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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02367456
Recruitment Status : Active, not recruiting
First Posted : February 20, 2015
Results First Posted : March 5, 2021
Last Update Posted : April 22, 2021
Sponsor:
Information provided by (Responsible Party):
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.

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

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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
Estimated Study Completion Date : June 30, 2021


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02367456


Locations
Show Show 34 study locations
Sponsors and Collaborators
Pfizer
Investigators
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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

Additional Information:
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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    Key Record Dates
Results First Posted: March 5, 2021
Last Update Posted: April 22, 2021
Last Verified: April 2021
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Pfizer:
MDS
AML
CMML
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors