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

Acute Myeloid Leukemia Clinical Trial

— BRIGHT 1012  

Official title:

An Open-label Phase 1b Study of PF-04449913 (Glasdegib) in Combination With Azacitidine in Patients With Previously Untreated Higher-Risk Myelodysplastic Syndrome, Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02367456
• Other study ID #: B1371012
• Secondary ID: 2014-001345-24BR
• Status: Completed
• Phase: Phase 1
• Start date: April 28, 2015
• Est. completion date: March 7, 2022

Study information

• Verified date: April 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 73
• Est. completion date: March 7, 2022
• Est. primary completion date: January 29, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Patients must have previously untreated MDS, AML, or CMML according to the WHO 2016 classification.

• MDS patients must have Intermediate (>3 to 4.5 points), High Risk (>4.5 - 6) or Very High Risk (>6 points) disease according to the Revised International Prognostic Scoring System 2012 (IPSS-R).

• Clinical indication for treatment with azacitidine for MDS or AML.

Exclusion criteria:

• Patients with AML who are candidates for standard induction chemotherapy as first line treatment.

• Patients with known active CNS leukemia.

• Prior treatment with a smoothened inhibitor (SMOi) and/or hypomethylating agent.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Chronic Myelomonocytic Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• PF-04449913 (Glasdegib)
Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles
• Azacitidine
75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC)	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.	maximum of approximately 15 months
Primary	Number of Participants With Serious Adverse Events (SAEs) in the LIC	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.	maximum of approximately 15 months
Primary	Number of Participants With Laboratory Abnormalities in the LIC	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.	maximum of approximately 16 months
Primary	Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts	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.	maximum of 23 months in AML cohort and 34 months in MDS cohort
Secondary	Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC	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.	maximum of approximately 16 months
Secondary	Number of Participants With Efficacy Measures Other Than CR in the LIC	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	maximum of approximately 16 months
Secondary	Number of Participants With TEAEs in the AML and MDS Cohorts	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 of around 23 months in AML cohort and 40 months in MDS cohort
Secondary	Number of Participants With SAEs in the AML and MDS Cohorts	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.	maximum of around 23 months in AML cohort and 40 months in MDS cohort
Secondary	Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts	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.	maximum of around 23 months in AML cohort and 40 months in MDS cohort
Secondary	Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort	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	maximum of 23 months
Secondary	Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort	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.	maximum of 34 months
Secondary	Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts	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.	maximum of approximately 32 months in AML cohort and 32 months in MDS cohort
Secondary	Duration of CR in the AML and MDS Cohorts	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.	maximum of 23 months in AML cohort and 34 months in MDS cohort
Secondary	Time to CR in the AML and MDS Cohorts	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.	maximum of 23 months in AML cohort and 34 months in MDS cohort
Secondary	Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort	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.	Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
Secondary	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	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.	Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
Secondary	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	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.	Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
Secondary	Cmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort	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.	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
Secondary	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	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.	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
Secondary	Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort	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.	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
Secondary	Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts	Trough plasma concentration was defined as the estimated lowest concentration before next dose administration.	Pre-dose and 1 and 4 hours post-dose on Cycle 1 Day 15 (C1D15) and Cycle 2 Day 1 (C2D1)
Secondary	Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts	Number of participants that met 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

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