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

Trial Status: Active

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.

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

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Amy Elizabeth DeZern
Phone: 410-955-8964

Ohio

Cleveland
Cleveland Clinic Foundation
Status: ACTIVE
Contact: Mikkael Aaron Sekeres
Phone: 216-444-6833

Texas

Houston
M D Anderson Cancer Center
Status: ACTIVE
Contact: Courtney DiNardo
Phone: 713-794-1141

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 Phase Phase II

Trial Type Treatment

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Courtney DiNardo

  • Primary ID 2016-0981
  • Secondary IDs NCI-2018-00987
  • Clinicaltrials.gov ID NCT03383575