Clinical Trials /

Phase 1/2 Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation

NCT01915498

Description:

Study AG221-C-001 is a Phase 1/2, 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 Phase 2 dose (RP2D) and an expansion phase to further evaluate the safety, tolerability and clinical activity of AG-221 in select populations.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1/2 Study of AG-221 in Subjects With Advanced Hematologic Malignancies 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

Clinical Trial IDs

  • ORG STUDY ID: AG-221-C-001
  • NCT ID: NCT01915498

Conditions

  • Hematologic Neoplasms

Interventions

DrugSynonymsArms
AG-221AG-221

Purpose

Study AG221-C-001 is a Phase 1/2, 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 Phase 2 dose (RP2D) and an expansion phase to further evaluate the safety, tolerability and clinical activity of AG-221 in select populations.

Trial Arms

NameTypeDescriptionInterventions
AG-221ExperimentalAG-221 administered orally. Multiple doses.
  • AG-221

Eligibility Criteria

        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 (subtype 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 NCCN Guidelines (NCCN 2015). 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 (Upper limit of normal), 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 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 IDH.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse Events (AEs)
Time Frame:Up to 26 weeks
Safety Issue:
Description:To assess the safety and tolerability of treatment with AG-221 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in subjects with advanced hematologic malignancies

Secondary Outcome Measures

Measure:Dose Limiting Toxicities
Time Frame:Up to 26 weeks
Safety Issue:
Description:For the Phase 1 Dose Escalation/Part 1 Expansion, to describe the dose limiting toxicities (DLTs) of AG-221 in subjects with advanced hematologic malignancies.
Measure:Pharmacokinetic Cmax
Time Frame:Up to 26 weeks
Safety Issue:
Description:Maximum observed concentration in plasma for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population
Measure:Pharmacokinetic Tmax
Time Frame:Up to 26 weeks
Safety Issue:
Description:Time to maximum concentration for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population
Measure:Clinical Activity pf AG-221 in subjects with hematologic malignancies
Time Frame:Up to 26 weeks
Safety Issue:
Description:For all participating subjects in the Phase 1 Dose Escalation/Part 1 Expansion, response to treatment assessed by the site Investigator's using International Working Group (IWG) or other appropriate response criteria
Measure:Pharmacokinetic AUC
Time Frame:Up to 26 weeks
Safety Issue:
Description:Area under the plasma concentration‐time curve for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population
Measure:Pharmacokinetic Elimination half-life
Time Frame:Up to 26 weeks
Safety Issue:
Description:Elimination half-life for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population
Measure:Pharmacodynamics Analyses Plasma
Time Frame:Up to 26 weeks
Safety Issue:
Description:To explore the potential relationship of plasma level of AG221 and plasma 2-HG levels, where appropriate for the entire population and in the R/R AML population and in the relapse/refractory AML population
Measure:Pharmacodynamics Analyses Urine
Time Frame:Up to 26 weeks
Safety Issue:
Description:For the Phase 1 Dose Escalation/Part 1 Expansion, to explore the potential relationship of plasma level of AG221 and urine 2-HG for the entire population and in the relapse/refractory AML population
Measure:Pharmacodynamics Analyses Bone Marrow (2-HG)
Time Frame:Up to 26 weeks
Safety Issue:
Description:To explore the potential relationship of plasma level of AG221 and bone marrow (2-HG) for the entire population and in the relapse/refractory AML population
Measure:Clinical Activity of AG-221 in subjects with Relapse/Refractory AML with an IDH2 mutation
Time Frame:up to 26 weeks
Safety Issue:
Description:For Expansion phase 2, an independent central review will assess clinical activity

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Celgene

Trial Keywords

  • acute myeloid leukemia
  • AML
  • myelodysplastic syndrome
  • MDS
  • hematologic malignancies
  • IDH2
  • Phase I
  • Phase II
  • AG-221
  • relapse AML
  • refractory AML

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