Phase 1 Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation

Study ID

Cancer Related

Healthy Volunteers

Study Sites

  • Clements University Hospital
  • UT Southwestern Ambulatory Services
  • Zale Lipshy University Hospital

Joyce Bolluyt

Principal Investigator
Robert Collins, M.D.

Official Title

A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation

Brief Overview

Study AG221-C-001 is a Phase 1, multicenter, open-label, dose-escalation, safety, PK/PD, and
clinical activity evaluation of orally administered AG-221 in subjects with advanced
hematologic malignancies that harbor an IDH2 mutation. The study includes a dose escalation
phase to determine the maximum tolerated dose (MTD) and/or the recommended Pase 2 dose
(RP2D) and an expansion phase to further evaluate the safety, tolerability and clinical
activity of AG-221 in select populations.

Participant Eligibility

Inclusion Criteria:

- Subject must be ≥18 years of age.

- Subjects must have documented IDH2 gene-mutated advanced hematologic malignancy based
on local evaluation.

- Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling,
and urine sampling during the study.

- Subjects must be able and willing to sign an informed consent.

- Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status (PS)
of 0 to 2.

- Platelet count ≥20,000/µL (Transfusions to achieve this level are allowed.) Subjects
with a baseline platelet count of <20,000/µL due to underlying malignancy are
eligible with Medical Monitor approval.

- Subjects must have adequate hepatic function as evidenced by Aspartate
aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase
(ALP) ≤3.0 × ULN, unless considered due to leukemic organ involvement, and serum
total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due to
Gilbert's disease or leukemic organ involvement.

- Subjects must have adequate renal function as evidenced by a serum creatinine ≤2.0 ×
ULN or creatinine clearance >40mL/min based on Cockroft-Gault glomerular filtration
rate (GFR) estimation

- Subjects must be recovered from any clinically relevant toxic effects of any prior
surgery, radiotherapy, or other therapy intended for the treatment of cancer.

- Female subjects with reproductive potential must have a negative serum pregnancy test
within 7 days prior to the start of therapy. Subjects with reproductive potential are
defined as one who is biologically capable of becoming pregnant. Women of
childbearing potential as well as fertile men and their partners must agree to
abstain from sexual intercourse or to use two highly effective forms of contraception
during the study and for 90 days (females and males) following the last dose of

Exclusion Criteria:

- Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days
of the first dose of AG-221, or subjects on immunosuppressive therapy post HSCT at
the time of screening, or with clinically significant graft-versus-host disease
(GVHD). (The use of a stable dose of oral steroids post GVHD and/or topical steroids
for ongoing skin GVHD is permitted with Medical Monitor approval.)

- Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to
their first day of study drug administration. (Hydroxyurea is allowed for up to 28
days after the start of AG-221 for the control of peripheral leukemic blasts in
subjects with white blood cell [WBC] counts >30,000/μL as well as prior to

- Subjects who received a small molecule investigational agent <14 days prior to their
first day of study drug administration. In addition, the first dose of AG-221 should
not occur before a period ≥5 half-lives of the investigational agent has elapsed.

- Subjects taking the following sensitive cytochrome P450 (CYP) substrate medications
that have a narrow therapeutic range are excluded from the study unless they can be
transferred to other medications within ≥5 half-lives prior to dosing: paclitaxel
(CYP2C8) warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine
(CYP2D6), theophylline and tizanidine (CYP1A2).

- Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)
transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the
study unless they can be transferred to other medications within ≥5 half-lives prior
to dosing.

- Subjects for whom potentially curative anticancer therapy is available.Subjects who
are pregnant or lactating.

- Subjects with an active severe infection that required anti-infective therapy or with
an unexplained fever >38.5°C during screening visits or on their first day of study
drug administration (at the discretion of the Investigator, subjects with tumor fever
may be enrolled).

- Subjects with known hypersensitivity to any of the components of AG-221.

- Subjects with New York Heart Association (NYHA) Class III or IV congestive heart
failure or left ventricular ejection fraction (LVEF) <40% by echocardiogram (ECHO) or
multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.

- Subjects with a history of myocardial infarction within the last 6 months of

- Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or
diastolic BP >100 mmHg) at screening are excluded. Subjects requiring 2 or more
medications to control hypertension are eligible with Medical Monitor approval.

- Subjects with known unstable or uncontrolled angina pectoris.

- Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.

- Subjects with heart-rate corrected QT (QTc) interval ≥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) at screening.

- Subjects 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.

- Subjects with known infection with human immunodeficiency virus (HIV) or active
hepatitis B or C.

- Subjects with any other medical or psychological condition, deemed by the
Investigator to be likely to interfere with a subject's ability to sign informed
consent, cooperate, or participate in the study.

- Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions
that limit the ingestion or gastrointestinal absorption of drugs administered orally.

- Subjects with clinical symptoms suggesting active central nervous system (CNS)
leukemia or known CNS leukemia.

- Subjects with immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation.