), per CTCAE v.4.03. - Recovery to Grade 1 from all clinically significant adverse events related to prior MF therapy, including transplant-related toxicities. - More than 2 months out from allogenic hematopoietic stem cell transplant prior to randomization. - Must be able to undergo MRI of abdomen (spleen and liver). Patients who are contra indicated for MRI may be enrolled and evaluated by CT scan at the discretion of the Sponsor. - 18 years of age. - Male subjects able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for 90 days after the last dose of assigned treatment. Exclusion criteria: - Prior treatment with a licensed or experimental smoothened inhibitor. - Randomized cohort only: Prior treatment with a Janus kinase inhibitor other than ruxolitinib. - Other anti-cancer therapy up to 14 days prior to enrollment, with the exception of hydroxyurea, which can be given up to 4 days prior to enrollment. - Splenic irradiation 3 months prior to enrollment. - History of congenital long QT syndrome, or a baseline >470 msec QTcF abnormality (average of the triplicate reading). - Evidence of significant cardiac disease, for example: symptomatic cardiac heart failure (CHF, NYHA class 3), complete bundle branch block, significant atrial or ventricular tachyarrhythmias and any unstable cardiac arrhythmias requiring medication. - History of myocardial infarction or unstable angina within 6 months prior to enrollment. - Uncontrolled inflammatory bowel disease, peptic ulcer disease or history of significant gastro intestinal bleeding within 6 months of enrollment. - Any condition requiring chronic use of moderate/high dose steroids (equivalent to 10 mg QD prednisone). - Hematopoietic growth factor receptor agonists (eg, erythropoietin (Epo), granulocyte colony stimulating factor, romiplostim, eltrombopag within 28 days of enrollment. - Currently active malignancy (other than MF). Prior malignancies are allowed so long as there is no evidence of disease recurrence within the last 2 years (with the exception of fully excised, non-complicated basal cell carcinoma which can have been active within the prior 2 years, and certain localized, non-invasive fully excised skin, cervical, breast, prostate or bladder tumors). - Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis [NASH]). - Active, uncontrolled bacterial, fungal or viral infection, including hepatitis B, hepatitis C, known human immunodeficiency virus or acquired immunodeficiency syndrome related illness. - Active graft versus host disease (GVHD) with other than grade 1 skin involvement or GVHD requiring immunosuppressive treatment. - Uncontrolled disseminated intravascular coagulation. - Current (including their administration within 3 days prior to study entry) use or anticipated need for food or drugs that are strong CYP3A4 inhibitors. - Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers. |
| Country | Name | City | State |
|---|---|---|---|
| Japan | Juntendo University Hospital | Bunkyo-ku | Tokyo |
| Japan | Kobe University Hospital | Kobe | Hyogo |
| Japan | Osaka University Hopsital | Suita-Shi | Osaka |
| Japan | Tokyo Medical University Hospital | Tokyo | |
| United States | University of Michigan | Ann Arbor | Michigan |
| United States | Cleveland Clinic - Taussig Cancer Institute | Cleveland | Ohio |
| United States | UC San Diego Moores Cancer Center - Investigational Drug Services | La Jolla | California |
| United States | UCSD Medical Center Clinical Laboratory - La Jolla | La Jolla | California |
| United States | University of California San Diego (UCSD) Moores Cancer Center | La Jolla | California |
| United States | Froedtert Hospital and Medical College of Wisconsin | Milwaukee | Wisconsin |
| United States | Herbert Irving Comprehensive Cancer Center-Columbia University Medical Center | New York | New York |
| United States | Weill Cornell Medical College - New York-Presbyterian Hospital | New York | New York |
| United States | Weill Cornell Medical College-New York Presbyterian Hospital | New York | New York |
| United States | Mayo Clinic Building - Phoenix | Phoenix | Arizona |
| United States | Mayo Clinic Hospital | Phoenix | Arizona |
| United States | Huntsman Cancer Institute-University of Utah | Salt Lake City | Utah |
| United States | University of Utah, Huntsman Cancer Hospital | Salt Lake City | Utah |
| United States | UC San Diego Medical Center- Hillcrest | San Diego | California |
| United States | Mayo Clinic | Scottsdale | Arizona |
| Lead Sponsor | Collaborator |
|---|---|
| Pfizer |
United States, Japan,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Percentage of Participants Achieving Spleen Volume Reduction (SVR) =35% as Measured by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) Scan at Week 24 in the Randomized Cohort | 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. | Week 24 | |
| Primary | 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. | Baseline up to Week 131 | |
| Primary | 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. | Baseline up to Week 131 | |
| Primary | 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. | Baseline up to Week 131 | |
| Primary | 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. | Baseline up to Week 131 | |
| Primary | 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:| Baseline up to Week 131 |
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| Primary | 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:| Baseline up to Week 131 |
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| Secondary | 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. | Week 24 | |
| Secondary | Percentage of Participants Achieving =50% Reduction From Baseline in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Diary (MPN-SAD) at Week 24 in the Lead-in Cohort | 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. | Week 24 | |
| Secondary | 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. | Weeks 12, 24, 36 and 48 | |
| Secondary | 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. | Baseline to end of treatment | |
| Secondary | Maximum Observed Glasdegib Plasma Concentration (Cmax), Minimum Glasdegib Plasma Concentration Observed Prior to the Next Dose (Cmin), and Average Observed Glasdegib Plasma Concentration (Cavg) in the Lead-in Cohort | 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. | Cycle 1, Day 15 | |
| Secondary | 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. | Cycle 1, Day 15 | |
| Secondary | 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. | Cycle 1, Day 15 | |
| Secondary | 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. | Week 24 | |
| Secondary | 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. | Weeks 12, 24, 36 and 48 | |
| Secondary | 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. | Baseline to end of treatment | |
| Secondary | 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. | Baseline to end of treatment | |
| Secondary | 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. | Baseline to end of treatment | |
| Secondary | 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. | Baseline to end of treatment | |
| Secondary | 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. | Cycle 1, Day 15 | |
| Secondary | 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. | Baseline to end of treatment | |
| Secondary | 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. | Baseline up to Week 131 | |
| Secondary | 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. | Baseline up to Week 131 | |
| Secondary | 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. | Baseline up to Week 131 | |
| Secondary | 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. | Baseline up to Week 131 | |
| Secondary | 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:| Baseline up to Week 131 |
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| Secondary | 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:| Baseline up to Week 131 |
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