A Study Evaluating Intensive Chemotherapy With or Without Glasdegib or Azacitidine With or Without Glasdegib In Patients With Previously Untreated Acute Myeloid Leukemia (BRIGHT AML1019)
Leukemia, Myeloid, Acute
About this trial
This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring glasdegib;, untreated;, Hedgehog Inhibitor
Eligibility Criteria
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the Intensive and Non Intensive study (unless where indicated):
Subjects with untreated AML according to the World Health Organization (WHO) 2016 Classification2, including those with:
- AML arising from MDS or another antecedent hematologic disease (AHD).
- AML after previous cytotoxic therapy or radiation (secondary AML).
- 18 years of age (In Japan, 20 years of age).
Adequate Organ Function as defined by the following:
- Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 3 x upper limit of normal (ULN), excluding subjects with liver function abnormalities due to underlying malignancy.
- Total serum bilirubin 2 x ULN (except subjects with documented Gilbert's syndrome).
- Estimated creatinine clearance 30 mL/min as calculated using the standard method for the institution.
- QTc interval 470 msec using the Fridericia correction (QTcF).
All anti cancer treatments (unless specified) should be discontinued 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines.
- For control of rapidly progressing leukemia, all trans retinoic acid (ATRA), hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after the first dose of glasdegib.
- Serum or urine pregnancy test (for female subjects of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) negative at screening.
- Male and female subjects of childbearing potential and at risk for pregnancy must agree to use at least one highly effective method of contraception throughout the study and for 180 days after the last dose of azacitidine, cytarabine, or daunorubicin; and the last dose of glasdegib or placebo, whichever occurs later.
Female subjects of non childbearing potential must meet at least 1 of the following criteria:
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure; or
- Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
- Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.
- Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
- Subjects who are willing and able to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow [BM] assessments).
Exclusion Criteria:
Subjects with any of the following characteristics/conditions will not be included in the study:
- Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016 classification).
AML with BCR ABL1 or t(9;22)(q34;q11.2) as a sole abnormality.
- Complex genetics may include t(9;22) cytogenetic translocation.
- Subjects with known active CNS leukemia.
- Participation in other clinical studies involving other investigational drug(s) (Phases 1 4) within 4 weeks prior study entry and/or during study participation.
- Subjects known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
- Subjects with another active malignancy on treatment with the exception of basal cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or concurrent malignancies will be considered on a case by case basis.
- Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias (including sustained ventricular tachyarrhythmia), right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms.
- Subjects with an active, life threatening or clinically significant uncontrolled systemic infection not related to AML.
- Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the Intensive Chemotherapy Study only.
- Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the Intensive Chemotherapy Study only.
- Known malabsorption syndrome or other condition that may significantly impair absorption of study medication in the investigator's judgment (eg, gastrectomy, lap band, Crohn's disease) and inability or unwillingness to swallow tablets or capsules.
- Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.
- Concurrent administration of herbal preparations.
- Major surgery or radiation within 4 weeks of starting study treatment.
Documented or suspected hypersensitivity to any one of the following:
- For subjects assigned to intensive chemotherapy, documented or suspected hypersensitivity to cytarabine (not including drug fever or exanthema, including known cerebellar side effects) or daunorubicin.
- For subjects assigned to non intensive chemotherapy, documented or suspected hypersensitivity to azacitidine or mannitol.
- Known active drug or alcohol abuse.
- Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
- Pregnant females or breastfeeding female subjects.
- Known recent or active suicidal ideation or behavior.
- Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
Sites / Locations
- UCLA Department of Medicine
- UCLA Drug Information/Investigational Drugs
- UCLA Hematology/Oncology Clinic
- UCLA Ronald Reagan Medical Center
- UC Irvine Health - Chao Family Comprehensive Cancer Center
- UCSF Helen Diller Family Comprehensive Cancer Center
- University of California, San Francisco
- UCLA Hematology/Oncology - Westlake Village
- Augusta University Medical Center
- Georgia Cancer Center at Augusta University
- Tufts Medical Center Investigational Drug Pharmacy
- Tufts Medical Center
- Massachusetts General Hospital
- Beth Israel Deaconess Medical Center
- MidAmerica Division, Inc., c/o Research Medical Center
- Northwell Health/Monter Cancer Center
- North Shore University Hospital
- Long Island Jewish Medical Center
- University of Rochester Medical Center
- University Hospitals Cleveland Medical Center
- Cleveland Clinic Foundation
- OHSU Center for Health and Healing
- Oregon Health & Science University
- Centennial Medical Center
- TriStar Bone Marrow Transplant
- Baylor University Medical Center
- Blood Cancer and Stem Cell Transplant Clinic
- Methodist Healthcare System of San Antonio
- Swedish Cancer Institute
- Swedish Medical Center
- St Vincent's Hospital Sydney
- St George Hospital
- Royal Adelaide Hospital
- Landeskrankenhaus Salzburg, Universitatsklinik fur Innere Medizin III der PMU
- Uniklinikum Salzburg, Landeskrankenhaus Salzburg
- Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel
- AZ Sint-Jan Brugge-Oostende av
- Universitaire Ziekenhuizen Brussel (UZ Brussel)
- Universitaire Ziekenhuizen Brussel
- Universitaire Ziekenhuizen Leuven
- Health Sciences Centre
- CancerCare Manitoba
- Sunnybrook Research Institute
- Princess Margaret Cancer Centre
- CIUSSS de l'Est-de-l'Ile-de- Montréal - Hôpital Maisonneuve-Rosemont
- Royal University Hospital
- Saskatoon Cancer Centre
- The First Affiliated Hospital of USTC, Anhui Provincial Hospital
- Anhui Provincial Hospital
- Fujian Medical University Union Hospital
- Guangdong Provincial People's Hospital
- Guangdong Second Provincial General Hospital
- Hebei Yanda Lu Daopei Hospital
- Henan Provincial People's Hospital/Hematology Department
- Henan Cancer Hospital
- Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology/Cancer Center
- West China Hospital, Sichuan University
- Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences
- The First Affiliated Hospital College of Medicine, Zhejiang University
- Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine
- Interni hematologicka a onkologicka klinika, Fakultni nemocnice Brno
- Nemocnicni lekarna
- Ustavni lekarna
- Klinika hematoonkologie
- Interní hematologická klinika, Fakultni nemocnice Královské Vinohrady
- Ústavni lékárna
- CHU Henri Mondor
- CHU de Nantes
- CHU de Nantes Hotel Dieu
- Hopital Saint Louis
- Centre Hospitalier Lyon Sud - Service d'Hematologie
- Institut Gustave Roussy
- Klinikum der Universitaet Muenchen
- Philipps-Universitaet Marburg
- Universitätsklinikum Köln
- Universitaetsklinikum Muenster
- Universitaetsklinikum Hamburg-Eppendorf
- Medizinische Hochschule Hannover
- Debreceni Egyetem Klinikai Kozpont Belgyogyaszati Klinika, Hematologia Tanszek
- Debreceni Egyetem Klinikai Kozpont Belgyogyaszati Klinika
- Petz Aladár Megyei Oktató Kórház, II. Belgyógyászat- Hematológiai Osztály
- Somogy Megyei Kaposi Mor Oktato Korhaz
- Szabolcs-Szatmar Bereg Megyei Korhazak es Egyetemi Oktatokorhaz, Josa Andras Korhaz, Hematologia
- Szabolcs-Szatmar Bereg Megyei Korhazak es Egyetemi Oktatokorhaz, Josa Andras Korhaz,
- Rambam Health Care Campus
- Shaare Zedek Medical Center
- Hadassah Medical Center (Ein Kerem)
- Hemato-oncology ambulatory Service
- Rabin Medical Center, Beilinson Hospital
- AOU Ospedali Riuniti Umberto I, G.M. Lancisi, G. Salesi, Clinica Di Ematologia
- SOD Farmacia-Dipt dei servizi -AOU Ospedali Riuniti Umberto I, G.M. Lancisi, G. Salesi
- A.O.U. di Ferrara- Arcispedale Sant'Anna,
- AO Ospedali Riuniti Marche Nord - Presidio Ospedaliero San Salvatore di Pesaro -
- Azienda Ospedaliera Universitaria Senese.
- Azienda Ospedaliero Universitaria di Bologna Policlinico S.Orsola Malpighi
- Azienda Ospedaliera Universitaria Senese
- Japanese Red Cross Nagoya Daini Hospital
- University of Fukui Hospital
- Gunma University Hospital
- Kobe University Hospital
- Yokohama City University Medical Center
- Tohoku University Hospital
- Osaka City University Hospital
- Kindai University Hospital
- Shizuoka Cancer Center
- National Hospital Organization Disaster Medical Center
- Akita University Hospital
- Kyushu University Hospital
- National Hospital Organization Kumamoto Medical Center
- Nagasaki University Hospital
- Tokyo Medical University Hospital
- Chonbuk National University Hospital
- Inje University Busan Paik Hospital
- Keimyung University Dongsan Hospital
- Gachon University Gil Medical Center
- Seoul National University Hospital
- Clinical Trial Center, Severance Hospital, Yonsei University Health System
- Severance Hospital, Yonsei University Health System
- Samsung Medical Center
- The Catholic University of Korea Seoul St. Mary's Hospital
- Instituto Nacional de Cancerología
- Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
- Klinika Hematologii i Transplantologii Uniwersyteckie Centrum Kliniczne
- WWCOiT im. M. Kopernika w Lodzi
- Institutul Oncologic 'Prof. Dr. Ion Chiricuta'
- Spitalul Clinic Municipal Filantropia Craiova, Sectia Clinica Hematologie
- Sp. Clinic de Urgenta Militar Central Dr. Carol Davila
- Spitalul Clinic Coltea, Clinica de Hematologie
- State Budgetary Healthcare Institution of Moscow
- SBHI NNR NN RCH n. a. N.A. Semashko
- State Budgetary Institution of Ryazan Region 'Regional Clinical Hospital' (SBI RR RCH)
- V.A Almazov NMRC
- Hospital del Mar
- Hospital de la Santa Creu i Sant Pau
- Hospital Universitario Arnau de Vilanova
- Hospital General Universitario Gregorio Maranon
- Hospital Universitario Ramon y Cajal
- Hospital Universitario Virgen del Rocio
- Hospital Universitari i Politecnic La Fe
- Universitetssjukhuset Orebro
- Karolinska Universitetssjukhuset Huddinge
- National Cheng Kung University Hospital
- National Taiwan University Hospital
- Taipei Veterans General Hospital
- Koo Foundation Sun Yat-Sen Cancer Center
- Chang Gung Memorial Hospital-Linkou Branch
- The Royal Marsden NHS Foundation Trust
- University Hospitals Birmingham NHS Foundation Trust
- Imperial College Healthcare NHS Trust
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Arm A (Intensive Study)
Arm B (Intensive Study)
Arm A (Non-intensive study)
Arm B (Non-intensive study)
Glasdegib + '7+3' Induction(s)
Placebo + '7+3' Induction(s)
Glasdegib + azacitidine
Placebo + azacitidine