Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation

Protocol: OSU-15225

Full Title

A Phase I, 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

Purpose

The purpose of this Phase I, multicenter, clinical trial is to evaluate the safety of AG-120

and AG-221 when given in combination with standard AML induction and consolidation therapy.

The study plans to evaluate 1 dose level of AG-120 in patients with an IDH1 mutation and 2

dose levels of AG-221 in patients with an IDH2 mutation. AG-120 or AG-221 will be

administered with 2 types of AML induction therapies (cytarabine with either daunorubicin or

idarubicin) and 2 types of AML consolidation therapies (mitoxantrone with etoposide [ME] or

cytarabine). After consolidation therapy, patients may continue on maintenance therapy and

receive daily treatment of AG-120 or AG-221 for up to 1 year from Day 1 of the first

induction cycle, or until relapse, development of an unacceptable toxicity, or hematopoietic

stem cell transplant (HSCT).

Are you eligible?

Inclusion Criteria:

Subjects must ≥18 years of age

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.

ECOG PS of 0 to 2

Adequate hepatic function as evidenced by: 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; 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

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)

Agree to serial blood and bone marrow sampling

Meet any criteria necessary for the safe and proper use of the induction and

consolidation agents involved in this trial

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).

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.

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.

Exclusion Criteria:

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).

Taking medications with narrow therapeutic windows, unless they can be transferred to

other medications prior to enrolling or unless the medications can be properly

monitored during the study.

Taking known strong cytochrome P450 (CYP) 3A4 inducers or inhibitors

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

Pregnant or breast feeding

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.

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: basal or squamous cell

carcinoma of the skin; carcinoma in situ of the cervix; carcinoma in situ of the

breast; incidental histologic finding of prostate cancer

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

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.

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)

Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C

Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the

ingestion or gastrointestinal absorption of orally administered drugs

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.

Immediate life-threatening, severe complications of leukemia such as uncontrolled

bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular

coagulation

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

Acute Myeloid Leukemia Endocrine Cancers Leukemia