A Study To Evaluate PF-04449913 With Chemotherapy In Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
A PHASE 1B/2 STUDY TO EVALUATE THE SAFETY AND EFFICACY OF PF-04449913, AN ORAL HEDGEHOG INHIBITOR, IN COMBINATION WITH INTENSIVE CHEMOTHERAPY, LOW DOSE ARA-C OR DECITABINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR HIGH-RISK MYELODYSPLASTIC SYNDROME
2 other identifiers
interventional
255
6 countries
81
Brief Summary
This is a study to evaluate PF-04449913 (an inhibitor of the Hedgehog pathway) in Acute Myeloid Leukemia and high-risk Myelodysplastic Syndrome in combination with standard agents used to treat these diseases.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Jun 2012
Longer than P75 for phase_2
81 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 1, 2012
CompletedFirst Posted
Study publicly available on registry
March 7, 2012
CompletedStudy Start
First participant enrolled
June 27, 2012
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 3, 2017
CompletedResults Posted
Study results publicly available
May 23, 2018
CompletedStudy Completion
Last participant's last visit for all outcomes
March 4, 2019
CompletedMarch 3, 2020
February 1, 2020
4.5 years
March 1, 2012
December 11, 2017
February 19, 2020
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
Number of Participants With Dose-limiting Toxicities (DLTs) at Phase 1B
A DLT was any of the following adverse events (AEs) in Cycle 1 and considered by the investigator possibly related to glasdegib in combination with chemotherapy: (1) Grade \>= 3 non-hematologic toxicity, excluding Grade \>= 3 infection, fever (including febrile neutropenia), infusion related AEs, electrolyte abnormalities and ALT/AST elevation that returned to Grade \<= 1 or baseline within 7 days; (2) prolonged myelosuppression that lasted longer than 42 days from the point of detection, defined as absolute neutrophil count (ANC) \< 500/microliter(mcL) or platelet count \< 10 \*10\^9/L with a normal bone marrow (\<5% blasts and no evidence of disease or dysplasia); (3) inability to deliver at least 80% of the planned study doses for all agents in a combination due to non-hematologic toxicities; (4) Delay of \>28 days in receiving the next scheduled cycle due to persisting non-hematologic toxicities. Arm A: Glasdegib+LDAC; Arm B: Glasdegib+Decitabine; Arm C: Glasdegib+Cytarabine/Daunorubicin.
Arms A and B: Cycle 1, Day 1 to Day 28; Arm C: Cycle 1, Day -3 to Day 21 or to Day 28 depending on when the next chemotherapy cycle was started
Percentage of Participants With Complete Response (CR) at Phase 2 Fit
For AML participants:CR were those with repeat bone marrow showing \<5% myeloblasts,spicules present and no Auer rods, peripheral blood showing neutrophils\>=1000/mcL and platelets\>=100,000/mcL, transfusion independent and no extramedullary disease. For MDS participants:CR were those with repeat bone marrow showing \<=5% myeloblasts, peripheral blood showing neutrophils\>=1000/mcL, platelets\>=100,000/mcL, 0% blast and hemoglobin (Hgb)\>= 11 g/dL, normal maturation of all cell lines.
4 years
Overall Survival (OS) at Phase 2 Unfit
OS was defined as duration from the date of randomization to the date of death from any cause. Kaplan-Meier (KM) method was used to estimate median OS. In this method, every participant had a follow-up time which was associated with an indicator, 1=event (death in our case), and 0 =censored. If the participants were not known to have died, time to date of last known to be alive was used as to calculate the follow-up time and indicator was 0 for these participants. KM method estimates the median OS based on the K-M curve. The K-M curve only drops when we had an event and censor data are the ticks in the graph. To estimate median OS, the K-M curve usually will be smoothed first and a line will be drawn at 50%. The median OS is the point when K-M curve and the horizontal hit. Survival status was collected every month for the first 2 months after discontinuation of study treatment and thereafter every 2 months until death or 4 years from time of randomization for each participant.
Randomization to Follow-up (4 years)
Secondary Outcomes (67)
Overall Survival (OS) at Phase 1B
First dose to Follow-up (4 years)
Overall Survival (OS) at Phase 2 Fit
First dose to Follow-up (4 years)
Percentage of Participants With CR / Complete Response With Incomplete Blood Count Recovery (CRi) at Phase 1B
4 years
Percentage of Participants With Complete Response (CR) at Phase 2 Unfit
4 years
Percentage of Participants With Disease-specific Efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit
4 years
- +62 more secondary outcomes
Study Arms (5)
Arm A (Phase 1B)
EXPERIMENTALPF-04449913 in combination with low dose ARA-C (LDAC)
Arm B (Phase 1B)
EXPERIMENTALPF-04449913 in combination with Decitabine
Arm C (Phase 1B)
EXPERIMENTALPF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy.
P2 Fit (Phase 2 Single Arm)
EXPERIMENTALPF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy.
P2 Unfit (Phase 2 Randomized)
OTHERPatients will be randomized 2:1 (low dose ARA-C in combination with PF-04449913: low dose ARA-C alone).
Interventions
Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10.
Eligibility Criteria
You may qualify if:
- Patients with AML or RAEB 2 High Risk MDS who are newly diagnosed according to the WHO 2008 Classification and previously untreated.
- Patients with AML (arising from an antecedent hematologic disease \[AHD\]) or MDS who may have had one prior regimen with commercially available agents for the treatment of their prior hematologic disease. The patients may not have had a prior therapy for their AML.
- AML patients include de novo AML, AML evolving from MDS or other AHD and AML after previous cytotoxic therapy or radiation (secondary AML)
- For a diagnosis of AML, a bone marrow blast count of 20% or more is required.
- For a diagnosis of high-risk Myelodysplastic Syndrome RAEB 2 the patient must have 10-19% bone marrow blasts
- Adequate Organ Function
- ECOG Performance Status 0, 1, or 2
You may not qualify if:
- AML M3 Acute Promyelocytic Leukemia (APL) or patients with a t(9:22) cytogenetic translocation.
- Patients with known active uncontrolled central nervous system (CNS) leukemia.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Pfizerlead
Study Sites (81)
University of Alabama at Birmingham
Birmingham, Alabama, 35233, United States
University of Alabama at Birmingham
Birmingham, Alabama, 35249-6909, United States
University of Alabama at Birmingham
Birmingham, Alabama, 35249, United States
UC San Diego Moores Cancer Center - Investigational Drug Services
La Jolla, California, 92037-0845, United States
UC San Diego Medical Center - La Jolla
La Jolla, California, 92037, United States
UC San Diego Moores Cancer Center
La Jolla, California, 92093-0698, United States
Keck Hospital of USC
Los Angeles, California, 90033, United States
LAC & USC Medical Center
Los Angeles, California, 90033, United States
USC/Norris Comprehensive Cancer Center / Investigational Drug Services
Los Angeles, California, 90033, United States
USC/Norris Comprehensive Cancer Center
Los Angeles, California, 90033, United States
Ronald Reagan UCLA Medical Center Drug Information Center
Los Angeles, California, 90095, United States
Ronald Reagan UCLA Medical Center
Los Angeles, California, 90095, United States
UCLA Drug lnformation/lnvestigational Drugs
Los Angeles, California, 90095, United States
UCLA Hematology/Oncology Clinic
Los Angeles, California, 90095, United States
UC San Diego Medical Center - Hillcrest
San Diego, California, 92103, United States
University of Colorado Denver
Aurora, Colorado, 80045, United States
University of Colorado Hospital
Aurora, Colorado, 80045, United States
H.Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, 33612, United States
Emory University Hospital
Atlanta, Georgia, 30322, United States
Investigational Drug Service, Emory University Clinic
Atlanta, Georgia, 30322, United States
The Emory Clinic
Atlanta, Georgia, 30322, United States
Winship Cancer Institute, Emory University
Atlanta, Georgia, 30322, United States
Northwestern Medical Faculty Foundation
Chicago, Illinois, 60611, United States
Northwestern Medicine Developmental Therapeutics Institute
Chicago, Illinois, 60611, United States
Northwestern Memorial Hospital
Chicago, Illinois, 60611, United States
The University of Chicago Medical Center
Chicago, Illinois, 60637, United States
The University of Chicago's Medical Center
Chicago, Illinois, 60637, United States
University of Kansas Clinical Research Center
Fairway, Kansas, 66205, United States
University of Kansas Hospital
Kansas City, Kansas, 66160, United States
University of Kansas Cancer Center and Medical Pavilion
Westwood, Kansas, 66205, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21287, United States
Tufts Medical Center
Boston, Massachusetts, 02111, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
Brigham and Women's Hospital
Boston, Massachusetts, 02115, United States
Dana Farber Cancer Institute (DFCI)
Boston, Massachusetts, 02215, United States
University of Michigan Comprehensive Cancer Center Clinical Trials Office
Ann Arbor, Michigan, 48109-2800, United States
University of Michigan Health System
Ann Arbor, Michigan, 48109, United States
Siteman Cancer Center - West County
Creve Coeur, Missouri, 63141, United States
Barnes Jewish Hospital North Campus
St Louis, Missouri, 63110, United States
Barnes-Jewish Hospital
St Louis, Missouri, 63110, United States
Washington University School of Medicine - Division of Bone Marrow Transplant & Leukemia
St Louis, Missouri, 63110, United States
Washington University School of Medicine, Siteman Cancer Center
St Louis, Missouri, 63110, United States
Hackensack University Medical Center
Hackensack, New Jersey, 07601, United States
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, 07601, United States
Roswell Park Cancer Institute
Buffalo, New York, 14263, United States
Cleveland Clinic Cancer Institute
Cleveland, Ohio, 44195, United States
Centennial Medical Center
Nashville, Tennessee, 37203, United States
Sarah Cannon Research Institute
Nashville, Tennessee, 37203, United States
Tennessee Oncology, PLLC
Nashville, Tennessee, 37203, United States
The University of Texas, MD Anderson Cancer Center
Houston, Texas, 77030, United States
University of Washington-Seattle Cancer Care Alliance
Seattle, Washington, 98109, United States
University of Washington Medical Center
Seattle, Washington, 98195, United States
Juravinski Cancer Centre @ Hamilton Health Sciences
Hamilton, Ontario, L8V 5C2, Canada
Centre de Sante et de Services Sociaux (CSSS) Champlain - Charles-Le Moyne
Greenfield Park, Quebec, J4V 2H1, Canada
Universitaetsklinikum Ulm
Ulm, Baden-Wurttemberg, 89081, Germany
Johann Wolfgang Goethe University
Frankfurt am Main, Hesse, 60590, Germany
Medizinische Hochschule Hannover
Hanover, Lower Saxony, 30625, Germany
Charite -Universitatsmedizin Berlin - Campus Benjamin Franklin
Berlin, 12203, Germany
Charite - Universitatsmedizin Berlin
Berlin, 13353, Germany
Universitaetsklinikum Hamburg-Eppendorf
Hamburg, 20246, Germany
Universitaetsklinikum Schleswig-Holstein
Kiel, 24105, Germany
Universitaetsklinikum Magdeburg A.oe.R.
Magdeburg, 39120, Germany
Johannes Gutenberg-Universitaet Mainz
Mainz, 55131, Germany
Universitaetsklinikum Muenster
Münster, 48149, Germany
Universitaetsklinikum Ulm
Ulm, 89081, Germany
Policlinico S. Orsola-Malpighi
Bologna, Province of Bologna, 40138, Italy
ASST Grande Ospedale Metropolitano Niguarda
Milan, 20162, Italy
Policlinico Universitario "Umberto I" Universita degli Studi "La Sapienza" Sezione di Ematologia
Rome, 00161, Italy
A.O. Citta della Salute e della Scienza di Torino - S.C. Ematologia
Torino, 10126, Italy
Azienda Sanitaria Universitaria Integrata di Udine
Udine, 33100, Italy
Uniwersyteckie Centrum Kliniczne Gdanskiego Uniwersytetu Medycznego
Gdansk, Pomeranian Voivodeship, 80-952, Poland
Oddzial Hematologii Z pododzialem chemioterapii-Klinika Hematologii Wojewodzkie Wielospecjalistyczne
Lodz, 93-513, Poland
Dolnoslaskie Centrum Transplantacji Komorkowych z Krajowym Bankiem Dawcow Szpiku
Wroclaw, 53-439, Poland
Hospital Universitario Virgen del Rocio
Seville, Andalusia, 41013, Spain
Hospital Universitario Germans Trias i Pujol
Badalona, Barcelona, 08916, Spain
Hospital del Mar
Barcelona, 08003, Spain
Hospital de la Santa Creu i Sant Pau
Barcelona, 08025, Spain
Hospital Universitari Vall d'Hebron
Barcelona, 08035, Spain
Hospital Clinic de Barcelona
Barcelona, 08036, Spain
Hospital Ramon y Cajal
Madrid, 28034, Spain
Hospital Universitario y Politecnico La Fe
Valencia, 46026, Spain
Related Publications (6)
Heuser M, Smith BD, Fiedler W, Sekeres MA, Montesinos P, Leber B, Merchant A, Papayannidis C, Perez-Simon JA, Hoang CJ, O'Brien T, Ma WW, Zeremski M, O'Connell A, Chan G, Cortes JE. Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial. Ann Hematol. 2021 May;100(5):1181-1194. doi: 10.1007/s00277-021-04465-4. Epub 2021 Mar 19.
PMID: 33740113DERIVEDLin S, Shaik N, Chan G, Cortes JE, Ruiz-Garcia A. An evaluation of overall survival in patients with newly diagnosed acute myeloid leukemia and the relationship with glasdegib treatment and exposure. Cancer Chemother Pharmacol. 2020 Oct;86(4):451-459. doi: 10.1007/s00280-020-04132-x. Epub 2020 Sep 3.
PMID: 32885274DERIVEDCortes JE, Heidel FH, Fiedler W, Smith BD, Robak T, Montesinos P, Candoni A, Leber B, Sekeres MA, Pollyea DA, Ferdinand R, Ma WW, O'Brien T, O'Connell A, Chan G, Heuser M. Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy. J Hematol Oncol. 2020 Jul 14;13(1):92. doi: 10.1186/s13045-020-00929-8.
PMID: 32664995DERIVEDCortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9. Epub 2018 Dec 16.
PMID: 30555165DERIVEDCortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, Pollyea DA, Sekeres MA, Robak T, Ma WW, Zeremski M, Naveed Shaik M, Douglas Laird A, O'Connell A, Chan G, Schroeder MA. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018 Nov;93(11):1301-1310. doi: 10.1002/ajh.25238. Epub 2018 Sep 9.
PMID: 30074259DERIVEDSavona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, McCloskey J, Kantarjian HM, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Cortes JE. Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-Risk MDS. Clin Cancer Res. 2018 May 15;24(10):2294-2303. doi: 10.1158/1078-0432.CCR-17-2824. Epub 2018 Feb 20.
PMID: 29463550DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Pfizer ClinicalTrials.gov Call Center
- Organization
- Pfizer, Inc.
Study Officials
- STUDY DIRECTOR
Pfizer CT.gov Call Center
Pfizer
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 1, 2012
First Posted
March 7, 2012
Study Start
June 27, 2012
Primary Completion
January 3, 2017
Study Completion
March 4, 2019
Last Updated
March 3, 2020
Results First Posted
May 23, 2018
Record last verified: 2020-02
Data Sharing
- IPD Sharing
- Will share
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.