| Eligibility |
INCLUSION CRITERIA:
1. Patient has provided an informed consent prior to initiation of any study specific
activities/procedures
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. 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
2. 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 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)
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 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
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) 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 > 480 ms for both male and 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
Korea)
EXCLUSION CRITERIA:
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
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