Clinical Trials /

Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation

NCT03683433

Description:

This phase II trial studies how well enasidenib and azacitidine work in treating patients with IDH2 gene mutation and acute myeloid leukemia that has come back or does not respond to treatment. Enasidenib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Acute Bilineal Leukemia
  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation
  • Official Title: Phase II Study of the Targeted Mutant IDH2 Inhibitor Enasidenib in Combination With Azacitidine for Relapsed/Refractory AML

Clinical Trial IDs

  • ORG STUDY ID: 2018-0499
  • SECONDARY ID: NCI-2018-01919
  • SECONDARY ID: 2018-0499
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03683433

Conditions

  • Acute Bilineal Leukemia
  • Acute Biphenotypic Leukemia
  • Chronic Myelomonocytic Leukemia
  • IDH2 Gene Mutation
  • Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, enasidenib mesylate)
Enasidenib Mesylate2-Methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol Methanesulfonate, 2-Propanol, 2-Methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-, Methanesulfonate (1:1), AG-221 Mesylate, CC-90007, Enasidenib Methanesulfonate, IdhifaTreatment (azacitidine, enasidenib mesylate)

Purpose

This phase II trial studies how well enasidenib and azacitidine work in treating patients with IDH2 gene mutation and acute myeloid leukemia that has come back or does not respond to treatment. Enasidenib and azacitidine 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 clinical activity of enasidenib mesylate (AG221, IDHIFA) in combination
      with azacitidine (AZA) for patients with relapsed/refractory acute myeloid leukemia is
      measured by overall response rate (ORR).

      SECONDARY OBJECTIVES:

      I. To determine duration of response, event-free survival (EFS), and overall survival (OS).

      II. To determine the safety of enasidenib in combination with azacitidine in patients with
      relapsed/refractory acute myeloid leukemia (AML).

      EXPLORATORY OBJECTIVES:

      I. To evaluate occurrence of minimal residual disease (MRD) negative status by IDH2 mutation
      analysis and flow cytometry.

      II. To investigate possible relationships between baseline protein and gene expression
      signatures and mutation profile and clinical response to the combination.

      III. To evaluate the incidence and characteristics of IDH-inhibitor related differentiation
      syndrome (IDH-DS) with combination therapy.

      OUTLINE:

      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30 minutes on
      days 1-7 and enasidenib mesylate orally (PO) once daily (QD) beginning on day 1. Courses
      repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 3-6
      months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, enasidenib mesylate)ExperimentalPatients receive azacitidine SC or IV over 30 minutes on days 1-7 and enasidenib mesylate PO QD beginning on day 1. Courses repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Enasidenib Mesylate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with AML or biphenotypic or bilineage leukemia (including a myeloid
             component) who have failed prior therapy. Patients with isolated extramedullary AML
             are eligible. The World Health Organization (WHO) classification will be used for AML

          -  Elderly (> 60 years old) patients with newly diagnosed AML not eligible for intensive
             chemotherapy are also eligible

          -  AML patients with prior history of myelodysplastic syndrome (MDS) or chronic
             myelomonocytic leukemia (CMML) regardless of prior therapy received, are eligible at
             the time of diagnosis of AML

          -  Subjects must have documented IDH2 gene mutation

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 3

          -  Adequate renal function including creatinine < 2 unless related to the disease

          -  Total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's
             disease or leukemic involvement

          -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN
             unless considered due to leukemic involvement

          -  Provision of written informed consent

          -  Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly
             proliferative disease is allowed before the start of study therapy, as needed, for
             clinical benefit and after discussion with the principal investigator (PI). Concurrent
             therapy for central nervous system (CNS) prophylaxis or continuation of therapy for
             controlled CNS disease is permitted

          -  Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
             at least 12 months) or if of childbearing potential, must have a negative serum or
             urine pregnancy test within 72 hours before the start of the treatment

          -  Women of childbearing potential must agree to use an adequate method of contraception
             during the study and until 3 months after the last treatment. Males must be surgically
             or biologically sterile or agree to use an adequate method of contraception during the
             study until 3 months after the last treatment

        Exclusion Criteria:

          -  Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia
             (French-American-British [FAB] class M3-AML)

          -  Active and uncontrolled comorbidities including active uncontrolled infection,
             uncontrolled hypertension despite adequate medical therapy, active and uncontrolled
             congestive heart failure New York Heart Association (NYHA) class III/IV, clinically
             significant and uncontrolled arrhythmia as judged by the treating physician

          -  Any other medical, psychological, or social condition that may interfere with study
             participation or compliance, or compromise patient safety in the opinion of the
             investigator

          -  Pregnant or breastfeeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description:The study will estimate the ORR for the combination treatment, along with the Bayesian 95% credible interval. ORR will be defined as the proportion of patients who had CR (complete remission), CRh (complete remission with incomplete hematologic recovery), CRi (complete remission with incomplete count recovery), PR (partial response), and/or marrow clearance of blasts (MLFS).

Secondary Outcome Measures

Measure:Event-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:Kaplan-Meier method will be used to estimate the probabilities of event-free survival.
Measure:Overall survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description:Kaplan-Meier method will be used to estimate the probabilities of overall survival.
Measure:Disease-free survival (DFS)
Time Frame:Up to 5 years
Safety Issue:
Description:Log-rank tests will be used to compare among subgroups of patients in terms of DFS or OS.
Measure:Duration of response
Time Frame:Up to 5 years
Safety Issue:
Description:Log-rank tests will be used.
Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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