A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In Untreated MDS, AML and CMML Patients (BRIGHT 1012)

• ClinicalTrials.gov Identifier: NCT02367456
• Recruitment Status: Completed
• First Posted: February 20, 2015
• Results First Posted: March 5, 2021
• Last Update Posted: May 31, 2022
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

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.

Condition or disease	Intervention/treatment	Phase
Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia	Drug: PF-04449913 (Glasdegib); Drug: Azacitidine	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 73 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: April 28, 2015
• Actual Primary Completion Date: January 29, 2020
• Actual Study Completion Date: March 7, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A; MDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2	Drug: PF-04449913 (Glasdegib); Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles; Drug: Azacitidine; 75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle
Experimental: Arm B; AML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2	Drug: PF-04449913 (Glasdegib); Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles; Drug: Azacitidine; 75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC) [ Time Frame: Cycle 1 Day 1 up to 28 days after last dose of study drug or beginning of new anti-cancer therapy (assessed up to 16 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 NCI CTCAE version 4.03.
2. Number of Participants With Serious Adverse Events (SAEs) in the LIC [ Time Frame: Cycle 1 Day 1 up to 28 days after last dose of study drug or beginning of new anti-cancer therapy (assessed up to 16 months) ]
   An 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. Grades of AEs were defined by NCI CTCAE version 4.03.
3. Number of Participants With Laboratory Abnormalities in the LIC [ Time Frame: Cycle 1 Day 1 to last follow up visit (at least 28 days after discontinuation of treatment) (assessed up to 17 months) ]
   Laboratory parameters included: hematology parameters (activated partial thromboplastin time, hemoglobin, INR, lymphocyte count, neutrophil count, platelet count, white blood cell), chemistry parameters (alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, CPK, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate). Grades of laboratory abnormalities were defined by NCI CTCAE version 4.03.
4. Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to End of Treatment (EoT) visit (within 14 days after last dose) (assessed up to 22 months) ]

   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.

Secondary Outcome Measures :

1. Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC [ Time Frame: Cycle 1 Day 1 to last follow up visit (at least 28 days after discontinuation of treatment) (assessed up to 18 months) ]
   RR (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.
2. Number of Participants With Efficacy Measures Other Than CR in the LIC [ Time Frame: Cycle 1 Day 1 to last follow up visit (at least 28 days after discontinuation of treatment) (assessed up to 18 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
3. Number of Participants With TEAEs in the AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 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. AEs were graded by NCI CTCAE version 4.03.
4. Number of Participants With SAEs in the AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 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. AEs were graded by NCI CTCAE version 4.03.
5. Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) ]
   Laboratory parameters included: hematology parameters (activated partial thromboplastin time, hemoglobin, INR, lymphocyte count, neutrophil count, platelet count, white blood cell), chemistry parameters (alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, CPK, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate). Laboratory abnormalities were graded by NCI CTCAE version 4.03.
6. Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort [ Time Frame: Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 20 months) ]
   Number of participants with CR 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
7. Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort [ Time Frame: Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 22 months) ]
   Number of participants with PR, marrow CR (mCR), SD, complete or partial cytogenetic response, and hematologic improvement (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.
8. Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to date of death from any cause (assessed up to 24 months) ]
   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.
9. Duration of CR in the AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) ]
   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.
10. Time to CR in the AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) ]
    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.
11. 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 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.
12. 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 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.
13. 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 Frame: Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and 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.
14. Maximum Plasma Concentration (Cmax) of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort [ Time Frame: 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1; pre-dose and 0.25, 0.5, 1, 2, 6 hours post-dose 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.
15. 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 [ Time Frame: 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1; pre-dose and 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 7. ]
    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 was estimated using non-compartmental analysis.
16. Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort [ Time Frame: 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1; pre-dose and 0.25, 0.5, 1, 2, 6 hours post-dose 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.
17. Trough Plasma Concentration (Ctrough) of Glasdegib on C1D15 and C2D1 in the AML and MDS Cohorts [ Time Frame: Pre-dose and 1 and 4 hours post-dose on Cycle 1 Day 15 and Cycle 2 Day 1. ]
    Trough plasma concentration was defined as the estimated lowest concentration before next dose administration.
18. Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts [ Time Frame: Cycle 1 Day 1 to EoT visit (assessed up to 16 months in the LIC cohort and 24 months in the AML and MDS cohorts) ]
    Number of participants that met categorical criteria of QTcF values in LIC, AML and MDS cohorts

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham the Kirklin Clinic

Birmingham, Alabama, United States, 35233

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35249

United States, California

UC San Diego Moores Cancer Center

La Jolla, California, United States, 92093

United States, Connecticut

Smilow Cancer Center at Yale New Haven Hospital

New Haven, Connecticut, United States, 06510

United States, Maryland

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States, 21287

United States, New York

Montefiore Einstein Center for Cancer

Bronx, New York, United States, 10461

Montefiore Medical Center

Bronx, New York, United States, 10467

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Stony Brook University Hospital Cancer Center

Stony Brook, New York, United States, 11794

Stony Brook University

Stony Brook, New York, United States, 11794

United States, North Carolina

Duke University Health System: Adult Bone Marrow Transplant Clinic

Durham, North Carolina, United States, 27705

Duke University Health System, Duke University Hospital

Durham, North Carolina, United States, 27710

Duke University Health System

Durham, North Carolina, United States, 27710

Investigational Chemotherapy Service

Durham, North Carolina, United States, 27710

United States, Ohio

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, United States, 44195

United States, Tennessee

Henry-Joyce Cancer Center

Nashville, Tennessee, United States, 37232

Vanderbilt - Ingram Cancer Center

Nashville, Tennessee, United States, 37232

United States, Utah

Huntsman Cancer Hospital

Salt Lake City, Utah, United States, 84112

Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

United States, Washington

Seattle Cancer Care Alliance (SCCA)

Seattle, Washington, United States, 98109

University of Washington Medical Center (UWMC)

Seattle, Washington, United States, 98195

Belgium

Ziekenhuis Netwerk Antwerpen - Campus Stuivenberg

Antwerpen, Belgium, 2060

UZ Leuven

Leuven, Belgium, 3000

Canada, Alberta

Tom Baker Cancer Center

Calgary, Alberta, Canada, T2N 4N2

University Of Alberta Hospital

Edmonton, Alberta, Canada, T6G 2B7

France

CHU d'Amiens-Picardie - Hopital SUD

Amiens cedex 01, France, 80054

Hopital Saint-Louis (AP-HP) - Service Hematologie Senior

Paris CEDEX 10, France, 75475

Hospices Civils de Lyon - Hopital Lyon Sud- Hematologie

Pierre Benite Cedex, France, 69495

CHU de Tours-Hopital Bretonneau-Centre Regional de cancerologie Henry Kaplan

Tours Cedex 01, France, 37044

Germany

Staedtisches Klinikum Braunschweig gGmbH

Braunschweig, Germany, 38114

United Kingdom

King's College Hospital

London, United Kingdom, SE5 9RS

The Newcastle Hospitals NHS Foundation Trust

Newcastle upon Tyne, United Kingdom, NE7 7DN

Oxford University Hospitals NHS Foundation Trust

Oxford, United Kingdom, OX3 9DU

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

  Study Documents (Full-Text)

Documents provided by Pfizer:

Study Protocol  [PDF] June 14, 2018

Statistical Analysis Plan  [PDF] December 18, 2017

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02367456
• Other Study ID Numbers: B1371012; 2014-001345-24 ( EudraCT Number ); BRIGHT MDS&AML1012 ( Other Identifier: Alias Study Number )
• First Posted: February 20, 2015
• Results First Posted: March 5, 2021
• Last Update Posted: May 31, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Pfizer:

MDS; AML; CMML

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Azacitidine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors