A Phase III study to evaluate the safety and efficacy of CPI-613® (devimistat) in combination
with High Dose Cytarabine and Mitoxantrone in comparison with high dose Cytarabine and
Mitoxantrone in older patients with relapsed/refractory Acute Myeloid Leukemia. CPI-613®
(devimistat) targets the altered energy metabolism and processes for production of ATP and
essential bio-intermediates unique to and characteristic of most cancer cell types. The
addition of CPI-613® (devimistat) to high dose cytarabine and mitoxantrone (CHAM) will
improve the complete remission (CR) rate in patients 50 years or older with relapsed or
refractory AML when compared to HAM alone.
1. Patient has provided an informed consent prior to initiation of any study specific
2. Males and females age ≥ 50 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. Persistent disease after one cycle of standard dose cytarabine (defined as no
decrease in marrow blast percentage from diagnosis on Day 14 marrow) or,
3. Persistent disease after at least 2 cycles of a hypomethylating agent
(azacytidine or decitabine) with or without venetoclax
4. 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.
5. ECOG PS 0-2
6. Expected survival greater than 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 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 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).
8. 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.
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 1 week prior to treatment with CPI-613®
(devimistat). 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
- 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) or
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).
15. 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
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 is allowed. Targeted therapies
including FLT3 or IDH1/2 inhibitors or Hydrea or venetoclax are allowed. Targeted
therapies and Hydrea may be taken until the day prior to starting CHAM or HAM therapy)
2. Vulnerable adult and patient whose health conditions does not allow them to give their
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 (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 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.
9. 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
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
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
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 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).
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.
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.
24. Cytarabine contraindications
- Hypersensitivity to the cytarabine or to any of the excipients of cytarabine
- 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
- Mitoxantrone Sterile Concentrate should not be used during pregnancy or