The primary objectives of Phase 1 Dose Escalation/Part 1 Expansion are:
- To assess the safety and tolerability of treatment with enasidenib administered
continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in
participants with advanced hematologic malignancies.
- To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and/or
the recommended Phase 2 dose (RP2D) of enasidenib in participants with advanced
hematologic malignancies.
The primary objective of Phase 2 is:
• To assess the efficacy of enasidenib as treatment for participants with relapsed or
refractory (R/R) acute myelogenous leukemia (AML) with an IDH2 mutation.
Inclusion Criteria:
1. Subject must be greater than or equal to 18 years of age.
2. Subjects must have an advanced hematologic malignancy including:
Phase 1/ Dose escalation:
1. Diagnosis of acute myelogenous leukemia (AML) according to World Health Organization
(WHO) criteria;
- Disease refractory or relapsed (defined as the reappearance of > 5% blasts in the
bone marrow).
- Untreated AML, greater than or equal to 60 years of age and are not candidates
for standard therapy due to age, performance status, and/or adverse risk factors,
according to the treating physician and with approval of the Medical Monitor;
2. Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with
refractory anemia with excess blasts (RAEB-1 or RAEB-2), or considered high-risk by
the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or
refractory, or the subject is intolerant to established therapy known to provide
clinical benefit for their condition (i.e., subjects must not be candidates for
regimens known to provide clinical benefit), according to the treating physician and
with approval of the Medical Monitor.
Phase 1/Part 1 Expansion:
Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any
subject with AML regardless of age who has relapsed following a bone marrow transplant
(BMT).
Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML who
have relapsed following a BMT.
Arm 3: Untreated AML and age greater than or equal to 60 years that decline standard
of care chemotherapy.
Arm 4: Isocitrate dehydrogenase protein, 2 (IDH2)-mutated advanced hematologic
malignancies not eligible for Arms 1 to 3.
Phase 2:
Diagnosis of AML according to World Health Organization (WHO) criteria and disease
relapsed or refractory as defined by:
- Subjects who relapse after allogeneic transplantation;
- Subjects in second or later relapse;
- Subjects who are refractory to initial induction or re-induction treatment
- Subjects who relapse within 1 year of initial treatment, excluding patients with
favorable-risk status according to National Comprehensive Cancer Network (NCCN)
Guidelines. Favorable-risk cytogenetics: inv(16), t(16;16), t(8;21), t(15;17)
3. Subjects must have documented IDH2 gene-mutated disease:
- For subjects in the dose escalation phase and Part 1 Expansion, IDH2 mutation may
be based on local evaluation. (Centralized testing will be performed
retrospectively.)
- For subjects in the Phase 2 portion of the trial, central testing of IDH2
mutation of bone marrow aspirate and peripheral blood, is required during
screening to confirm eligibility
4. Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling
and urine sampling during the study.
- The diagnosis and evaluation of AML or MDS will be made by bone marrow aspiration
and/or biopsy. If an aspirate is unobtainable (i.e., a "dry tap"), the diagnosis
may be made from the core biopsy.
- Screening bone marrow aspirate and peripheral blood samples are required of all
subjects. A bone marrow biopsy must be collected if adequate aspirate is not
attainable unless:
- A bone marrow aspirate and biopsy was performed as part of the standard of
care within 28 days prior to the start of the study treatment; and
- Slides of bone marrow aspirate, biopsy and stained peripheral blood smear
are available for both local and central pathology reviewers; and
- A bone marrow aspirate sample acquired within 28 days prior to the start of
study treatment has been sent for cytogenetic analysis.
5. Subjects must be able to understand and willing to sign an informed consent. 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 and/or sites
Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
6. Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status (PS)
of 0 to 2.
7. 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.
8. Subjects must have adequate hepatic function as evidenced by:
- Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless considered due
to Gilbert's disease, a gene mutation in UGT1A1, or leukemic organ 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 organ
involvement.
9. Subjects must have adequate renal function as evidenced by:
• Serum creatinine ≤ 2.0 × ULN OR
• Creatinine clearance greater than 40 mL/min based on the Cockroft-Gault glomerular
filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x
serum creatinine
10. Subjects must be recovered from any clinically relevant toxic effects of any prior
surgery, radiotherapy, or other therapy intended for the treatment of cancer.
(Subjects with residual Grade 1 toxicity, for example Grade 1 peripheral neuropathy or
residual alopecia, are allowed with approval of the Medical Monitor)
11. Female subjects of child-bearing potential must agree to undergo 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), and
on the day of the first study drug administration and confirmed negative prior to
dosing and Day 1 before dosing all subsequent cycles.
12. 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 sexually mature women who have not undergone a hysterectomy, bilateral
oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e.,
who have not menstruated at all) for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 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 120 days (females and males) following the last dose of 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.
13. Able to adhere to the study visit schedule (ie, clinic visits at the study sites are
mandatory, unless noted otherwise for particular study visits) and other protocol
requirements.
Exclusion Criteria:
1. 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.)
2. 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
enrollment).
3. 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.
4. 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).
5. 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.
6. Subjects for whom potentially curative anticancer therapy is available.
7. Subjects who are pregnant or lactating.
8. 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).
9. Subjects with known hypersensitivity to any of the components of AG-221.
10. 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 Cycle 1, Day 1
(C1D1).
11. Subjects with a history of myocardial infarction within the last 6 months of
screening.
12. 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.
13. Subjects with known unstable or uncontrolled angina pectoris.
14. Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
15. 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.
16. 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.
17. Subjects with known infection with human immunodeficiency virus (HIV) or active
hepatitis B or C.
18. 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.
19. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions
that limit the ingestion or gastrointestinal absorption of drugs administered orally.
20. Subjects with clinical symptoms suggesting active central nervous system (CNS)
leukemia or known CNS leukemia.
21. Subjects with immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation.
22. In the Phase 2 portion of the trial only, subjects who have previously received
treatment with an inhibitor of Isocitrate dehydrogenase ( IDH).
