| Eligibility |
Inclusion Criteria:
- Confirmed diagnosis of AML harboring a mutation in IDH2 relapsed or refractory to
first line cytarabine/anthracycline induction chemotherapy, failed to respond to or
relapsed following at least 2 cycles of hypomethylating agent (azacitidine,
decitabine, sgi-110) or at least 1 cycle of hypomenthylating agent with venetoclax or
other targeted therapies
- Patients will be identified and deemed eligible based upon the identification of
an IDH2 mutation identified at either at the time of disease relapse prior to
re-induction chemotherapy or following 1-2 cycles of chemotherapy induction. Each
institution will test using their standard local FDA-approved or cleared assay
per the institutional standard of care workup for relapsed disease.
- First relapse defined as untreated hematologic relapse (according to
International Working Group criteria) after one line of intensive regimen for AML
including at least one cytarabine containing induction block with a total dose no
less than 700 mg/m^2 per cycle and 3 days of an anthracycline that induced a
complete remission (CR)/complete remission with incomplete hematologic recovery
(CRi)/complete remission with incomplete platelet recovery (CRp). Subjects are
allowed to receive induction, consolidation, transplant and/or maintenance
therapy prior to achieving their first CR/CRi/CRp
- Refractory to induction therapy is defined as never achieving CR, CRi or CRp
(according to International Working Group criteria) after one line of intensive
regimen for AML (reinduction, consolidation and/or transplant allowed) including
at least one cytarabine containing induction block with a total dose no less than
700 mg/m^2 per cycle and 3 days of an anthracycline
- Subjects considered eligible for intensive chemotherapy
- Subjects had received a first salvage within the last 60 days (day 15 to 60 following
most recent cytarabine-based standard salvage number [#] 1 therapy) who achieved
either > 50% reduction in blast percentage from the pre-treatment bone marrow OR < 20%
cellularity with any blast percentage AND < 5% peripheral blood blasts
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- Adequate liver function within 72 hours of enrollment, defined as:
o Blood 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
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x upper
limit of normal (ULN) (within 72 hours of enrollment)
- Adequate renal function within 72 hours of enrollment, defined as blood creatinine =<
2.5 x ULN
- Females of childbearing potential (FCBP) 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 (6 months following the last dose
of cytarabine); and
- Have a negative serumblood ß-subunit of human chorionic gonadotropin (ß-hCG)
pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
- Have a negative serum or urine (investigator's discretion under local
regulations) 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 serumblood 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).
- Men must use a latex condom during any sexual contact with women of childbearing
potential
- Willing to adhere to protocol specific requirements
- Clinically significant toxic effects of prior therapy (except hydroxyurea) resolved to
grade =< 1 before the start of study
- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure
Exclusion Criteria:
- Acute promyelocytic leukemia (APL)
- Subject has or is suspected of having central nervous system (CNS) leukemia.
Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
suspected during screening
- Clinically active or unstable graft-versus-host disease (GVHD) requiring treatment
that precludes administration of chemotherapy as defined in this protocol
- Prior anti-leukemia therapy within 5 x the half-life for other investigational agents
- Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e.,
control of white blood count [WBC]) are allowed but should be discontinued at
least 24 hours prior to enrollment. Other agents used strictly with palliative
intent might be allowed during this period after discussing with principal
investigator
- Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic
steatohepatitis, sclerosing cholangitis)
- Subject is known seropositive or active infection with human immunodeficiency virus
(HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
- 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)
- Pregnant or nursing female participants
- Subjects of childbearing potential not willing to use adequate contraception
- 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 28 days prior to the start of study treatment
- Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions
that in the opinion of the investigator may impair the participation in the study or
the evaluation of safety and/or efficacy
- Subject has immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation
- Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered orally
- Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
diastolic BP > 90 mmHg)
- Subject has known (or suspected to have) hypersensitivity to any of the components of
study treatment
- Subject has corrected QT (QTc) interval (i.e., Fridericia's correction [QTcF]) >= 450
ms or other factors that increase the risk of QT prolongation or arrhythmic events
(e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at
screening
- Subject is taking the following sensitive CYP 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 half-lives prior to the start of study treatment:
phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
tizanidine (CYP1A2)
- Subject who is taking the breast cancer resistance protein (BCRP)
transporter-sensitive substrate (i.e., rosuvastatin) should be excluded from the study
unless the subject can be transferred to other medications at least 5 half-lives prior
to the start of study treatment
- Subject with prior history of malignancy, other than myelodysplastic syndrome (MDS),
myeloproliferative neoplasm (MPN) or AML may be eligible after discussion with the
study doctor. Diagnoses of basal or squamous cell carcinoma of the skin, carcinoma in
situ of the cervix, carcinoma in situ of the breast, and previously treated prostate
cancer (T1a/T1b by TNM staging) are not exclusionary :
- Concurrent participation in another therapeutic clinical trial
- Unwilling or unable to follow protocol requirements
- Any condition which in the investigator's opinion deems the participant an unsuitable
candidate to receive study drug Subject has any condition including the presence of
laboratory abnormalities, which places the subject at unacceptable risk if he/she were
to participate in the study.
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