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B1371019 Bright

AcronymISRCTNEudraCTClinicaltrials.govDRKS
B13710192017-002822-19

A randomized (1:1), double-blind, multi-center, Placebo controlled study evaluating intensive chemotherapy with or without Glasdegib (PF-04449913) or Azacitidine (AZA) with or without Glasdegib in patients with previously untreated acute myeloid leukemia

Status: Active (Recruitment Closed)

Purpose / Objectives

Primary Outcome

  • Overall survival

 

Secondary Outcomes

 

  • Fatigue score measured by the MDASI-AML/MDS questionnaire;
  • Rate of CR (including CRMRD-negative as assessed by multiparametric flow cytometry), CRi as defined by the ELN recommendations (2017), MLFS, PR, and CR with partial hematologic recovery (CRh) for the Non-intensive study only;
  • Duration of response (defined as CR [includes CRMRD-neg], CRi);
  • Time to response (CR+ [includes CRMRD-neg], CRi ) in the non-intensive study only;
  • Event-free Survival
  • PROs as measured by the M.D. Anderson Symptom Inventory AML/MDS Module (MDASI-AML/MDS), EuroQoL 5 Dimension questionnaire 5-Level version (EQ-5D-5L), Patient Global Impression of Symptoms (PGIS) and Patient Global Impression of Change (PGIC);
  • Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy;
  • Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing;
  • PK of glasdegib;
  • QTc interval

 

 

 

Diagnosis

Acute Myeloid Leukemia (AML) is a heterogeneous cancer of the hematopoietic system characterized by increased blast counts, pancytopenias causing infections and bleeding, and reduced survival. AML is characterized by multiple genetic mutations at the time of diagnosis that evolve with treatment, resulting in treatment resistance, disease relapse, and reduced survival.

 

Patient attributes

Age

18-99

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 Classification, 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).
  • Does not apply to subjects with bundle branch blocks if otherwise asymptomatic.
  • 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 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. 
  • […]

Trial design

  • Phase III
  • Multicenter
  • Randomized
  • Four-arm
  • Double-blind

Intervention

Intensive Study:

  • Arm A:  Intensive Chemotherapie (Cytarabine+ Daunorubicin) and Glasdegib (100 mg) for up to 2 years
  • Arm B: Intensive Chemotherapie (Cytarabine+ Daunorubicin)Placebo  for up to 2 years

 Non-intensive Study:

  • Arm A: Glasdegib (100 mg) and Azacitidine
  • Arm B. Azacitidine and Placebo

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Documents (password protected)

Responsibilities in overall trial

Pfizer Inc. (USA)

    National Coordinating Investigator

    Prof. Dr. med. Karl-Anton Kreuzer

    Study Sites

    Klinik I für Innere Medizin

    Study office

    • Klinisches Studienzentrum der Klinik I für Innere Medizin Köln

    Status

    Active (Recruitment Closed)

    Principal Investigator

    Prof. Dr. med. Karl-Anton Kreuzer

    Deputy of Principal Investigator

    • Dr. med. Anja Jühling
    • Prof. Dr. med. Hans Christian Reinhardt

    Subinvestigator

    • Dr. med. Jan-Michel Heger
    • Dr. med. Christian Maurer
    • Florian Simon
    • Dr. med. Armin Tuchscherer

    Contact at Site