Two separate registration trials conducted under one protocol number are proposed to
adequately and independently evaluate the addition of glasdegib in intensive and
non-intensive chemotherapy populations. Each study will have an experimental treatment arm
and a placebo arm. Endpoints are the same for each study except where specifically indicated.
Assignment to the Intensive Study or the Non-Intensive Study will be made by the Investigator
based on the 2017 European LeukemiaNet (ELN) recommendations.
Study B1371019 is a randomized (1:1), double-blind, multi-center, placebo controlled study of
chemotherapy in combination with glasdegib versus chemotherapy in combination with placebo in
adult patients with previously untreated AML.
Glasdegib is being studied in combination with azacitidine for the treatment of adult
patients with previously untreated acute myeloid leukemia (AML) who are not candidates for
intensive induction chemotherapy (Non-intensive AML population).
Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment
of adult patients with previously untreated acute myeloid leukemia (Intensive AML
Subjects must meet all of the following inclusion criteria to be eligible for enrollment
into the Intensive and Non Intensive study (unless where indicated):
1. 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).
2. 18 years of age (In Japan, 20 years of age).
3. 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
- Estimated creatinine clearance 30 mL/min as calculated using the standard method
for the institution.
4. QTc interval 470 msec using the Fridericia correction (QTcF).
5. 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.
6. 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.
7. 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.
8. Female subjects of non childbearing potential must meet at least 1 of the following
1. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
2. Have medically confirmed ovarian failure; or
3. 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.
9. Consent to a saliva sample collection for a germline comparator, unless prohibited by
local regulations or ethics committee (EC) decision.
10. Evidence of a personally signed and dated informed consent document indicating that
the patient has been informed of all pertinent aspects of the study.
11. 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).
Subjects with any of the following characteristics/conditions will not be included in the
1. Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016
2. AML with BCR ABL1 or t(9;22)(q34;q11.2) as a sole abnormality.
- Complex genetics may include t(9;22) cytogenetic translocation.
3. Subjects with known active CNS leukemia.
4. Participation in other clinical studies involving other investigational drug(s)
(Phases 1 4) within 4 weeks prior study entry and/or during study participation.
5. Subjects known to be refractory to platelet or packed red cell transfusions per
Institutional Guidelines, or a patient who refuses blood product support.
6. 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.
7. 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.
8. Subjects with an active, life threatening or clinically significant uncontrolled
systemic infection not related to AML.
9. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the
Intensive Chemotherapy Study only.
10. Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the
Intensive Chemotherapy Study only.
11. 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.
12. Current use or anticipated requirement for drugs that are known strong CYP3A4/5
13. Concurrent administration of herbal preparations.
14. Major surgery or radiation within 4 weeks of starting study treatment.
15. 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.
16. Known active drug or alcohol abuse.
17. 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
18. Pregnant females or breastfeeding female subjects.
19. Known recent or active suicidal ideation or behavior.
20. 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.