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 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