A Phase 1 Study of AC220 (ASP2689) in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia
- Subject has a diagnosis of previously-untreated de novo acute myeloid leukemia (AML)
according to World Health Organization (WHO) classification (2008) documented within
28 days prior to enrollment and defined as > 20% myeloblasts on the marrow aspirate
or peripheral blood differential, with or without extramedullary involvement, with
confirmatory immunophenotyping or immunocytochemistry (e.g. myeloperoxidase). In
addition, subjects with the clonal, recurring cytogenetic abnormalities:
t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) should be considered to have
AML regardless of the blast percentage. Subjects with both positive and negative
FMS-like tyrosine kinase - internal tandem duplication (FLT3-ITD) mutation status
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
- Subject must have adequate renal, hepatic, and coagulation parameters as indicated by
the following laboratory values:
- Alkaline phosphatase, AST, ALT ≤ 2.5 x institutional upper limit of normal (ULN)
- Total bilirubin ≤ 1.5 x institutional ULN
- Serum creatinine ≤ 1.5 x institutional ULN or an estimated glomerular filtration
rate (eGFR) of >50 ml/min as calculated by the Modification of Diet in Renal
Disease (MDRD) equation.
- Subject is a woman of childbearing potential (WOCBP) or a male subject with female
partner of childbearing potential who agrees to use a medically-approved method of
contraception to avoid pregnancy throughout the study and for at least 3 months after
the last dose of study drug.
- Subject is a WOCBP and has a negative serum or urine pregnancy test (sensitivity ≤ 25
IU human chorionic gonadotropin [hCG]/L) within 72 hours prior to the start of study
- Subject is able to comply with study procedures and follow-up examinations.
- Subject has a diagnosis of acute promyelocytic leukemia (APL),
French-American-British (FAB) classification M3 or World Health Organization (WHO)
classification of APL with t(15;17)(q22;q12), or BCR-ABL positive leukemia (chronic
myelogenous leukemia in blast crisis).
- Subject has a diagnosis of AML following an antecedent hematologic disorder
(diagnosis of myelodysplasia or myeloproliferative neoplasm by bone marrow aspirate
and/or biopsy documented at least 12 weeks prior to first dose of study drug).
- Subject has a diagnosis of acute bilineal/biphenotypic leukemia.
- Subject has therapy-related AML.
- Subject received previous treatment with AC220.
- Subject has received previous therapy for AML, with the exception of the following:
- Emergency leukapheresis;
- Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 5 days;
- Growth factor or cytokine support;
- Steroids for the treatment of hypersensitivity or transfusion reactions.
- Subject has uncontrolled disseminated intravascular coagulation.
- Subject has Central Nervous System (CNS) leukemia. A Subject with symptoms suggestive
of CNS leukemia must undergo a lumbar puncture; and subject with a positive
cerebrospinal fluid (CSF) for AML blasts is not eligible.
- Subject has a known positive test for human immunodeficiency virus, hepatitis C, or
hepatitis B surface antigen.
- Subject had major surgery within 4 weeks prior to the start of study drug.
- Subject has uncontrolled or significant cardiovascular disease, including
- A myocardial infarction within 12 months prior to the start of study drug;
- Uncontrolled angina within 6 months prior to the start of study drug;
- History of congestive heart failure (CHF) New York Heart Association (NYHA)
class 3 or 4,unless a screening echocardiogram (ECHO) or Multiple Gate
Acquisition Scan (MUGA) performed either within 1 month prior to or during study
screening results in a left ventricular ejection fraction (LVEF) that is ≥ 45%
(or institutional lower limit of normal value);
- Heart rate < 50 beats per minute
- Diagnosed or suspected congenital long QT syndrome;
- Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes [TdP])
(any other history of arrhythmia will be discussed with the Sponsor's Medical
Monitor prior to subject's entry into the study);
- QTc interval calculated by Fridericia's correction factor (QTcF) pre-AC220 dose
≥ 450 ms. The QTcF will be derived from the average QTcF in triplicate;
- Any history of second or third degree heart block;
- Uncontrolled hypertension defined as systolic blood pressure ≥ 180 mmHg or
diastolic blood pressure ≥ 110 mmHg;
- Obligate need for a cardiac pacemaker or defibrillator;
- Complete left bundle branch block; or
- Atrial fibrillation documented within 2 weeks prior to first dose of study drug.
- Subject has a pre-existing disorder predisposing the subject to a serious or
life-threatening infection (e.g. cystic fibrosis, congenital or acquired
immunodeficiency, bleeding disorder, or cytopenias).
- Subject has an active acute or chronic systemic fungal, bacterial, viral, or other
- Subject has a concurrent disease (e.g. a history of serious organ dysfunction or
disease) that may place the subject at undue risk to undergo induction therapy per
protocol, or that might obscure assessments of drug safety.
- Subject requires treatment with concomitant drugs that prolong QT/QTc interval or
strong cytochrome P-3A4 (CYP3A4) inhibitors or inducers with the exception of
antibiotics, antifungals, and antivirals that are used as standard of care to prevent
or treat infections and other such drugs that are considered absolutely essential for
the care of the subject.
- Subject requires treatment with anticoagulant therapy.
- Subject is a female who is lactating.
- Subject has any medical, psychiatric, addictive or other kind of disorder which
compromises the ability of the subject to give written informed consent and/or to
comply with procedures.