Study Evaluating Efficacy and Safety of CPI-613 in Combination With HD Cytarabine and Mitoxantrone vs HD Cytarabine and Mitoxantrone in Older Patients With R/R AML

INCLUSION CRITERIA:

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

2. Males and females age ≥ 60 years must have histologically documented AML that is
relapsed from, or refractory to, prior standard therapies.

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

1. Two standard dose Cytarabine based induction cycles or one HiDAC based cycle, or

2. Failure to respond to one cycle of either standard dose or HiDAC (defined as no
decrease in marrow blast percentage from diagnosis on Day 14 marrow), or

3. No response after at least 3 cycles of a hypomethylating agent (azacytidine or
decitabine).

4. Relapse is defined as development of recurrent AML (as described by Döhner et al,
2010)6 after CR or CRi has been achieved with a prior chemotherapy or after disease
progression on a hypomethylating agent.

5. ECOG PS 0-2.

6. Expected survival >3 months.

7. Women of child-bearing potential (i.e. women who are pre-menopausal or < 2 years post
menopausal or not surgically sterile) must use 2 effective contraceptive methods
(abstinence, intrauterine device [IUD], oral contraceptive, injectable or implantable
agent/device or double barrier device (diaphragm + spermicide) during and for 6 months
after the last administered dose of CHAM or HAM therapy, and must have a negative
serum pregnancy test within 1 week prior to treatment initiation (Note: pregnant
patients are excluded because the effects of CPI 613 on a fetus are unknown).

8. Fertile men must practice effective contraceptive methods (condom + spermicide) during
the study period and up to 6 months after completion of the study screening, unless
documentation of infertility exists.

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

10. No radiotherapy, treatment with cytotoxic chemotherapy, treatment with biologic agents
or any anti-cancer therapy within the 2 weeks prior to treatment with CPI 613.
Hydroxyurea and oral tyrosine kinase (FLT3) or Isocitrate Dehydrogenase 1 and 2
(IDH1/2) inhibitors being used with Grade ≤ 2 toxicity can be taken until the day
prior to starting study therapy. Previous exposure to a hypomethylating agent either
alone or in combination with Venetoclax is allowed. 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.

11. 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).

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

13. No marked baseline prolongation of QT/QTc interval (repeated exhibition of a QTc
interval > 450 ms for male and > 470 ms for female patients).

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

EXCLUSION CRITERIA:

1. Patients who have received previous cytotoxic chemotherapy treatment for their
relapsed or refractory AML. Previous treatment with hypomethylating agents (decitabine
or azacytidine) either alone or in combination with Venetoclax is allowed. Targeted
therapies including FLT3 or IDH1/2 inhibitors or Hydrea are allowed. Targeted
therapies and Hydrea may be taken until the day prior to starting CHAM or HAM therapy.

2. 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.

3. Patients with active Central Nervous System (CNS) involvement (leukemic infiltration,
blast in the spinal fluid).

4. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g.
active peptic ulcer disease).

5. 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 (the teratogenic potential of CPI-613 is unknown). Female patients of
childbearing potential with a positive pregnancy test assessed by a serum pregnancy
test at Screening.

6. Female patients of childbearing potential unwilling to use 1 highly effective method
of contraception during treatment and for 6 months after completion of CHAM or HAM
therapy for AML.

7. 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.

8. Male patients unwilling to abstain from donating sperm during treatment and for 6
months after completion of CHAM or HAM therapy with potential highest teratogenic
risk.

9. Patient has known sensitivity to any of the CHAM or HAM medications to be administered
during dosing.

10. Life expectancy less than 3 months.

11. Any condition or abnormality which may, in the opinion of the investigator, compromise
the safety of patients.

12. Unwilling or unable to follow protocol requirements.

13. Patients with large and recurrent pleural or peritoneal effusions requiring frequent
drainage (e.g. weekly).

14. Patients with any amount of clinically significant pericardial effusion that requires
drainage.

15. Evidence of ongoing, uncontrolled bacterial, viral or fungal infection.

16. Patients with known human immunodeficiency virus infection.

17. 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.

18. Patients receiving any other standard or investigational treatment for AML, or any
other investigational agent for any indication within the past 2 weeks prior to
initiation of CPI-613 treatment (the use of Hydrea and/or oral tyrosine kinase
inhibitors FLT3 or IDH 1/2 inhibitors is allowed until the day prior to starting CHAM
or HAM therapy). Previous exposure to a hypomethylating agent either alone or in
combination with Venetoclax is allowed.

19. Patients who have received immunotherapy of any type within the past 2 weeks prior to
initiation of CPI-613 treatment.

20. Requirement for immediate palliative treatment of any kind including minor surgery.

21. Patients who have received a chemotherapy regimen with autologous stem cell support
(bone marrow transplantation) within 6 months of starting CHAM or HAM therapy.

22. Patients who have had allogenic bone marrow transplantation.