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

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 population).

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 population).

• Drug: glasdegib

  Daily Glasdegib (100 mg, PO), beginning on Day 1 and is to continue up to 2 years post randomization.

  Following consolidation therapy, glasdegib or placebo will be administered daily for up to 2 years after randomization or until they have minimal residual disease (MRD) negative disease, whichever comes first.

  Daily Glasdegib (100 mg, PO) or matching placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy.

  Other Name: PF-04449913
• Drug: daunorubicin + cytarabine

  '7+3' (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days).

  If a second induction is needed, Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days ('5+2') or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days ('7+3');

• Drug: azacitidine
  Azacitidine (75 mg/m2, SC or IV) daily for 7 days, in 28 day cycles for as long as they do not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal, or death.
• Drug: Placebo

  Matching placebo (PO) given on Day 1 and is to continue up to 2 years post randomization. Following consolidation therapy, placebo will be administered daily for up to 2 years after randomization or until they have MRD negative disease, whichever comes first.

  Daily placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy.

• Drug: Placebo
  Matching placebo (PO) is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment. Subjects will continue placebo until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.
• Drug: glasdegib

  Glasdegib 100 mg PO QD is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment.

  Subjects will continue glasdegib until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.

• Drug: cytarabine
  Consolidation with single agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1, 3, and 5, every 28 days for up to 4 cycles or alternative single agent cytarabine consolidation schedules may be used per local prescribing information.
• Procedure: HSCT
  If required, and done per standard of care post Induction(s).

• Experimental: Arm A (Intensive Study)
  Glasdegib + '7+3' Induction(s)
  Interventions:

  • Drug: glasdegib
  • Drug: daunorubicin + cytarabine
  • Drug: cytarabine
  • Procedure: HSCT
• Placebo Comparator: Arm B (Intensive Study)
  Placebo + '7+3' Induction(s)
  Interventions:

  • Drug: daunorubicin + cytarabine
  • Drug: Placebo
  • Drug: cytarabine
  • Procedure: HSCT
• Experimental: Arm A (Non-intensive study)
  Glasdegib + azacitidine
  Interventions:

  • Drug: azacitidine
  • Drug: glasdegib
• Placebo Comparator: Arm B (Non-intensive study)
  Placebo + azacitidine
  Interventions:

  • Drug: azacitidine
  • Drug: Placebo

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):

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 syndrome).
   • 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 criteria:

   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).

Exclusion Criteria:

Subjects with any of the following characteristics/conditions will not be included in the study:

1. Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016 classification).

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 inducers.
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 study.
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.