A Phase 1 Study of AC220 (ASP2689) in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia
The goal of this clinical research study is to learn the highest tolerable dose and best schedule of the combination of up to 2 cycles of Induction chemotherapy (daunorubicin, cytarabine, and AC220), up to 3 cycles of Consolidation chemotherapy (AC220 and high dose cytarabine), and then up to 12 cycles of Maintenance chemotherapy (AC220) that can be given to patients with AML. The safety of this combination of drugs will also be studied.
Disease Group: Leukemia
Treatment Agent: AC220,Cytarabine,Daunorubicin
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
The primary objectives are to: Describe the dose limiting toxicities (DLT) of AC220 when combined with cytarabine/daunorubicin remission induction in a 7+3 schedule. Define the maximum tolerated dose (MTD) of AC220 when combined with cytarabine/daunorubicin remission induction in a 7+3 schedule. Define the recommended Phase 2/3 dose of AC220 when given with 7+3 induction and high-dose cytarabine (HiDAC) consolidation therapy in subjects with newly diagnosed acute myeloid leukemia. Evaluate the safety and tolerability of AC220 given with 7+3 induction and high-dose cytarabine (HiDAC) consolidation therapy in subjects with newly diagnosed acute myeloid leukemia. Define the DLTs and MTD of AC220 given as maintenance following 7+3 induction and HiDAC consolidation therapy. The secondary objectives are to: Characterize the pharmacokinetics (PK) of AC220 and AC886 (pharmacologically active metabolite of AC220) when AC220 is given in combination with remission induction and consolidation therapy, and as maintenance monotherapy post consolidation in newly diagnosed acute myeloid leukemia. Evaluate the effect of AC220 on the pharmacokinetics of cytarabine, daunorubicin, and daunorubicinol (pharmacologically active metabolite of daunorubicin) when given in combination with AC220 at the MTD. The exploratory objectives are to: Evaluate the efficacy of AC220 when combined with 7+3 induction followed by HiDAC plus AC220 consolidation chemotherapy. Evaluate the pharmacodynamic effect of AC220 treatment on FMS-like tyrosine kinase (FLT3) and cKIT inhibition. Evaluate pharmacodynamic effect of AC220 treatment on FLT3 ligand and cKIT ligand/stem cell factor.
IRB Review and Approval Date: 10/06/2011
Recruitment Status: Closed
Projected Accrual: up to 58
1) Subject is eligible for Part 1 and Part 2 of the study if all of the
2) Subject has provided an Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA Authorization for U.S. sites) prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
3) Subject is male or female aged >/= 18 years and </= 60 years of age.
4) Subject has a diagnosis of previously-untreated de novo acute myeloid leukemia (AML) according to WHO classification 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.
5) Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of </= 2.
6) 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.
7) 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.
8) 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.
9) Subject is able to comply with study procedures and follow-up examinations.
10) Subject is eligilble for Part 3 of the study if all of the following apply:
11) Subject has provided an additional Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA Authorization for U.S. sites) prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
12) Subject has completed at least one cycle of consolidation in the study.
13) Subject is in CRc.
14) Subject must have absolute neutrophil count (ANC) > 1000/mm3 and platelet count > 50,000/mm3 without platelet transfusion support within 24 hours prior to Cycle 1 Day 1 dose.
15) Subject must have adequate renal and hepatic parameters as indicated by the following laboratory values within 24 hours prior to Cycle 1 Day 1 dose: Alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (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.
16) Subject is able to begin maintenance within 56 days after the last consolidation cycle start.
1) Subject will be excluded from participation in Parts 1 and 2 if any
of the following apply:
2) 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).
3) Subject has a diagnosis of AML following an antecedent hematologic disorder (myelodysplasia or myeloproliferative neoplasm by bone marrow aspirate and/or biopsy documented at least 12 weeks prior to first dose of study drug).
4) Subject has a diagnosis of acute bilineal/biphenotypic leukemia.
5) Subject has therapy-related AML.
6) Subject received previous treatment with AC220.
7) 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.
8) Subject has uncontrolled disseminated intravascular coagulation
9) Subject has CNS leukemia. A subject with symptoms suggestive of CNS leukemia must undergo a lumbar puncture; and a subject with a positive cerebrospinal fluid (CSF) for AML blasts is not eligible.
10) Subject has had a known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen.
11) Subject had major surgery within 4 weeks prior to the start of study drug.
12) 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 at screening ECG; Diagnosed or suspected congenital long QT syndrome; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsade 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);
13) **continued from above: QTc interval calculated by Fridericia’s correction factor (QTcF) at Screening and Day 4 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.
14) Subject has a pre-existing disorder predisposing the subject to a serious or lifethreatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias).
15) Subject has an active acute or chronic systemic fungal, bacterial, viral, or other infection.
16) 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.
17) Subject requires treatment with concomitant drugs that prolong QT/QTc interval or strong 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.
18) Subject requires treatment with anticoagulant therapy.
19) Subject is a female who is lactating.
20) 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.
21) There are no exclusions for Part 3.