Clinical Trials /

Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome

NCT03383575

Description:

The goal of this clinical research study is to learn if enasidenib (AG-221) alone or in combination with azacitidine can help to control myelodysplastic syndrome (MDS). The safety of this drug will also be studied. If you are reading and signing this form on behalf of a potential participant, please note: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant. This is an investigational study. Enasidenib is not FDA approved or commercially available. It is currently being used for research purposes only. Azacitidine is FDA approved and commercially available for the treatment of MDS. It is considered investigational to give enasidenib and azacitidine in combination for the treatment of MDS. The study doctor can explain how the study drug(s) are designed to work. Up to 105 participants will be enrolled in this multicenter study. Up to 75 will take part at MD Anderson.

Related Conditions:
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome
  • Official Title: Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: 2016-0981
  • SECONDARY ID: NCI-2018-00987
  • NCT ID: NCT03383575

Conditions

  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
AzacitidineAzacytidine, 5-azacytidine, 5-AZA, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816Arm A: Azacitidine + Enasidenib
EnasidenibAG-221, IDHIFAArm A: Azacitidine + Enasidenib

Purpose

The goal of this clinical research study is to learn if enasidenib (AG-221) alone or in combination with azacitidine can help to control myelodysplastic syndrome (MDS). The safety of this drug will also be studied. If you are reading and signing this form on behalf of a potential participant, please note: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant. This is an investigational study. Enasidenib is not FDA approved or commercially available. It is currently being used for research purposes only. Azacitidine is FDA approved and commercially available for the treatment of MDS. It is considered investigational to give enasidenib and azacitidine in combination for the treatment of MDS. The study doctor can explain how the study drug(s) are designed to work. Up to 105 participants will be enrolled in this multicenter study. Up to 75 will take part at MD Anderson.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be assigned to 1 of 2
      study groups based on the status of your disease and the treatment you may have received in
      the past.

        -  If you have never received a hypomethylating drug (such as azacitidine or decitabine),
           you will be assigned to Arm A.

        -  If you have received a hypomethylating drug (such as azacitidine or decitabine) and you
           have relapsed (has come back) or refractory (has not responded to treatment) MDS, you
           will be assigned to Arm B.

      Participants in Arm A will receive azacitidine and enasidenib.

      Participants in Arm B will receive enasidenib alone.

      Study Drug Administration:

      Each study cycle is 28 days.

      If you are in Arm A, you will receive azacitidine by vein over about 30-60 minutes on Days
      1-7 of every cycle. If needed, you may be given azacitidine as an injection under the skin.
      If you are receiving azacitidine at a clinic that closes over the weekend, alternate dosing
      schedules (such as receiving azacitidine on Days 1-5 and 8-9 of each cycle) are possible.

      All participants will take enasidenib tablets by mouth with a cup (about 8 ounces) of water
      at the same time every day. You should swallow the tablets whole without chewing them. You
      should fast (not have anything to eat or drink except water) for 2 hours before and 1 hour
      after each dose.

      If you miss your dose, you can still take it as long as it is within 6 hours of your
      scheduled dose time. If more than 6 hours have passed, you should skip that dose and wait to
      take the next dose at the normal time the next day.

      Length of Treatment:

      You may continue taking the study drug(s) for as long as the doctor thinks it is in your best
      interest. You will no longer be able to take the study drug(s) if the disease gets worse, if
      intolerable side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visits.

      Study Visits:

      On Day 1 of Cycle 1, you will have the following procedures. You should fast before this
      visit, so do not eat breakfast until the study staff tells you that you can eat. You may have
      water during this time. You will take your dose of enasidenib during your clinic visit:

        -  You will have a physical exam.

        -  Blood (about 4 teaspoons) will be drawn for routine, pharmacokinetic (PK), and biomarker
           testing, which may include genetic biomarkers. Biomarkers are found in the blood/tissue
           and may be related to your reaction to the study drug. PK testing measures the amount of
           study drug in the body at different time points.

        -  You will have a bone marrow aspirate/biopsy for biomarker testing.

      On Days 8, 15, and 22 (+/- 3 days) of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 3 teaspoons) will be drawn for routine tests.

      On Day 1 (+/- 5 days) of Cycle 2 and beyond, you will have the following procedures. During
      Cycles 2 and 3 only, you should take your dose of enasidenib during your clinic visit:

        -  You will have a physical exam.

        -  Blood (about 4 teaspoons) will be drawn for routine and biomarker testing.

        -  During Cycle 2 only, you will have a bone marrow biopsy/aspirate to check the status of
           the disease and for biomarker and pharmacodynamic (PD) testing. PD testing measures how
           the level of study drug in your body may affect the disease.

        -  During Cycles 2 and 3 only, blood (about 2 tablespoons) will be drawn for PK testing
           before your dose of study drug. During Cycle 2, blood will also be drawn 4 times over
           the 8 hours after the dose. During Cycle 3, blood will also be drawn about 4 hours after
           the dose.

      On Day 1 (+/- 5 days) of Cycle 4, 6, and every 3 cycles after that (Cycle 9, 12, 15, and so
      on), you will have a bone marrow biopsy/aspirate for biomarker testing, PD testing, and to
      check the status of the disease.

      End-of-Study Visit:

      Within 28 days of your last dose of study drug(s):

        -  You will have a physical exam.

        -  Blood (about 4 teaspoons) will be drawn for routine testing.

        -  You will have an EKG.

        -  If the disease appears to be getting worse or returns, you will have a bone marrow
           aspirate/biopsy for biomarker and PD testing.

        -  If you are able to become pregnant, blood (about 1 tablespoon) or urine will be
           collected for a pregnancy test.

      Long-Term Follow-Up:

      Every 3 months for up to 3 years after the last patient enrolls on this study, a member of
      the study staff will call and ask you how you are doing and if you have started any new
      anti-cancer treatments. This phone call should last about 5 minutes.

      Additional Information:

      Your body may not show a response to enasidenib and azacitidine until after you've received 6
      cycles.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Azacitidine + EnasidenibExperimentalParticipants that have never received a hypomethylating drug (such as azacitidine or decitabine), assigned to Arm A. Participants in Arm A receive Azacitidine and Enasidenib.
  • Azacitidine
  • Enasidenib
Arm B: EnasidenibExperimentalParticipants that have received a hypomethylating drug (such as azacitidine or decitabine) and have relapsed or refractory MDS, assigned to Arm B. Participants in Arm B receive Enasidenib alone.
  • Enasidenib

Eligibility Criteria

        Inclusion Criteria:

          1. Signed, informed consent must be obtained prior to any study specific procedures.

          2. Subjects must be >/= 12 years of age at the time of informed consent

          3. Subjects with a histologically confirmed diagnosis of MDS, including both MDS and
             RAEB-T (AML with 20-30% blasts and multilineage dysplasia by FAB criteria) by World
             Health Organization (WHO), and chronic myelomonocytic leukemia (CMML) are eligible.

          4. Subjects must have an IDH2 gene mutation (IDH2-R140 or R172) as determined by local
             laboratory result.

          5. (Arm A only): Subject must be hypomethylating agent naïve (i.e. prior azacitidine,
             decitabine, SGI-110 is exclusionary). Receipt of other MDS-directed therapy such as
             lenalidomide is allowed

          6. (Arm A only): Subjects with high-risk MDS (i.e. IPSS Intermediate-2 or high-risk; or
             R-IPSS high or very-high risk). Patients with Intermediate-1 risk by IPSS or
             Intermediate risk by R-IPSS with high-risk molecular features including TP53, ASXL1,
             EZH2, and/or RUNX1 mutations are also eligible.

          7. (Arm B only): Subject must be relapsed or refractory to prior hypomethylating agent
             therapy, defined as prior receipt of 6 cycles of HMA therapy with failure to attain a
             response, or relapse after prior response to HMA therapy

          8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

          9. Adequate liver function, as evidenced by a serum bilirubin </= 2x the ULN (except for
             patients with Gilbert's disease), ALT and/or AST </= 3x the laboratory ULN

         10. Serum creatinine </= 2x the ULN

         11. Able to understand and voluntarily sign a written informed consent, and willing and
             able to comply with protocol requirements

         12. Resolution of all clinically significant treatment-related, non-hematological
             toxicities, except alopecia, from any previous cancer therapy to </= Grade 1 prior to
             the first dose of study treatment

         13. Female patients of childbearing potential must have a negative serum or urine
             pregnancy test within 7 days of the first dose of study drug and agree to use dual
             methods of contraception during the study and for a minimum of 3 months following the
             last dose of study drug. Post-menopausal females (> 45 years old and without menses
             for > 1 year) and surgically sterilized females are exempt from these requirements.
             Male patients must use an effective barrier method of contraception during the study
             and for a minimum of 3 months following the last dose of study drug if sexually active
             with a female of childbearing potential.

        Exclusion Criteria:

          1. Any prior or coexisting medical condition that in the investigator's judgment will
             substantially increase the risk associated with the subject's participation in the
             study.

          2. Subject has received a prior targeted IDH2 inhibitor

          3. Psychiatric disorders or altered mental status precluding understanding of the
             informed consent process and/or completion of the necessary study procedures

          4. Active uncontrolled infection at study enrollment including known diagnosis of human
             immunodeficiency virus or chronic active Hepatitis B or C infection

          5. Clinically significant gastrointestinal conditions or disorders that may interfere
             with study drug absorption, including prior gastrectomy

          6. Patients with known active CNS disease, including leptomeningeal involvement

          7. Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant
             cardiac disease including the following: a) New York Heart Association Grade III or IV
             congestive heart failure, b) myocardial infarction within the last 6 months

          8. Subjects with a QTc > 480 ms (QTc > 510 msec for subjects with a bundle branch block
             at baseline

          9. Nursing or pregnant women

         10. Subjects with known hypersensitivity to study drugs or their excipients
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse Events
Time Frame:Every third cycle of 28 days up to 3 years
Safety Issue:
Description:Adverse events determined by the overall incidence and severity of all reported adverse events using Common Toxicity Criteria v 4.0.

Secondary Outcome Measures

Measure:Evaluation of Molecular and Cellular Markers That May be Predictive of Antitumor Activity
Time Frame:Cycle 2 Day 1 and on Cycle 3 Day 1 where each cycle is 28 days
Safety Issue:
Description:Blood samples to be collected for analysis.
Measure:Overall Survival
Time Frame:Baseline up to three years
Safety Issue:
Description:Overall survival determined by death from any cause.
Measure:Event-Free Survival
Time Frame:Baseline up to 3 years
Safety Issue:
Description:Event-free survival defined as the number of days from the date of treatment initiation to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, and calculated for all patients.
Measure:Duration of Response
Time Frame:Baseline up to 3 years
Safety Issue:
Description:Duration of response is defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Myelodysplastic Syndrome
  • MDS
  • Enasidenib
  • AG-221
  • IDHIFA
  • Azacitidine
  • 5-Azacytidine
  • Azacytidine
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816

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