Details

Details

Title 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

IRB PFIZ 2918

CC 18-609

Hospital Main Campus

Disease Leukemia - Acute Myeloid (AML)

Drug Azacitidine, Glasdegib

Description

Description

Primary Objective
  • To demonstrate that glasdegib is superior to placebo in combination with azacitidine (non-intensive study) or cytarabine and daunorubicin (intensive study) in prolonging OS in subjects with untreated AML.
Secondary Objectives
  • To compare fatigue score post-baseline as measured by MDASI-AML/MDS in both treatment arms;
  • To compare glasdegib versus placebo in combination with azacitidine (non-intensive study) or '7+3' (cytarabine and daunorubicin) in improving other clinical efficacy measures;
  • To estimate the duration of response in both treatment arms;
  • To estimate the time to response in both treatment arms in the Non-intensive study only;
  • To compare Event-free Survival (EFS) in both treatment arms;
  • To compare PRO measurements in both treatment arms;
  • To evaluate the overall safety profile in both treatment arms;
  • To evaluate laboratory abnormalities in both treatment arms;
  • To characterize the PK of glasdegib;
  • To characterize treatment effects on the QTc interval.
Exploratory Objectives
  • Bone marrow and blood biomarkers of response and/or resistance to glasdegib in combination with azacitidine or daunorubicin and cytarabine;
  • PROs for symptomatic AEs;
  • To collect banked bio specimens for exploratory research, unless prohibited by local regulations or ethics committee decision.
Inclusion Criteria

Inclusion Criteria

  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:
    • 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.
  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

Exclusion Criteria

  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 (Appendix 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 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.