Phase 1/2 Study of Enasidenib (AG-221) in Adults With Advanced Hematologic Malignancies With an Isocitrate Dehydrogenase Isoform 2 (IDH2) Mutation

Not Recruiting

Trial ID: NCT01915498


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.

Official Title

A Phase 1/2, 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


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

   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

      - 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

   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

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

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

   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

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

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).


drug: Enasidenib

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305

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