CPX-351 and Glasdegib for Newly Diagnosed Acute Myelogenous Leukemia With MDS Related Changes or Therapy-related Acute Myeloid Leukemia

Inclusion Criteria:

• Previously untreated therapy-related AML or AML with myelodysplastic related changesas described by World Health Organization (WHO) 2016

1. AML arising in MDS (including CMML) or MDS/MPN syndrome

2. AML with MDS-related cytogenetic abnormalities (Appendix A, metaphase FISHallowable as surrogate for cytogenetics)

3. AML with multi-lineage dysplasia involving the presence of 50% or moredysplastic cells in at least two cell lines and in the absence of mutation inNPM1 or biallelic CEBPA (as per WHO 2016)

• Adults 18 years of age or older

• ECOG performance status 0 to 2

• Adequate organ function as defined as:

1. Left Ventricular Ejection Fraction (LVEF) > 50%

2. Serum total bilirubin < 2.0 mg/dL, unless considered due to Gilbert's diseaseor leukemic involvement

3. AST, ALT and alkaline phosphatase < 3 times the upper limit of normal, unlessconsidered due to leukemic involvement

4. Serum creatinine < 2.0 mg/dL, or creatinine clearance > 40 mL/min based onCockcroft-Gault GFR

• Absence of unstable cardiac disease defined as myocardial infarction within 6months, uncontrolled heart failure, or uncontrolled cardiac arrhythmia

• Ability to understand and the willingness to sign a written informed consent orsubject's legally authorize representative (LAR) has provided informed consent priorto any study-specific activities/procedures being initiated when the subject has anykind of condition that, in the opinion of the investigator, may compromise theability of the subject to give written informed consent

• Women of child-bearing potential and men with partners of child-bearing potentialmust agree to use 2 methods of birth control or be surgically sterile, or abstainfrom heterosexual activity for the course of the study through 120 days after thelast dose of study medication

1. A woman of child-bearing potential is any female (regardless of sexualorientation, having undergone a tubal ligation, or remaining celibate bychoice) who meets the following criteria:

2. Has not undergone a hysterectomy or bilateral oophorectomy; or

3. Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

4. Women of child-bearing potential has negative pregnancy test within 72 hours ofinitiating study drug dosing

5. Male subjects must agree to use a latex condom during sexual contact withfemales of childbearing potential even if they have had a successful vasectomystarting with the first dose of study therapy through 120 days after the lastdose of study therapy

• Leukapheresis, corticosteroid and hydroxyurea are permitted as initial management ofhyperleukocytosis at the investigator's discretion for up to 7 days after startingstudy therapy. Hyperleukocytosis is defined as greater than 30k WBC. When possible,a bone marrow biopsy for screening should be performed prior to the initiationhyperleukocytosis

Exclusion Criteria:

• Prior treatment with Glasdegib or CPX-351

• Previously treated AML except for initial management of hyperleukocytosis. Treatmentwith hypomethylating therapy for MDS is allowable but not since their diagnosis ofAML. No prior treatment with cytarabine or daunorubicin are allowed

• Concurrent FLT3 mutation that the treating physician deems necessary to treat withmidostaurin, whereas patients with FLT3-mutated AML not treated with midostaurin canbe enrolled. Patients with known Core Binding Factor -t(8;21), inv(16), t(16;16) areallowed for study participation at the treating investigator's discretion

• Active CNS or testicular involvement by leukemia; diagnostic lumbar puncture is notrequired

• History of neurologic disorder including but not limited to: prior seizure,epilepsy, structural brain abnormality, benign brain tumor, stroke, brain injuries,dementia, movement disorder or other significant CNS abnormalities

• Baseline QT corrected interval based on Fridericia's formula (QTcF) interval > 450ms

• Acute coronary syndrome in the past 12 months, NYHA class III or VI

• Known history of Wilson's disease or other copper handling disorder

• History of GI malabsorptive disease

• Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of theskin, or in situ cervical cancer that has undergone potentially curative therapy

• Known HIV infection

• Active hepatitis B or hepatitis C infection (patients who successfully completedcurative hepatitis C therapy can be enrolled)

• Any uncontrolled infection, active bacterial or viral infection manifesting asfevers or hemodynamic instability within the past 72 hours

• Proven active invasive fungal infection

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 120 days after the last dose of trial treatment

• Severe or uncontrolled medical disorder that would, in the investigator's opinion,impair ability to receive study treatment (i.e., uncontrolled diabetes, chronicrenal disease, chronic pulmonary disease or active, uncontrolled infection,psychiatric illness/social situations that would limit compliance with studyrequirements

• Current or anticipated use of other investigational agents

• For patients with prior anthracycline exposure, the cumulative life-time dose shouldnot exceed 386mg/m2 at the time of study entry (to convert different anthracyclineto daunorubicin-equivalent, see Appendix H for conversion factors)