NCT02367456 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1
Status at capture: COMPLETED
Registry last update: 2024-01-19

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC)

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outcome · POSTED

Number of Participants With Serious Adverse Events (SAEs) in the LIC

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outcome · POSTED

Number of Participants With Laboratory Abnormalities in the LIC

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outcome · POSTED

Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts

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outcome · POSTED

Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC

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outcome · POSTED

Number of Participants With Efficacy Measures Other Than CR in the LIC

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outcome · POSTED

Number of Participants With TEAEs in the AML and MDS Cohorts

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outcome · POSTED

Number of Participants With SAEs in the AML and MDS Cohorts

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outcome · POSTED

Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts

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outcome · POSTED

Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort

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outcome · POSTED

Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort

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outcome · POSTED

Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts

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outcome · POSTED

Duration of CR in the AML and MDS Cohorts

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outcome · POSTED

Time to CR in the AML and MDS Cohorts

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outcome · POSTED

Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Cmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort

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outcome · POSTED

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

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outcome · POSTED

Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort

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outcome · POSTED

Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts

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outcome · POSTED

Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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.
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
MDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
intervention Names
Drug: PF-04449913 (Glasdegib)
Drug: Azacitidine
label
Arm A
type
EXPERIMENTAL
description
AML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
intervention Names
Drug: PF-04449913 (Glasdegib)
Drug: Azacitidine
label
Arm B
type
EXPERIMENTAL

interventions

arm Group Labels
Arm A
Arm B
description
Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles
name
PF-04449913 (Glasdegib)
type
DRUG
arm Group Labels
Arm A
Arm B
description
75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle
name
Azacitidine
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 73
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC)
time Frame
maximum of approximately 15 months
description
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.
measure
Number of Participants With Serious Adverse Events (SAEs) in the LIC
time Frame
maximum of approximately 15 months
description
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.
measure
Number of Participants With Laboratory Abnormalities in the LIC
time Frame
maximum of approximately 16 months
description
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.
measure
Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts
time Frame
maximum of 23 months in AML cohort and 34 months in MDS cohort

secondary Outcomes

description
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.
measure
Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC
time Frame
maximum of approximately 16 months
description
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
measure
Number of Participants With Efficacy Measures Other Than CR in the LIC
time Frame
maximum of approximately 16 months
description
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.
measure
Number of Participants With TEAEs in the AML and MDS Cohorts
time Frame
maximum of around 23 months in AML cohort and 40 months in MDS cohort
description
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.
measure
Number of Participants With SAEs in the AML and MDS Cohorts
time Frame
maximum of around 23 months in AML cohort and 40 months in MDS cohort
description
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.
measure
Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts
time Frame
maximum of around 23 months in AML cohort and 40 months in MDS cohort
description
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
measure
Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort
time Frame
maximum of 23 months
description
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.
measure
Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort
time Frame
maximum of 34 months
description
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.
measure
Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts
time Frame
maximum of approximately 32 months in AML cohort and 32 months in MDS cohort
description
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.
measure
Duration of CR in the AML and MDS Cohorts
time Frame
maximum of 23 months in AML cohort and 34 months in MDS cohort
description
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.
measure
Time to CR in the AML and MDS Cohorts
time Frame
maximum of 23 months in AML cohort and 34 months in MDS cohort
description
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.
measure
Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort
time Frame
Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
description
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.
measure
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
time Frame
Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15

Full study description

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.

Source references

references

citation
Sekeres MA, Schuster M, Joris M, Krauter J, Maertens J, Breems D, Gyan E, Kovacsovics T, Verma A, Vyas P, Wang ES, Ching K, O'Brien T, Gallo Stampino C, Ma WW, Kudla A, Chan G, Zeidan AM. A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes. Ann Hematol. 2022 Aug;101(8):1689-1701. doi: 10.1007/s00277-022-04853-4. Epub 2022 Apr 30.
pmid
35488900
type
DERIVED