Clinical Trials /

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

NCT02367456

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In Untreated MDS, AML and CMML Patients
  • 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 IDs

  • ORG STUDY ID: B1371012
  • SECONDARY ID: 2014-001345-24
  • SECONDARY ID: BRIGHT MDS&AML1012
  • NCT ID: NCT02367456

Conditions

  • Myelodysplastic Syndrome
  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
PF-04449913 (Glasdegib)Arm A
AzacitidineArm A

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalMDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
  • PF-04449913 (Glasdegib)
  • Azacitidine
Arm BExperimentalAML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
  • PF-04449913 (Glasdegib)
  • Azacitidine

Eligibility Criteria

        Inclusion criteria:

          -  Patients must have previously untreated MDS or AML 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.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete remission (CR) rate
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:CR rate - percentage of patients achieving CR as defined by modified IWG criteria (2006) for MDS and ELN (2017) for AML (Expansion cohorts)

Secondary Outcome Measures

Measure:Response Rate
Time Frame:All cycles until progression, a median of 1 year
Safety Issue:
Description:Response rate - Percentage of participants achieving complete remission + partial remission as defined by modified IWG criteria (2006) (Safety lead-in phase)
Measure:Hematologic Improvement
Time Frame:All cycles until progression, a median of 1 year
Safety Issue:
Description:Hematologic Improvement, as defined by modified IWG criteria (2006) (Safety lead-in phase)
Measure:Marrow Complete Response (mCR)
Time Frame:All cycles until progression, a median of 1 year
Safety Issue:
Description:Marrow Complete Response, as defined by modified IWG criteria (2006) (Safety lead-in phase)
Measure:Cytogenetic Response
Time Frame:All cycles until progression, a median of 1 year
Safety Issue:
Description:Cytogenetic Response, as defined by modified IWG criteria (2006) (Safety lead-in phase)
Measure:Stable Disease
Time Frame:All cycles until progression, a median of 1 year
Safety Issue:
Description:Stable Disease, as defined by modified IWG criteria (2006) (Safety lead-in phase)
Measure:QTc interval
Time Frame:All cycles through end of treatment, a median of 1 year
Safety Issue:
Description:QTc interval corrected using Fridericia's Formula (msec) (Safety lead-in phase and Expansion cohorts)
Measure:Duration of CR
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:Duration of response defined as duration from date of first achieving complete remission to date of disease progression or death due to any cause, whichever occurs first (Expansion cohorts)
Measure:Time to CR
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:Duration from date of first dose of study drug to date of first complete remission (Expansion cohorts)
Measure:Overall Survival (OS)
Time Frame:All cycles until death or 24 months from first visit of last patient
Safety Issue:
Description:Time from date of first study treatment to date of death due to any cause. Patients last known to be alive will be censored at the date of last contact. (Expansion cohorts)
Measure:Complete remission with partial hematologic recovery (AML Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:CRh is defined as CR but with absolute neutrophil count >500/uL, platelets >50,000/uL, and not qualifying for CR.
Measure:Adverse events (Expansion cohorts)
Time Frame:Screening through 28 days following last dose of study drug
Safety Issue:
Description:Type, frequency, severity, timing, and relationship to study therapy of adverse events and laboratory abnormalities (graded by NCI CTCAE v.4.03) (Expansion cohorts)
Measure:AUC for PF-04449913
Time Frame:First 5 months of treatment
Safety Issue:
Description:Area under the Concentration-Time Curve (ng*h/mL) (Safety lead-in phase)
Measure:Cmax for PF-04449913
Time Frame:First 5 months of treatment
Safety Issue:
Description:Maximum Observed Plasma Concentration (ng/mL) (Safety lead-in phase)
Measure:Tmax for PF-04449913
Time Frame:First 5 months of treatment
Safety Issue:
Description:Time to Reach Maximum Observed Plasma Concentration (hrs) (Safety lead-in phase)
Measure:AUC for Azacitidine
Time Frame:First 2 weeks of treatment
Safety Issue:
Description:Area under the Concentration-Time Curve (ng*h/mL) (Safety lead-in phase)
Measure:Cmax for Azacitidine
Time Frame:First 2 weeks of treatment
Safety Issue:
Description:Maximum Observed Plasma Concentration (ng/mL) (Safety lead-in phase)
Measure:Tmax for Azacitidine
Time Frame:First 2 weeks of treatment
Safety Issue:
Description:Time to Reach Maximum Observed Plasma Concentration (hrs) (Safety lead-in phase)
Measure:Ctrough for PF-04449913
Time Frame:First 1 month of treatment
Safety Issue:
Description:Minimum plasma concentration following daily dosing to steady state (ng/mL) (Expansion cohorts)
Measure:Complete remission with incomplete hematologic recovery (AML Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by ELN criteria (2017) (AML expansion cohort)
Measure:Morphologic leukemia free state (AML Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by ELN criteria (2017) (AML expansion cohort)
Measure:Partial remission (AML Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by ELN criteria (2017) (AML expansion cohort)
Measure:Stable disease (AML Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by ELN criteria (2017) (AML expansion cohort)
Measure:Marrow complete remission (MDS Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by modified IWG criteria (2006) (MDS expansion cohort)
Measure:Partial remission (MDS Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by modified IWG criteria (2006) (MDS expansion cohort)
Measure:Stable disease (MDS Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by modified IWG criteria (2006) (MDS expansion cohort)
Measure:Partial or complete cytogenetic response (MDS Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by modified IWG criteria (2006) (MDS expansion cohort)
Measure:Hematologic improvement (MDS Expansion cohort)
Time Frame:All cycles until progression or 24 months from first visit of last patient
Safety Issue:
Description:As defined by modified IWG criteria (2006) (MDS expansion cohort)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • MDS
  • AML

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