Subjects will receive escalating doses of AC220 plus standard 7+3 cytarabine and daunorubicin remission induction therapy. Subjects may receive up to 2 cycles of induction therapy. Subjects who have a complete response (including complete remission (CR) with incomplete hematologic recovery) are eligible to receive up to 3 consolidation cycles. In consolidation subjects will receive AC220 plus high dose cytarabine.Subjects achieving a composite Complete Remission (CRc) will be eligible to receive AC220 alone for up to 12 additional 28 day cycles.
Subjects will be enrolled into successive gender balanced cohorts of 6 subjects (at least 3 must be females) to determine the maximum tolerated dose (MTD). Dose escalation decision will be made based on dose limiting toxicities (DLTs) that occur during the first remission induction cycle. Seven and 14 day schedules will be evaluated.
After the MTD and schedule is established, the study will open to enroll between 14 to 34 subjects. Subjects will receive AC220 during induction and consolidation at the MTD and schedule established. Stopping rules will be used to evaluate safety at the current dose. If testing at a dose level must be stopped, then a lower dose may be tested. MTD will also be established for the maintenance therapy.
- 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 are eligible.
- 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 drug administration.
- 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 infection.
- 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.
Last updated: 03/25/2013
NCT ID: NCT01390337