This phase III trial is trying to determine if the addition of a new drug (CPI-613) to high-dose chemotherapy (CHAM) will improve the likelihood of remission in patients who are greater than 60 years old and have acute myeloid leukaemia that has got worse or not responded to other treatmentsPhase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613 in Combination With High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥60 Years) With Relapsed/Refractory Acute Myeloid Leukemia (AML)

Exclusion

1. Patients who have received cytotoxic chemotherapy treatment for their current relapsed or refractory AML. (Treatment with hypomethylating agents (decitabine or azacytidine) either alone or in combination with venetoclax are allowed until the day prior to starting of CHAM or HAM therapy and control sub-groups (MEC and FLAG). Targeted therapies including FLT3 or IDH1/2 inhibitors and/or Hydrea and/or venetoclax are allowed. Targeted therapies and Hydrea may be taken until the day prior to starting CHAM or HAM therapy or control sub-groups (MEC and FLAG)
2. Vulnerable adult and patient whose health conditions does not allow them to give their consent
3. History or evidence of any other clinically significant disorder, condition or disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, symptomatic myocardial infection, uncontrolled cardiac arrhythmia, pericardial disease or heart failure New York Heart Association Class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients' risk for toxicity and in the opinion of the Investigator, would pose a risk to patient safety or interfere with the study evaluation, procedures or completion
4. Patients with active Central Nervous System (CNS) involvement (leukemic infiltration, blast in the spinal fluid)
5. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g. active peptic ulcer disease)
6. Female patients who are pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of CHAM or HAM therapy or control sub-groups, MEC and FLAG (the teratogenic potential of CPI-613® (devimistat) is unknown). Female patients of childbearing potential with a positive pregnancy test assessed by a serum pregnancy test at Screening
7. Women of childbearing potential (i.e. women who are pre-menopausal or < 2 years postmenopausal or not surgically sterile) unwilling to practice a highly effective method of birth control consistent with local regulations regarding the use of birth control methods during treatment and for 6 months after completion of CHAM or HAM therapy or control sub-groups, MEC and FLAG for AML
8. Male patients with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for 6 months after completion of CHAM or HAM therapy or control sub-groups, MEC and FLAG
9. Male patients unwilling to abstain from donating sperm during treatment and for 6 months after completion of CHAM or HAM therapy or control sub-groups, MEC and FLAG with potential highest teratogenic risk
10. Known hypersensitivity to study treatment drugs or any of the excipient(s) contained in the drug formulation
11. Life expectancy less than 3 months
12. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
13. Unwilling or unable to follow protocol requirements
14. Patients with large and recurrent pleural or peritoneal effusions requiring frequent drainage (e.g. weekly)
15. Patients with any amount of clinically significant pericardial effusion that requires drainage.
16. Evidence of ongoing, uncontrolled bacterial, viral or fungal infection
17. Patients with known human immunodeficiency virus infection

18. History of other malignancy within the past 5 years, with the following exception(s):

    1. Malignancy treated with curative intent and with no known active disease present for ≥ 5 years before enrolment and felt to be at low risk for recurrence by the treating physician
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of recurrent or residual disease
    3. Adequately treated cervical carcinoma in situ without evidence of disease
    4. Prostate cancer Stage 1
19. Patients receiving any other standard or investigational treatment for AML, or any other investigational agent for any indication within the past 1 week prior to initiation of CPI-613® (devimistat) treatment (the use of Hydrea and/or venetoclax, oral tyrosine kinase inhibitors FLT3 or IDH 1/2 inhibitors are allowed until the day prior to starting CHAM or HAM therapy or control sub-groups, MEC and FLAG. Previous exposure to a hypomethylating agent either alone or in combination with venetoclax are allowed until the day prior to starting of CHAM or HAM therapy and control sub-groups (MEC and FLAG))
20. Patients who have received immunotherapy of any type within the past 1 week prior to initiation of CPI-613® (devimistat) treatment
21. Requirement for immediate palliative treatment of any kind including minor surgery
22. Patients who have received a chemotherapy regimen with autologous stem cell support (bone marrow transplantation) within 6 months of starting CHAM or HAM therapy or control sub-groups (MEC and FLAG)
23. Patients who have had allogenic bone marrow transplantation within the last 6 months. Patients who have had an allogenic transplant more than 6 months ago are eligible provided they have no graft vs host disease. (Note: Exclude only patients with active GVHD requiring therapy with immunosuppressive agents and not patients with stable GVHD not requiring immunosuppression.)

24. Cytarabine contraindications

    • Hypersensitivity to the cytarabine or to any of the excipients of cytarabine injection
    • Anemia, leucopenia and thrombocytopenia of non-malignant aetiology (e.g bone marrow aplasia); unless the clinician feels that such management offers the most hopeful alternative for the patient
    • Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation

25. Mitoxantrone contraindications

    • Mitoxantrone Sterile Concentrate is contraindicated in patients who have demonstrated prior hypersensitivity to mitoxantrone hydrochloride, other anthracyclines or any of its components. Use in patients with profound bone marrow suppression is a relative contraindication depending on the clinical circumstances
    • Mitoxantrone Sterile Concentrate should not be used during pregnancy or lactation
26. Strong CYP450 inducers should be prohibited

27. Etoposide contraindications

    •. Contraindicated in patients with a history of a severe hypersensitivity reaction to etoposide products

28. Fludarabine contraindications

    •. Contraindicated in those patients who are hypersensitive to this drug or its components

29. Filgrastim contraindications •. Contraindicated in patients with known hypersensitivity to E coli-derived proteins, Filgrastim, or any component of the product