A Phase 1, Multicenter, Open-Label, Safety Study of AG-120 or AG-221 in Combination with Induction Therapy and Consolidation Therapy in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 and/or IDH2 Mutation
AG-221 (AG-221 mesylate),AG120,Cytarabine,Idarubicin
The goal of this clinical research study is to study the safety and tolerability of AG-120 and AG-221 when given in combination with standard chemotherapy to patients with AML. During Maintenance, you will not receive chemotherapy. You will only receive AG-120 or AG-221.
Disease Group: Leukemia
Treatment Agent: AG-221 (AG-221 mesylate),AG120,Cytarabine,Idarubicin
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Agios ,Celgene
The primary objective of this study is to: • Determine the safety and tolerability of AG-120 and AG-221 when administered with induction and consolidation therapy in patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) and/or isocitrate dehydrogenase-2 (IDH2) mutation Secondary objectives of this study are to: • Characterize the pharmacokinetics (PK) of AG-120 and AG-221 in plasma samples when administered with AML induction therapy and consolidation therapy • Establish the recommended Phase 2 dose (RP2D) of AG-120 and AG-221 when administered with AML induction and consolidation therapy • Evaluate the 2-hydroxygluturate (2-HG) levels in plasma • Evaluate the clinical activity of AG-120 and AG-221 in combination with AML induction and consolidation therapy Exploratory objectives of this study are to: • Evaluate the PK and pharmacodynamic (PD) relationship of AG-120 and AG-221 and 2-HG inhibition in bone marrow samples • Characterize the effects of AG-120 and AG-221 (when administered with induction and consolidation therapy) in AML by the assessment of changes in the cellular differentiation and changes in histone and deoxyribonucleic acid (DNA) methylation profiles of IDH1 and/or IDH2 mutated and wild-type cells • Evaluate gene mutation status, global gene expression profiles, and other potential prognostic markers (cytogenetics) in IDH1 and/or IDH2 mutated cells and plasma, as well as populations of IDH wild-type cells, to explore predictors of anti-tumor activity and/or resistance • Evaluate minimal residual disease (MRD)/leukemic stem cells (LSC) using multiparameter flow cytometry (MFC) and molecular techniques. • Utilizing next generation sequencing (NGS) or real time quantitative polymerase chain reaction (RT-qPCR), for patients receiving AG-120 or AG-221, assess IDH1 or IDH2 variant allele fraction (VAF) in blood or cells before and after induction treatment and consolidation cycles.
IRB Review and Approval Date: 12/30/2015
Recruitment Status: Open
Projected Accrual: 90
1) >/= 18 years of age
2) Previously untreated AML (de novo or secondary) defined according to WHO criteria, excluding APL [AML with t(15;17)], with locally documented IDH1 and/or IDH2 gene mutation scheduled for induction therapy followed by consolidation therapy. Secondary AML is defined as AML arising after myelodysplastic syndromes (MDS) or antecedent hematologic disorder (AHD) or AML arising after exposure to genotoxic injury including radiation and/or chemotherapy. Patients may have had previous treatment with hypomethylating agents (HMAs) for MDS.
3) ECOG PS of 0 to 2
4) Adequate hepatic function as evidenced by: a. Serum total bilirubin </=1.5 × ULN unless considered due to Gilbert’s disease, a gene mutation in UGT1A1 (only for patients who will be receiving AG-221), or leukemic involvement following approval by the Medical Monitor b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) </=3.0 × ULN, unless considered due to leukemic involvement following approval by the Medical Monitor.
5) Adequate renal function as evidenced by serum creatinine </=2.0 × ULN or creatinine clearance >40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
6) Agree to serial blood and bone marrow sampling
7) Meet any criteria necessary for the safe and proper use of the induction and consolidation agents involved in this trial
8) Able to understand and willing to sign an informed consent form. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to, and approved by, the site’s Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
9) Female subjects with reproductive potential must agree to undergo a medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration). A pregnancy test should also be performed on the day of the first study drug administration and confirmed negative prior to dosing as well as before dosing on Day 1 of all subsequent cycles.
10) Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of the therapy. Subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal for at least 24 consecutive months. Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study, and for 90 days (females and males) following the last dose of AG-120 or AG-221. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (e.g., synthetic condoms, diaphragm or cervical cap with spermicidal foam, cream, or gel) or male partner sterilization
1) Prior chemotherapy for AML. Hydroxyurea is allowed for the control of
peripheral leukemic blasts in subjects with leukocytosis (white blood
cell [WBC] counts >30,000/µL).
2) Taking medications with narrow therapeutic windows listed in the protocol, unless they can be transferred to other medications prior to enrolling or unless the medications can be properly monitored during the study.
3) Taking known strong cytochrome P450 (CYP) 3A4 inducers or inhibitors.
4) Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter-sensitive substrate medications unless they can be transferred to other medications within >/=5 half-lives prior to administration of AG-120 or AG-221, or unless the medications can be properly monitored during the study.
5) Pregnant or breast feeding
6) Uncontrolled active infection or uncontrolled invasive fungal infection (positive blood or tissue culture). An infection controlled with an approved or closely monitored antibiotic/antifungal treatment is allowed.
7) Prior history of malignancy, other than MDS or AML, unless the subject has been free of the disease for >/=1 year prior to the start of study treatment. However, subjects with the following history/concurrent conditions are allowed: a. Basal or squamous cell carcinoma of the skin b. Carcinoma in situ of the cervix c. Carcinoma in situ of the breast d. Incidental histologic finding of prostate cancer
8) 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; myocardial infarction, unstable angina and/or stroke; or LVEF < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment
9) QTc interval using Fridericia’s formula (QTcF)>/=450 msec 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). Bundle branch block and prolonged QTc interval are permitted with approval of the Medical Monitor.
10) Taking medications that are known to prolong the QT interval unless they can be transferred to other medications within >/=5 half-lives prior to dosing (If equivalent medication is not available QTc will be closely monitored)
11) Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
12) Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
13) Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
14) Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
15) Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient’s ability to give informed consent or participate in the study.
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