A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In Untreated MDS, AML and CMML Patients

Phase 1

Completed

Conditions: Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome

Interventions: Drug: PF-04449913 (Glasdegib)
Drug: Azacitidine

Registration Number: NCT02367456

Lead Sponsor: Pfizer

Brief Summary: This multi center open label Phase 1b study is designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib (PF-04449913) when combined with azacitidine in patients with previously untreated Higher Risk Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). This clinical study includes two components: (a) a safety lead in cohort (LIC) and (b) an expansion phase with an AML cohort and an MDS cohort.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 73

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B	PF-04449913 (Glasdegib)	AML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
Arm A	PF-04449913 (Glasdegib)	MDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
Arm A	Azacitidine	MDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
Arm B	Azacitidine	AML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC)	maximum of approximately 15 months	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. TEAEs were AEs that occurred after initiation of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. Grades of AEs were defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE.
Number of Participants With Serious Adverse Events (SAEs) in the LIC	maximum of approximately 15 months	A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator.
Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts	maximum of 23 months in AML cohort and 34 months in MDS cohort	Percentage of participants achieving CR as defined by the 2017 European Leukemia Net (ELN) Response Criteria for all participants with AML and modified International Working Group (IWG) criteria (2006) for all participants with MDS in the expansion cohorts. For AML cohort, CR was defined as neutrophils ≥ 1 x 10\^9/L, platelets ≥ 1 x 10\^11/L, percentage of bone marrow blasts (BMB) \<5% with no peripheral blasts and no blasts with Auer rods, no extramedullary disease (EMD), and transfusion independent. For MDS cohort, CR was defined as having responses of hemoglobin ≥11 g/dL, neutrophils ≥1 x 10\^9/L, platelets ≥1 x 10\^11/L, percentage of blasts = 0%, percentage of BMB≤5%, and normal maturation of all cell lines (note if has persistent dysplasia), and all responses must last at least 4 weeks.
Number of Participants With Laboratory Abnormalities in the LIC	maximum of approximately 16 months	Hematology lab parameters included activated partial thromboplastin time, hemoglobin, prothrombin international normalized ratio, lymphocyte, neutrophil, platelet, white blood cell; chemistry parameters included alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, creatine phosphokinase, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate. Grades of lab abnormalities were defined by NCI CTCAE version 4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. Grade 1-4 results are reported.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC	maximum of approximately 16 months	Response rate (Percentage of participants achieving CR + PR among all the enrolled and treated patients) as defined by modified International Working Group (IWG) criteria (2006) in the LIC. CR was defined as having responses of hemoglobin ≥11 g/dL, neutrophils ≥1 x 10\^9/L, platelets ≥1 x 10\^11/L, percentage of blasts = 0%, percentage of BMB≤5%, and normal maturation of all cell lines (note if has persistent dysplasia), and all responses must last at least 4 weeks. PR was defined as meeting all CR criteria if abnormal before treatment except BMB, percentage of BMB decreased by ≥50% but still \>5% for at least 4 weeks.
Number of Participants With TEAEs in the AML and MDS Cohorts	maximum of around 23 months in AML cohort and 40 months in MDS cohort	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. TEAEs were AEs that occurred after initiation of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. Grades of AEs were defined by NCI CTCAE version 4.03.Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE.
Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort	Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15	Maximum plasma concentration of glasdegib dosed in combination with azacitidine (C1D7) and when dosed alone (C1D15) in the Lead-in Cohort was estimated using non-compartmental analysis.
Time to CR in the AML and MDS Cohorts	maximum of 23 months in AML cohort and 34 months in MDS cohort	Time to CR was defined for participants in the expansion cohorts who had achieved response on study as the time from date of the first dose of study drug to date of the first documentation of response. Time to CR was analyzed using the Kaplan-Meier method.
Number of Participants With SAEs in the AML and MDS Cohorts	maximum of around 23 months in AML cohort and 40 months in MDS cohort	An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator.
Number of Participants With Efficacy Measures Other Than CR in the LIC	maximum of approximately 16 months	Number of participants with efficacy measures other than CR as defined by modified IWG criteria (2006) in LIC, including marrow CR(mCR), stable disease(SD), hematologic improvement(HI). CR: hemoglobin≥11 g/dL, neutrophils≥1 x 10\^9/L, platelets≥1 x 10\^11/L, percentage of blasts=0%, percentage of BMB≤5%, normal maturation of all cell lines (note if has persistent dysplasia), all responses last at least 4 weeks. mCR: BMB≤5% \& decreased by≥50%. SD: failure to achieve PR, no evidence of progression. HI: erythroid response (pretreatment\<11g/dL): hemoglobin increase by≥1.5 g/dL, relevant reduction of units of red blood cell transfusions by at least 4 transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks; platelet response (pretreatment\<1x10\^11/L): increase of≥30x10\^9/L if starting with \>20x10\^9/L, and increase from \<20x10\^9/L to \>20x10\^9/L and by at least 100%; neutrophil response (pretreatment\<1x10\^9/L): at least a 100% increase, absolute increase \>0.5x10\^9/L
Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts	maximum of approximately 32 months in AML cohort and 32 months in MDS cohort	Overall survival (OS) was defined as the time from date of first study treatment to date of death from any cause. Patients last known to be alive were to be censored at the date of last contact. OS was analyzed and displayed graphically for each expansion cohort separately using the Kaplan-Meier method. The median event time and corresponding two-sided 95%CI were provided for each cohort. OS was first analyzed when the primary endpoint of CR was analyzed in the respective expansion cohort.
Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort	0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7	Time to first occurrence of maximum plasma concentration of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis.
Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts	maximum of approximately 15 months in the LIC cohort, 23 months in AML cohort, and 40 months in MDS cohort	Number of participants that met categorical criteria of QTcF values in LIC, AML and MDS cohorts
Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts	maximum of around 23 months in AML cohort and 40 months in MDS cohort	Hematology lab parameters included activated partial thromboplastin time, hemoglobin, prothrombin international normalized ratio, lymphocyte, neutrophil, platelet, white blood cell; chemistry parameters included alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, creatine phosphokinase, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate. Grades of lab abnormalities were defined by NCI CTCAE version 4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. Grade 1-4 results are reported.
Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort	maximum of 23 months	Number of participants with partial hematologic recovery (CRh), CR with incomplete blood count recovery (CRi), partial remission (PR), stable disease (SD), and morphologic leukemia free state (MLFS). CRh: neutrophils\>5x10\^8/L, platelets\>5x10\^10/L, BMB\<5%, no peripheral blasts, no blasts with Auer rods, no extramedullary disease (EMD), not qualifying for CR. CRi: neutrophils \<1x10\^9/L or platelets\<1x10\^11/L; BMB \<5%, no peripheral blasts, no blasts with Auer rods; no EMD; neutrophils or platelets not recovered; not qualifying for CRh. PR: neutrophils ≥1x10\^9/L; platelets ≥1x10\^11/L; blasts decreased to 5-25% and ≥50% decrease from pretreatment; blasts≤5% if Auer rod positive. SD: ≥3 months of absence of CR without minimal residual disease (CRMRD-), CR, CRh, CRi, PR, and MLFS, criteria for PD not met. MLFS: neutrophils \<1x10\^9/L and platelets\<1x10\^11/L, BMB\<5%, no blasts with Auer rods; no EMD; neutrophils and platelets not recovered; not qualifying for CRi
Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort	maximum of 34 months	Number of participants with PR, mCR, SD, complete or partial cytogenetic response, and HI. PR: BMB \>5% and decreased by ≥50% (at least 4 weeks), meeting all CR criteria if abnormal before treatment except BMB. mCR: BMB ≤5% and decreased by ≥50%. SD: failure to achieve PR, no evidence of progression. Complete or partial cytogenic response: disappearance of chromosomal abnormality without new ones, or ≥ 50% reduction of chromosomal abnormality. HI: erythroid response (pretreatment \<11g/dL): hemoglobin increase by≥1.5 g/dL, relevant reduction of units of red blood cell transfusions by at least 4 transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks; platelet response (pretreatment \<1x10\^11/L): increase of ≥30x10\^9/L if starting with \>20x10\^9/L, and increase from \<20x10\^9/L to \>20x10\^9/L and by at least 100%; neutrophil response (pretreatment \<1x10\^9/L): at least a 100% increase, absolute increase \>0.5x10\^9/L.
Duration of CR in the AML and MDS Cohorts	maximum of 23 months in AML cohort and 34 months in MDS cohort	Duration of CR was defined as the duration from date of first achieving CR to the date of disease progression (relapse) after CR, or death due to any cause. Participants last known to be alive who were free from disease progression or relapse after CR were censored at the date of the last assessment that verified their disease status. Duration of CR was analyzed using the Kaplan-Meier method. Disease progression was defined as: percentage of bone marrow blasts increased by ≥50% to \>5% (for participants with \<5% blasts at screening), \>10% (for participants with 5-10% blasts at screening), \>20% (for participants with 11-20% blasts at screening) or \>30% (for participants with 21-30% blasts at screening), and with any of the following condition: at least 50% decrease from maximum remission/response in granulocytes or platelets; reduction in hemoglobin by ≥2 g/dL; transfusion dependence.
Area Under the Plasma Concentration Curve From Time Zero to End of Dosing Interval (AUCtau) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort	Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15	Area under the plasma concentration curve from time zero to end of dosing interval (AUCtau) of glasdegib dosed in combination with azacitidine (C1D7) and when dosed alone (C1D15) in the Lead-in Cohort was estimated using non-compartmental analysis.
Cmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort	0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7	Maximum plasma concentration of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis.
Time to First Occurrence of Maximum Plasma Concentration (Tmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort	Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15	Time to first occurrence of maximum plasma concentration of glasdegib dosed in combination with azacitidine (C1D7) and when dosed alone (C1D15) in the Lead-in Cohort was estimated using non-compartmental analysis.
Area Under the Plasma Concentration Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort	0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7	Area under the plasma concentration curve from time zero to extrapolated infinite time of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis.
Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts	Pre-dose and 1 and 4 hours post-dose on Cycle 1 Day 15 (C1D15) and Cycle 2 Day 1 (C2D1)	Trough plasma concentration was defined as the estimated lowest concentration before next dose administration.

Trial Locations

Locations (33): UZ Leuven
🇧🇪
Leuven, Belgium
CHU d'Amiens-Picardie - Hopital SUD
🇫🇷
Amiens cedex 01, France
Staedtisches Klinikum Braunschweig gGmbH
🇩🇪
Braunschweig, Germany
CHU de Tours-Hopital Bretonneau-Centre Regional de cancerologie Henry Kaplan
🇫🇷
Tours Cedex 01, France
Oxford University Hospitals NHS Foundation Trust
🇬🇧
Oxford, United Kingdom
The Newcastle Hospitals NHS Foundation Trust
🇬🇧
Newcastle upon Tyne, United Kingdom
University Of Alberta Hospital
🇨🇦
Edmonton, Alberta, Canada
Hopital Saint-Louis (AP-HP) - Service Hematologie Senior
🇫🇷
Paris CEDEX 10, France
King's College Hospital
🇬🇧
London, United Kingdom
Investigational Chemotherapy Service
🇺🇸
Durham, North Carolina, United States
University of Alabama at Birmingham the Kirklin Clinic
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
UC San Diego Moores Cancer Center
🇺🇸
La Jolla, California, United States
Smilow Cancer Center at Yale New Haven Hospital
🇺🇸
New Haven, Connecticut, United States
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸
Baltimore, Maryland, United States
Montefiore Einstein Center for Cancer
🇺🇸
Bronx, New York, United States
Stony Brook University Hospital Cancer Center
🇺🇸
Stony Brook, New York, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Stony Brook University
🇺🇸
Stony Brook, New York, United States
Duke University Health System: Adult Bone Marrow Transplant Clinic
🇺🇸
Durham, North Carolina, United States
Duke University Health System, Duke University Hospital
🇺🇸
Durham, North Carolina, United States
Duke University Health System
🇺🇸
Durham, North Carolina, United States
Cleveland Clinic Taussig Cancer Center
🇺🇸
Cleveland, Ohio, United States
Seattle Cancer Care Alliance (SCCA)
🇺🇸
Seattle, Washington, United States
University of Washington Medical Center (UWMC)
🇺🇸
Seattle, Washington, United States
Henry-Joyce Cancer Center
🇺🇸
Nashville, Tennessee, United States
Vanderbilt - Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Huntsman Cancer Hospital
🇺🇸
Salt Lake City, Utah, United States
Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
Hospices Civils de Lyon - Hopital Lyon Sud- Hematologie
🇫🇷
Pierre Benite Cedex, France
Tom Baker Cancer Center
🇨🇦
Calgary, Alberta, Canada
Ziekenhuis Netwerk Antwerpen - Campus Stuivenberg
🇧🇪
Antwerpen, Belgium
Montefiore Medical Center
🇺🇸
Bronx, New York, United States