Clinical trial NCT02367456: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelodysplastic Syndrome
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Keywords: MDS
AML
CMML
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2015-02-20
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC)
timeFrame: maximum of approximately 15 months
measure: Number of Participants With Serious Adverse Events (SAEs) in the LIC
timeFrame: maximum of approximately 15 months
measure: Number of Participants With Laboratory Abnormalities in the LIC
timeFrame: maximum of approximately 16 months
measure: Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts
timeFrame: maximum of 23 months in AML cohort and 34 months in MDS cohort
Secondary outcomes:
measure: Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC
timeFrame: maximum of approximately 16 months
measure: Number of Participants With Efficacy Measures Other Than CR in the LIC
timeFrame: maximum of approximately 16 months
measure: Number of Participants With TEAEs in the AML and MDS Cohorts
timeFrame: maximum of around 23 months in AML cohort and 40 months in MDS cohort
measure: Number of Participants With SAEs in the AML and MDS Cohorts
timeFrame: maximum of around 23 months in AML cohort and 40 months in MDS cohort
measure: Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts
timeFrame: maximum of around 23 months in AML cohort and 40 months in MDS cohort
measure: Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort
timeFrame: maximum of 23 months
measure: Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort
timeFrame: maximum of 34 months
measure: Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts
timeFrame: maximum of approximately 32 months in AML cohort and 32 months in MDS cohort
measure: Duration of CR in the AML and MDS Cohorts
timeFrame: maximum of 23 months in AML cohort and 34 months in MDS cohort
measure: Time to CR in the AML and MDS Cohorts
timeFrame: maximum of 23 months in AML cohort and 34 months in MDS cohort
measure: Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort
timeFrame: Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
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
timeFrame: Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
measure: 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
timeFrame: Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
measure: Cmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort
timeFrame: 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
measure: 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
timeFrame: 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
measure: Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort
timeFrame: 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
measure: Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts
timeFrame: Pre-dose and 1 and 4 hours post-dose on Cycle 1 Day 15 (C1D15) and Cycle 2 Day 1 (C2D1)
measure: Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts
timeFrame: maximum of approximately 15 months in the LIC cohort, 23 months in AML cohort, and 40 months in MDS cohort
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham the Kirklin Clinic
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: New Haven
country: United States
facility: Smilow Cancer Center at Yale New Haven Hospital
state: Connecticut
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Bronx
country: United States
facility: Montefiore Einstein Center for Cancer
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Hospital Cancer Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University
state: New York
city: Durham
country: United States
facility: Duke University Health System: Adult Bone Marrow Transplant Clinic
state: North Carolina
city: Durham
country: United States
facility: Duke University Health System, Duke University Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Durham
country: United States
facility: Investigational Chemotherapy Service
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Nashville
country: United States
facility: Henry-Joyce Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt - Ingram Cancer Center
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Hospital
state: Utah
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance (SCCA)
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center (UWMC)
state: Washington
city: Antwerpen
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen - Campus Stuivenberg
city: Leuven
country: Belgium
facility: UZ Leuven
city: Calgary
country: Canada
facility: Tom Baker Cancer Center
state: Alberta
city: Edmonton
country: Canada
facility: University Of Alberta Hospital
state: Alberta
city: Amiens cedex 01
country: France
facility: CHU d'Amiens-Picardie - Hopital SUD
city: Paris CEDEX 10
country: France
facility: Hopital Saint-Louis (AP-HP) - Service Hematologie Senior
city: Pierre Benite Cedex
country: France
facility: Hospices Civils de Lyon - Hopital Lyon Sud- Hematologie
city: Tours Cedex 01
country: France
facility: CHU de Tours-Hopital Bretonneau-Centre Regional de cancerologie Henry Kaplan
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum Braunschweig gGmbH
city: London
country: United Kingdom
facility: King's College Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: The Newcastle Hospitals NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
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.