Clinical Trials /

Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome

NCT03383575

Description:

This phase II trial studies the side effects and how well azacitidine and enasidenib work in treating patients with IDH2-mutant myelodysplastic syndrome. Azacitidine and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine and Enasidenib in Treating Patients With 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
  • SECONDARY ID: 2016-0981
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03383575

Conditions

  • Acute Myeloid Leukemia
  • Blasts 20-30 Percent of Bone Marrow Nucleated Cells
  • Chronic Myelomonocytic Leukemia
  • IDH2 Gene Mutation
  • Myelodysplastic Syndrome With Excess Blasts
  • Recurrent High Risk Myelodysplastic Syndrome
  • Refractory High Risk Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaArm I (enasidenib, azacitidine)
EnasidenibAG-221, CC-90007Arm I (enasidenib, azacitidine)

Purpose

This phase II trial studies the side effects and how well azacitidine and enasidenib work in treating patients with IDH2-mutant myelodysplastic syndrome. Azacitidine and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of enasidenib alone, and enasidenib in
      combination with azacitidine (AZA), for patients with isocitrate dehydrogenase 2 (IDH2)
      mutated myelodysplastic syndrome (MDS).

      II. To assess the efficacy of the combination of enasidenib + azacitidine in hypomethylating
      agent (HMA) naive subjects with IDH2-mutated MDS, and to assess the efficacy of enasidenib
      single-agent in subjects with IDH2-mutated MDS who are relapsed/refractory to HMA therapy.

      SECONDARY OBJECTIVES:

      I. To evaluate molecular and cellular markers that may be predictive of antitumor activity
      and/or resistance including evaluation of IDH2 variant allele fraction (VAF) levels during
      treatment and presence of co-occurring mutations.

      II. To assess overall survival, event-free survival and duration of response of enasidenib
      alone, and enasidenib in combination with azacitidine.

      EXPLORATORY OBJECTIVES:

      I. To assess changes in cellular differentiation and changes in deoxyribonucleic acid (DNA)
      methylation profiles in IDH2-mutated MDS treated with enasidenib alone and with enasidenib +
      azacitidine.

      II. To evaluate quality of life (QOL) using an MDS-specific measure.

      OUTLINE: Patients are assigned to 1 of 2 arms.

      ARM I: Patients who are HMA-naive receive enasidenib orally (PO) once daily (QD) on days 1-28
      and azacitidine intravenously (IV) oveer 30-60 minutes or subcutaneously (SC) on days 1-7.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients relapsed and/or refractory to HMA therapy receive enasidenib PO QD on days
      1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 3
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (enasidenib, azacitidine)ExperimentalPatients who are HMA-naive receive enasidenib PO QD on days 1-28 and azacitidine IV over 30-60 minutes or SC on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Enasidenib
Arm II (enasidenib)ExperimentalPatients relapsed and/or refractory to HMA therapy receive enasidenib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Enasidenib

Eligibility Criteria

        Inclusion Criteria:

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

          -  Subjects with a histologically confirmed diagnosis of MDS, including both MDS and
             refractory anemia with excess blasts in transformation (RAEB-T) (acute myeloid
             leukemia [AML] with 20-30% blasts and multilineage dysplasia by
             French-American-British [FAB] criteria) by World Health Organization (WHO), and
             chronic myelomonocytic leukemia (CMML) are eligible

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

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

          -  (Arm A only): Subjects with high-risk MDS (i.e. International Prostate Symptom Score
             [IPSS] intermediate-2 or high-risk; or revised [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

          -  (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

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Serum bilirubin =< 2 x the upper limit of normal (ULN) (except for patients with
             Gilbert's disease)

          -  Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x the
             laboratory ULN

          -  Serum creatinine =< 2 x the ULN

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

          -  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

          -  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:

          -  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

          -  Subject has received a prior targeted IDH2 inhibitor

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

          -  Active uncontrolled infection at study enrollment including known diagnosis of human
             immunodeficiency virus or chronic active hepatitis B or C infection

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

          -  Patients with known active central nervous system (CNS) disease, including
             leptomeningeal involvement

          -  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

          -  Subjects with a corrected QT (QTc) > 480 ms (QTc > 510 msec for subjects with a bundle
             branch block at baseline

          -  Nursing or pregnant women

          -  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:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Will use the Bayesian method by Thall, Simon and Estey for toxicity monitoring. For purpose of toxicity monitoring, toxicity is defined as any grade 3 or higher treatment related-toxicities by Common Terminology Criteria for Adverse Events criteria.

Secondary Outcome Measures

Measure:Event-free survival (EFS)
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities of EFS. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.
Measure:Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities of OS. Log-rank tests will be used to compare among subgroups of patients in terms of OS.
Measure:Anti-tumor activity
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized graphically and with descriptive statistics.
Measure:Pharmadynamics (PDn) markers
Time Frame:Up to 3 years
Safety Issue:
Description:PDn markers will be summarized graphically and with descriptive statistics.
Measure:Drug exposure levels
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized graphically and with descriptive statistics.

Details

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

Last Updated

June 23, 2020