| Eligibility |
Inclusion Criteria:
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
2. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.
3. Subject is = 18 years of age at the time of signing the ICF.
4. Subject has either primary (ie, de novo) or secondary (associated with myelodysplastic
syndrome [MDS], myeloproliferative neoplasms [MPN], or prior therapy with hematotoxins
and/or radiation {ie, therapy-related disease}) AML according to the WHO
classification.
5. Subject either:
a. has received at least first line of AML therapy and any number of subsequent
lines/regimens Note: For subjects having AML secondary to prior higher risk
[Intermediate-2 or High risk according to the International Prognostic Scoring System]
MDS treated with a hypomethylating agent [eg, azacitidine or decitabine], the
hypomethylating therapy can be counted as a line/regimen if there is disease
progression to AML during or shortly [eg, within 60 days] after the hypomethylating
therapy.); or b. has never been treated for AML, but has declined standard of care
chemotherapy.
6. Subject has the following disease status:
1. Refractory to, or relapsed after first, second, or third line regimen of
intensive therapy for AML (eg, the "7 + 3" protocol) with at least 5% leukemic
blasts in bone marrow (the minimum number of treatment cycles of the intensive
therapy is per the investigator's discretion); or
2. Refractory to, or relapsed after first, second or third line low-intensity AML
therapy (eg, low dose cytarabine (LDAC), azacitidine or decitabine) with at least
5% leukemic blasts in bone marrow after at least 2 treatment cycles; or
7. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
8. Subject has IDH2 gene mutations revealed by local testing in samples of bone marrow
aspirate and/or peripheral blood, and confirmed positive in bone marrow aspirate
and/or peripheral blood. Local testing may be performed during screening or within two
months prior to screening with appropriate documentation and concurrence of Sponsor's
Medical Monitor.
9. Subject has adequate organ function defined as:
- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)
and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) = 3
x upper limit of normal (ULN), unless considered to be due to leukemic organ
involvement, following review by the Sponsor's Medical monitor; and
- Serum total bilirubin = 1.5 x ULN, unless considered due to Gilbert's syndrome
(eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review
by the Investigator and the Sponsor's Medical Monitor; and
- Estimated glomerular filtration rate (GFR) > 30 mL/min based on the Modification
of Diet in Renal Disease (MDRD) formula: GFR (mL/min/1.73 m2) = 175 × (serum
creatinine)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
10. Females of childbearing potential (FCBP)2 may participate, providing they meet the
following conditions:
- Agree to practice true abstinence from sexual intercourse or to use highly
effective contraceptive methods (eg, combined [containing estrogen and
progestogen] or progestogen-only associated with inhibition of ovulation, oral,
injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral
tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or
male partner sterilization [note that vasectomized partner is a highly effective
birth control method provided that partner is the sole sexual partner of the FCBP
trial participant and that the vasectomized partner has received medical
assessment of the surgical success]) at screening and throughout the study, and
for 4 months following the last study treatment; and
- Have a negative serum ß-subunit of human chorionic gonadotropin (ß-hCG) pregnancy
test (sensitivity of at least 25 mIU/mL) at screening; and
- Have a negative serum ß-hCG pregnancy test (sensitivity of at least 25 mIU/mL)
within 72 hours prior to the start of study treatment in the Treatment Phase
(note that the screening serum pregnancy test can be used as the test prior to
the start of study treatment in the Treatment Phase if it is performed within the
72-hour timeframe).
11. Male subjects must agree to practice true abstinence from sexual intercourse or to the
use of highly effective contraceptive methods with non-pregnant female partners of
childbearing potential at screening and throughout the course of the study, and should
avoid conception with their partners during the course of the study and for 4 months
following the last study treatment.
Exclusion Criteria:
Presence of any of the following will exclude a subject from enrollment:
1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype.
2. Subject has AML secondary to chronic myeloid leukemia (CML).
3. Subject has received a targeted agent against an IDH2 mutation.
a. Prior treatment with an IDH2-targeted agent is acceptable if such treatment was
interrupted for bone marrow or stem cell transplantation AND the patient was
responsive to IDH2 treatment without progressive disease prior to transplantation.
4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to
the start of study treatment. Note that hydroxyurea is allowed prior to the start of
study treatment for the control of leukocytosis (however, hydroxyurea should not be
given within 72 hours prior to and after administration of azacitidine).
5. Subject has received non-cytotoxic or investigational agents < 14 days or 5
half-lives, whichever is longer, prior to the start of study treatment.
6. Subject has undergone hematopoietic stem cell transplantation (HSCT) within 60 days
prior to the start of study treatment, or on immunosuppressive therapy post HSCT at
the time of screening, or with clinically significant graft-versus-host disease
(GVHD).
a. The use of a stable dose of oral steroid post-HSCT and/or topical steroids for
ongoing skin GVHD is permitted.
7. Subject has persistent, clinically significant non-hematologic toxicities from prior
therapies.
8. Subject has or is suspected of having central nervous system (CNS) leukemia.
a. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia
is suspected during screening.
9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection
(defined as ongoing signs/symptoms related to the infection without improvement
despite appropriate antibiotics, antiviral therapy, and/or other treatment).
10. Subject has immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation.
11. Subject has significant active cardiac disease within 6 months prior to the start of
study treatment, including New York Heart Association (NYHA) class III or IV
congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or left
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 6 months starting study treatment.
1. The LVEF should be representative of the subject's daily status (ie, not
collected during temporary disturbances such as sepsis, acute cardiac drug
toxicity, acute pulmonary embolism, etc).
2. An imaging-based assessment of left ventricular function may be collected at
Investigator's discretion as part of screening if needed to resolve uncertainty
regarding prior tests or current clinical status.
12. Subject is known seropositive or is infected with human immunodeficiency virus (HIV)
or has active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
13. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered orally.
14. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
diastolic BP > 100 mmHg).
15. Subject is a pregnant or lactating female.
16. Subject is known or suspected to have hypersensitivity to any of the components of PK
probe compounds or study treatment.
Note: A subject may be enrolled into an alternate arm of the study to which the
subject does not have hypersensitivity if that alternate arm has not been filled, and
if the alternate arm is available in the respective country. Subject is planning, or
has reasonable probability, to violate the restrictions. Note in particular the
medication restrictions.
17. Subject has QTc interval (ie, Fridericia's correction [QTcF]) = 480 ms or other
factors that increase the risk of QT prolongation or arrhythmic events (eg, heart
failure, hypokalemia, family history of long QT interval syndrome) at screening.
Reversible factors such as hypokalemia or hypomagnesemia may be corrected prior to
dosing if the Investigator and Sponsor's Medical Monitor concur.
18. In conjunction with the restrictions, subject is taking the following CYP-sensitive
substrate medications that have a narrow therapeutic range are excluded from the study
unless the subject can be transferred to other medications at least 5 halflives prior
to the start of study treatment: paclitaxel and docetaxel (CYP2C8), phenytoin
(CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine
(CYP1A2).
19. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that places the subject at unacceptable risk or would prevent the subject from
participating in the study.
20. Subject has any condition that confounds the ability to interpret data from the study.
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