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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03683433
Recruitment Status : Recruiting
First Posted : September 25, 2018
Last Update Posted : August 16, 2019
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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 (recurrent) or does not respond to treatment (refractory). Enasidenib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Acute Bilineal Leukemia Acute Biphenotypic Leukemia Chronic Myelomonocytic Leukemia IDH2 Gene Mutation Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Azacitidine Drug: Enasidenib Mesylate Phase 2

Detailed Description:


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).


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).


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.


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. Cycles 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of the Targeted Mutant IDH2 Inhibitor Enasidenib in Combination With Azacitidine for Relapsed/Refractory AML
Actual Study Start Date : September 18, 2018
Estimated Primary Completion Date : September 20, 2021
Estimated Study Completion Date : September 20, 2021

Arm Intervention/treatment
Experimental: Treatment (azacitidine, enasidenib mesylate)
Patients receive azacitidine SC or IV over 30 minutes on days 1-7 and enasidenib mesylate PO QD beginning on day 1. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Drug: Enasidenib Mesylate
Given PO
Other Names:
  • 2-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
  • Idhifa

Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 5 years ]
    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 :
  1. Event-free survival [ Time Frame: Up to 5 years ]
    Kaplan-Meier method will be used to estimate the probabilities of event-free survival.

  2. Overall survival (OS) [ Time Frame: Up to 5 years ]
    Kaplan-Meier method will be used to estimate the probabilities of overall survival.

  3. Disease-free survival (DFS) [ Time Frame: Up to 5 years ]
    Log-rank tests will be used to compare among subgroups of patients in terms of DFS or OS.

  4. Duration of response [ Time Frame: Up to 5 years ]
    Log-rank tests will be used.

  5. Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ]

Other Outcome Measures:
  1. Minimal residual disease (MRD) [ Time Frame: Up to 5 years ]
    MRD negative status and exploratory biomarkers will be summarized graphically and with descriptive statistics.

  2. Association of biomarkers to overall response [ Time Frame: Up to 5 years ]
    Association between molecular and cellular markers and overall response and/or resistance assessed through logistic regression analyses.

  3. Change in markers over time [ Time Frame: Baseline up to 5 years ]
    Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03683433

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Contact: Courtney DiNardo 713-794-1141

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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Courtney DiNardo    713-794-1141      
Principal Investigator: Courtney DiNardo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
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Principal Investigator: Courtney DiNardo M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT03683433    
Other Study ID Numbers: 2018-0499
NCI-2018-01919 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0499 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: September 25, 2018    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Leukemia, Biphenotypic, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors