Eligibility Details:
Inclusion Criteria:
- Subject is considered an adult according to local regulation at the time of obtaining
informed consent.
- Subject has a diagnosis of previously-untreated AML according to World Health
Organization (WHO) classification [Swerdlow et al, 2008] as determined by pathology
review at the treating institution.
- Subject is positive for FLT3 mutation (internal tandem duplication [ITD] or tyrosine
kinase domain [TKD] [D835/I836] mutation) (or for Korea only: ITD alone or ITD with
concurrent TKD activating mutation) in bone marrow or whole blood as determined by
central laboratory. Note: Only requirement of FLT3 mutation assessment by central
laboratory is only applicable to the randomization portion of the study.
- Subject is ineligible for intensive induction chemotherapy by meeting at least 1 of
the following criteria:
- Subject is ≥ 65 years of age and ineligible for intensive induction chemotherapy.
- Subject is ≥ 18 to 64 years of age and has any of the following comorbidities:
Congestive heart failure (New York Heart Association {NYHA} class ≤ 3) or
ejection fraction (Ef) ≤ 50%; Creatinine > 2 mg/dL (177 µmol/L), dialysis or
prior renal transplant; ECOG performance status ≥ 2; o Known pulmonary disease
with decreased diffusion capacity of lung for carbon monoxide (DLCO) and/or
requiring oxygen ≤ 2 liters per minute; Prior or current malignancy that does not
require concurrent treatment; Subject has received a cumulative anthracycline
dose above 400 mg/m2 of doxorubicin (or cumulative maximum dose of another
anthracycline). Any other comorbidity incompatible with intensive chemotherapy
must be reviewed and approved by the Medical Monitor during screening and before
randomization.
- Subject must meet the following criteria as indicated on the clinical laboratory
tests:
- Serum AST and ALT ≤ 3.0 x Institutional upper limit of normal (ULN)
- Serum total bilirubin ≤ 1.5 x Institutional ULN
- Serum potassium ≥ Institutional lower limit of normal (LLN)
- Serum magnesium ≥ Institutional LLN Repletion of potassium and magnesium levels
during the screening period is allowed.
- Subject is suitable for oral administration of study drug.
- Female subject is eligible to participate if female subject is not pregnant and at
least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP); OR
- WOCBP agrees to follow the contraceptive guidance starting at screening and
continue throughout the study period, and for at least 180 days after the final
study drug administration.
- Female subject must agree not to breastfeed starting at screening and throughout the
study period, and for 60 days after the final study drug administration.
- Female subject must not donate ova starting at screening and throughout the study
period, and for 180 days after the final study drug administration.
- Male subject with female partners of childbearing potential must agree to use
contraception as detailed in Contraception Requirements, starting at screening and
continue throughout the study period, and for 120 days after the final study drug
administration.
- Male subject must not donate sperm starting at screening and throughout the study
period and for 120 days after the final study drug administration.
- Subject agrees not to participate in another interventional study while on treatment.
Exclusion Criteria:
- Subject was diagnosed as acute promyelocytic leukemia (APL).
- Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
- Subject has received previous therapy for AML, with the exception of the following:
- Emergency leukapheresis
- Hydroxyurea
- Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days
- Growth factor or cytokine support
- Steroids
- Subject has clinically active central nervous system leukemia.
- Subject has been diagnosed with another malignancy that requires concurrent treatment
(with the exception of hormone therapy limited to those therapies that prevent
recurrence and/or spread of cancer) or hepatic malignancy regardless of need for
treatment.
- Subject requires treatment with concomitant drugs that are strong inducers of
cytochrome P450 CYP3A/P-glycoprotein (P-gp).
- Subject requires treatment with concomitant drugs that are strong inhibitors or
inducers of P-gp with the exception of drugs that are considered absolutely essential
for the care of the subject.
- Subject requires treatment with concomitant drugs that target serotonin
5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the
exception of drugs that are considered absolutely essential for the care of the
subject.
- Subject has congestive heart failure classified as New York Heart Association Class
IV.
- Subject with mean Fridericia-corrected QT interval (QTcF) > 480 ms at screening based
on central reading.
- Subject with a history of Long QT Syndrome at screening.
- Subject has known pulmonary function tests with diffusion capacity of lung for carbon
monoxide (DLCO) ≤ 50%, forced expiratory volume in the first second (FEV1) ≤ 60%,
dyspnea at rest or requiring oxygen or any pleural neoplasm (Transient use of
supplemental oxygen is allowed.)
- Subject has active hepatitis B or C or other active hepatic disorder.
- Subjects with positive hepatitis B surface antigen (HBsAg) or detectable
hepatitis B DNA are not eligible.
- Subjects with negative HBsAg, positive hepatitis B core antibody and negative
hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable.
- Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA
is undetectable
- Subject has any condition which makes the subject unsuitable for study participation,
including any contraindications of azacitidine.
- Subject has a known or suspected hypersensitivity to ASP2215, azacitidine or any
components of the formulations used.