A Study Evaluating Intensive Chemotherapy With or Without Glasdegib or Azacitidine With or Without Glasdegib In Patients With Previously Untreated Acute Myeloid Leukemia

Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollmentinto the Intensive and Non Intensive study (unless where indicated):

1. Subjects with untreated AML according to the World Health Organization (WHO) 2016Classification2, 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) 3x upper limit of normal (ULN), excluding subjects with liver functionabnormalities due to underlying malignancy.
• Total serum bilirubin 2 x ULN (except subjects with documented Gilbert'ssyndrome).
• Estimated creatinine clearance 30 mL/min as calculated using the standard methodfor the institution.

4. QTc interval 470 msec using the Fridericia correction (QTcF).
5. All anti cancer treatments (unless specified) should be discontinued 2 weeks fromstudy 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 afterthe first dose of glasdegib.

6. Serum or urine pregnancy test (for female subjects of childbearing potential) with aminimum 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 mustagree to use at least one highly effective method of contraception throughout thestudy and for 180 days after the last dose of azacitidine, cytarabine, ordaunorubicin; 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 followingcriteria:
9. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
10. Have medically confirmed ovarian failure; or
11. Achieved postmenopausal status, defined as follows: cessation of regular mensesfor at least 12 consecutive months with no alternative pathological orphysiological cause; status may be confirmed by having a serum folliclestimulating hormone (FSH) level confirming the postmenopausal state. All other female subjects (including female subjects with tubal ligations) areconsidered to be of childbearing potential.
12. Consent to a saliva sample collection for a germline comparator, unless prohibited bylocal regulations or ethics committee (EC) decision.
13. Evidence of a personally signed and dated informed consent document indicating thatthe patient has been informed of all pertinent aspects of the study.
14. Subjects who are willing and able to comply with the study scheduled visits, treatmentplans, 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 thestudy:

1. Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016classification).
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 perInstitutional Guidelines, or a patient who refuses blood product support.
6. Subjects with another active malignancy on treatment with the exception of basal cellcarcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior orconcurrent 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 (includingsustained ventricular tachyarrhythmia), right or left bundle branch block andbifascicular 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 uncontrolledsystemic infection not related to AML.
9. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from theIntensive Chemotherapy Study only.
10. Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for theIntensive Chemotherapy Study only.
11. Known malabsorption syndrome or other condition that may significantly impairabsorption of study medication in the investigator's judgment (eg, gastrectomy, lapband, Crohn's disease) and inability or unwillingness to swallow tablets or capsules.
12. Current use or anticipated requirement for drugs that are known strong CYP3A4/5inducers.
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 suspectedhypersensitivity to cytarabine (not including drug fever or exanthema, includingknown cerebellar side effects) or daunorubicin.
• For subjects assigned to non intensive chemotherapy, documented or suspectedhypersensitivity to azacitidine or mannitol.

16. Known active drug or alcohol abuse.
17. Other acute or chronic medical or psychiatric condition including recent (within thepast year) or active suicidal ideation or behavior or laboratory abnormality that mayincrease the risk associated with study participation or investigational productadministration or may interfere with the interpretation of study results and, in thejudgment of the investigator, would make the subject inappropriate for entry into thisstudy.
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 andtheir family members, site staff members otherwise supervised by the investigator, orsubjects who are Pfizer employees, including their family members, directly involvedin the conduct of the study.