GLAD-AML - Glasdegib (Pf-04449913) With Two Standard Decitabine Regimens for Older Patients With Poor-risk Acute Myeloid Leukemia
Condition: ACUTE MYELOID LEUKEMIA
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Glasdegib; Decitabine
Intervention description: Glasdegib will be administered at the starting dose of 100 mg orally once daily.; Decitabine will be administered per local label and will be administered by IV infusion at a dose of 20 mg/m2/day for either 5 days or 10 days as determined by randomization. Each cycle will be every 28 days.
Intervention MeSH terms: Decitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This multi-center, randomized phase 2 study is designed to evaluate the complete remission
      (including complete remission with incomplete count recovery) rates of glasdegib in
      combination with either decitabine on a 5-day or 10-day schedule in patients with
      newly-diagnosed poor-risk AML who either refuse or are ineligible for intensive therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have a morphologically-confirmed diagnosis of AML according to WHO 2016
             classification with poor-risk disease as defined by the cytogenetic or molecular
             abnormalities (excluding FLT3-mutated AML).

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.

          -  Adequate Renal Function:

             a. Calculated creatinine clearance (determined by MDRD) ≥50mL/min/1.73m2, or serum
             creatinine <1.5x upper limit of normal (ULN);

          -  Adequate Liver Function:

               1. Total serum bilirubin ≤ 2.0 x ULN (unless the bilirubin is principally
                  unconjugated and there is strong suspicion of sub-clinical hemolysis or the
                  patient has documented Gilbert's disease);

               2. Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3.0 x ULN;

               3. Alkaline phosphatase ≤ 3.0 x ULN.

          -  Serum or urine pregnancy test (for female patients of childbearing potential) with a
             minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin
             (HCG) negative at screening.

          -  Males and female patients both of childbearing potential and at risk for pregnancy
             must agree to use two highly effective method(s) of contraception throughout the study
             and for 180 days after the last dose of decitabine and the last dose of glasdegib,
             whichever occurs later.

          -  Female patients who are not of childbearing potential (i.e. meet at least 1 of the
             following criteria):

               1. Have undergone a documented hysterectomy and/or bilateral oophorectomy;

               2. Have medically confirmed ovarian failure;

               3. Have 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 within the laboratory's reference range for
                  postmenopausal women.

        Exclusion Criteria:

          -  Patients who are candidates for and willing to receive intensive induction
             chemotherapy.

          -  Prior use of a hypomethylating agent.

          -  Prior use of cytotoxic chemotherapy for any myeloid malignancy (prior
             immunosuppressive therapy is permitted provided that treatment is stopped within 8
             weeks from study entry; hydroxyurea is allowed through the end of cycle 1 on study).

          -  Previous hematopoietic stem cell transplant.

          -  Prior treatment with a licensed or experimental smoothened inhibitor (SMOi) and/or
             hypomethylating agent (HMA).

          -  Participation in a clinical study involving an investigational drug(s) (Phases 1-4)
             within 4 weeks prior to study entry or within 5 half-lives of the investigational
             agent, whichever is greater.

          -  Major surgery or radiation within 12 weeks prior to study entry.

          -  Patients known to be refractory to platelet or packed red cell transfusions as per
             institutional guidelines, or who are known to refuse or who are likely to refuse blood
             product support.

          -  Treatment with hematopoietic growth factors including: erythropoietin, granulocyte
             colony stimulating factor (G-CSF), and granulocyte macrophage colony stimulating
             factor (GM-CSF), or thrombopoietin receptor agonists within 3 weeks prior to study
             entry.

          -  Any ongoing medical condition requiring chronic use of moderate to high dose steroids
             (defined as ≥10 mg/day of prednisone or equipotent dose of another corticosteroid).

          -  Any anti-cancer treatment within 2 weeks prior to study entry (including hydroxyurea
             as above).

          -  Current use or anticipated requirement for drugs that are known moderate to strong
             CYP3A4 inducers (Appendix 2).

          -  Presence of concurrent active malignancy requiring active systemic therapy

          -  Patients with known active, uncontrolled bacterial, fungal or viral infection,
             including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus
             (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.

          -  Known uncontrolled central nervous system (CNS) involvement.

          -  Poorly-controlled active medical conditions that as per investigator judgement would
             interfere with the conduct of the study.

          -  Active cardiac dysrhythmias of NCI CTCAE Grade ≥2 (e.g. atrial fibrillation) or QTcF
             interval >470 msec.

          -  Pregnant or breastfeeding female patients.