Study of Standard Intensive Chemotherapy Versus Intensive Chemotherapy with CPX-351 in Adult Patients with Newly Diagnosed AML and Intermediate- or Adverse Genetics

Patient Inclusion Criteria:

1. Patients with newly diagnosed AML and intermediate- or adverse-risk genetics (according to 2017 ELN criteria [Appendix B]), including AML withmyelodysplasia-related changes (AML-MRC) and therapy-related AML according to theWorld Health Organization (WHO) classification

2. Age ≥ 18 years, no upper age limit

3. Patient considered eligible for intensive chemotherapy

4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening

5. Genetic assessment in AMLSG central laboratory

6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × ULN or creatinineclearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR)

7. Adequate hepatic function as evidenced by:

• Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) unless considered dueto Gilbert's disease, or leukemic involvement following approval by theCoordinating Investigator or Co-Coordinating Investigator

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkalinephosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvementfollowing approval by the Coordinating Investigator or Co-CoordinatingInvestigator

8. No prior chemotherapy for acute leukemia except hydroxyurea for up to 14 days duringthe diagnostic screening phase for the control of peripheral leukemic blasts inpatients with leukocytosis (e.g., white blood cell [WBC] counts >30x109/l); priortreatment of myelo-dysplastic syndrome with hypomethylating agents is allowed

9. Non-pregnant and non-nursing women of childbearing potential (WOCBP) must have anegative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mLwithin 72 hours prior to randomization ("Women of childbearing potential" is definedas a sexually active mature woman who has not undergone a hysterectomy or bilateraloophorectomy or who has had menses at any time in the preceding 24 consecutivemonths)

10. Female patients of childbearing potential must agree to avoid getting pregnant whileon therapy and for 27 weeks after the last dose of study drug

11. Women of childbearing potential must either commit to continued abstinence fromheterosexual intercourse or apply one highly effective method of birth control (suchas IUD, bilateral tubal ligation, or partner's vasectomy) in combination with oneacceptable method of birth control at the same time (such as hormonal contraceptionor the male partner has to use a latex condom coated with spermicide lubricant orcombined with spermicide gel or foam) while on therapy and for 27 weeks after thelast dose of study drug. Hormonal contraception is only a highly effective method ofbirth control in case of combined (estrogen and progestogen containing) associatedwith inhibition of ovulation or progestogen-only hormonal contraception associatedwith inhibition of ovulation is used

12. Men must use a latex condom coated with a spermicide lubricant or combined withspermicide gel or foam during any sexual contact with women of childbearingpotential, even if they have undergone a successful vasectomy and must agree toavoid to father a child (while on therapy and for 6 months after the last dose ofstudy drug). In addition, their female partners of childbearing potential have touse a highly effective method of birth control

13. Able to understand and willing to sign an informed consent form (ICF)

Patient Exclusion Criteria:

1. AML with favorable-risk genetics according to 2017 ELN criteria [Appendix B]:

• AML with t(8;21)(q22;q22.1), RUNX1-RUNX1T1

• AML with inv(16)(p13.1q22)/t(16;16)(p13.1;q22), CBFB-MYH11

• AML with mutated NPM1 without FLT3-ITD or with FLT3-ITDlow

• AML with biallelic CEBPA mutation

2. AML with FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD andFLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratioof ≥ 0.05 (5%).

3. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of theother pathognomonic variant chromosomal translocations/ fusion genes

4. AML with BCR-ABL1

5. Prior treatment of myelodysplastic syndrome (MDS) with intensive chemotherapy orbone marrow transplant with a curative intent

6. Significant active cardiac disease within 6 months prior to the start of studytreatment, including New York Heart Association (NYHA) class III or IV congestiveheart failure; myocardial infarction, unstable angina and/or stroke; severe cardiacarrhythmias, or left ventricular ejection fraction (LVEF) <50% by ultrasoundobtained within 28 days prior to the start of study treatment

7. Severe obstructive or restrictive ventilation disorder

8. Uncontrolled infection

9. Clinical symptoms suggestive of active central nervous system (CNS) leukemia orknown CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is onlyrequired, if there is a clinical suspicion of CNS involvement by leukemia duringscreening

10. Evidence of active hepatitis B or C infection or known Human Immunodeficiency Virus (HIV) infection

11. Patients with a "currently active" second malignancy. Patients are not considered tohave a currently active malignancy, if they have completed therapy and areconsidered by their physician to be at < 30% risk of relapse within one year.However, subjects with the following history/concurrent conditions are allowed:

• Basal or squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer

12. Severe neurological or psychiatric disorder interfering with ability to give aninformed consent

13. No consent for registration, storage and processing of the individual diseasecharacteristics and course as well as information of the family physician aboutstudy participation

14. No consent for biobanking of patient's biological specimens

15. Current participation in any other interventional clinical trial within 30 daysbefore the first administration of the investigational product or at any time duringthe trial

16. Patients with prior cumulative anthracycline exposure of daunorubicin (orequivalent) can be included but the maximum of daunorubicin (or equivalent) dose of 550 mg/m2 must not be exceeded. Anthracycline-based therapy should be avoided untilexposure to the previous cardiotoxic agents is negligible. If this is not possible,the patient's cardiac function should be carefully monitored and an absolutecumulative dose of 400 mg/m² in adults can be exceeded only with great caution. Inpatients who received radiation therapy to the mediastinum the maximum ofdaunorubicin (or equivalent) dose of 400 mg/m2 must not be exceeded.

17. Known or suspected hypersensitivity to cytarabine, daunorubicin or liposomalproducts and/or any excipients

18. History of Wilson's disease or other copper-metabolism disorder

19. Receipt of live, attenuated vaccine within 30 days prior to the inclusion in theclinical trial (NOTE: Subjects, if enrolled, should not receive live vaccine duringthe trial and until 6 months after the therapy).