Phase 3 Multicenter Randomized Trial to Evaluate Efficacy and Safety of CPI-613 in Combination With HD Cyt. and Mito. vs HD Cyt. and Mito. Therapy and Control Sub-groups in Older Patients With R/R AML

• Patient has provided an informed consent prior to initiation of any study specific activities/procedures

• Males and females age ≥ 50 years must have histologically documented AML that is relapsed from, or refractory to, prior standard therapies

• Refractory is defined as failure to achieve CR or CRi following:

∙ At least one cycle of any anthracycline, cytarabine or fludarabine containing induction regimen or persistence of disease on a nadir marrow following at least one cycle of any anthracycline, cytarabine or fludarabine containing induction regimen

‣ Persistent disease after at least 2 cycles of a hypomethylating agent (azacytidine or decitabine) with or without venetoclax

• Relapse is defined as development of recurrent AML (as described by Döhner et al, 2017)6 after CR or CRi has been achieved with a prior chemotherapy or after disease progression on a hypomethylating agent with or without venetoclax

• ECOG PS 0-2

• Expected survival greater than 3 months

• Women of child-bearing potential (i.e. women who are pre-menopausal or \< 2 years post menopausal or not surgically sterile) must practice a highly effective method of birth control consistent with local regulations regarding the use of birth control methods. Examples: use of oral, injected or implanted hormonal methods of contraception; placement of an intra uterine device (IUD) or intrauterine system (IUS); male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence during and for 6 months after the last administered dose of CHAM or HAM therapy and control sub-groups (MEC and FLAG), and must have a negative serum pregnancy test within 1 week prior to treatment initiation and at 1st day of each cycle and at the end of systemic exposure. (Note: pregnant patients are excluded because the effects of CPI-613® (devimistat) on a fetus are unknown)

• Fertile men who are sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during the study period and up to 6 months after completion of the study screening, unless documentation of infertility exists

• Good state of mental health, ability to understand and willingness to sign the informed consent form (ICF)

⁃ No radiotherapy, treatment with cytotoxic chemotherapy, treatment with biologic agents or any anti-cancer therapy for R/R AML within the 1 week prior to treatment with CPI-613® (devimistat). Hydroxyurea and/or venetoclax and oral tyrosine kinase (FLT3) or Isocitrate Dehydrogenase 1 and 2 (IDH1/2), BCL-2 or hedgehog inhibitors being used with Grade ≤ 2 toxicity can be taken until the day prior to starting of CHAM or HAM therapy or control sub-groups (MEC and FLAG). Previous exposure to a hypomethylating agent either alone or in combination with Isocitrate Dehydrogenase 1 and 2 (IDH1/2), BCL-2 or hedgehog inhibitors are allowed until the day prior to starting of CHAM or HAM therapy and control sub-groups (MEC and FLAG). Patients must have fully recovered from the acute, non-hematological, non-infectious toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities with the exception of alopecia (returned to baseline status as noted before most recent treatment). Patients with persisting, non-hematologic, non-infectious toxicities from prior treatment Grade ≤ 2 are eligible but must be documented as such

⁃ Laboratory values ≤ 2 weeks before dosing must be:

∙ Adequate hepatic function (aspartate aminotransferase/serum glutamic-oxaloacetic transaminase \[AST/SGOT\] ≤ 5 x upper limit of normal \[ULN\], alanine aminotransferase/serum glutamic oxaloacetic transaminase \[ALT/SGPT\] ≤ 5 × ULN, bilirubin ≤ 1.5 × ULN)

‣ Adequate renal function (serum creatinine clearance ≥ 60 mL/min per CockCroft Gault formula)

‣ Adequate coagulation (International Normalized Ratio \[INR\] must be \< 1.7 unless on vitamin k antagonist anticoagulation)

⁃ Left Ventricular Ejection Fraction (LVEF) by Transthoracic Echocardiogram (TTE) or Multigated Acquisition Scan (MUGA) or cardiac Magnetic Resonance Imaging (MRI), sufficient to safely administer mitoxantrone. Subjects must have an LVEF ≥ 45%

⁃ No marked baseline prolongation of QT/QTc interval (repeated exhibition of a QTc interval \> 480 ms for both male and female patients)

⁃ No history of additional risk factors for torsade de pointes (e.g. clinically significant heart failure, hypokalemia, immediate family history of Long QT Syndrome)

⁃ Allow only patients who experienced relapse after 1 year from previous HiDAC treatment or who didn't receive HiDAC previously (Note: This inclusion applies only to South Korea)