--- title: Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome nct_id: NCT03383575 overall_status: RECRUITING phase: PHASE2 sponsor: M.D. Anderson Cancer Center study_type: INTERVENTIONAL primary_condition: Acute Myeloid Leukemia countries: United States canonical_url: "https://parkinsonspathways.com/agent/trials/NCT03383575.md" clinicaltrials_gov: "https://clinicaltrials.gov/study/NCT03383575" ct_last_update_post_date: 2026-02-17 last_seen_at: "2026-05-12T07:14:30.285Z" source: ClinicalTrials.gov (mirrored, no enrichment) --- # 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 **NCT ID:** [NCT03383575](https://clinicaltrials.gov/study/NCT03383575) ## Key Facts - **Status:** RECRUITING - **Phase:** PHASE2 - **Study Type:** INTERVENTIONAL - **Target Enrollment:** 63 - **Lead Sponsor:** M.D. Anderson Cancer Center - **Collaborators:** National Cancer Institute (NCI), Celgene - **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 - **Start Date:** 2018-01-17 - **Completion Date:** 2027-02-28 - **CT.gov Last Update:** 2026-02-17 ## Brief Summary 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. ## Eligibility - **Minimum age:** 12 Years - **Sex:** ALL - **Healthy Volunteers:** No ``` 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 ``` ## Arms - **Arm I (enasidenib, azacitidine)** (EXPERIMENTAL) — Patients 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. - **Arm II (enasidenib)** (EXPERIMENTAL) — 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. ## Interventions - **Azacitidine** (DRUG) — Given IV or SC - **Enasidenib** (DRUG) — Given PO - **Quality-of-Life Assessment** (OTHER) — Ancillary studies ## Primary Outcomes - **Incidence of adverse events** _(time frame: Up to 3 years)_ — 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. - **Overall response rate** _(time frame: Up to 3 years)_ — Defined as complete response (CR), partial response, and marrow CR assessed by International Working Group criteria. Will be estimated along with the 90% credible interval. ## Secondary Outcomes - **Event-free survival (EFS)** _(time frame: Up to 3 years)_ - **Overall survival (OS)** _(time frame: Up to 3 years)_ - **Anti-tumor activity** _(time frame: Up to 3 years)_ - **Pharmadynamics (PDn) markers** _(time frame: Up to 3 years)_ - **Drug exposure levels** _(time frame: Up to 3 years)_ ## Locations (3) - Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, Maryland, United States — _ACTIVE_NOT_RECRUITING_ - Cleveland Clinic Foundation, Cleveland, Ohio, United States — _ACTIVE_NOT_RECRUITING_ - M D Anderson Cancer Center, Houston, Texas, United States — _RECRUITING_ ## Recent Field Changes (last 30 days) - `status.overallStatus` — added _(2026-05-12)_ - `status.primaryCompletionDate` — added _(2026-05-12)_ - `status.completionDate` — added _(2026-05-12)_ - `status.lastUpdatePostDate` — added _(2026-05-12)_ - `design.phases` — added _(2026-05-12)_ - `design.enrollmentCount` — added _(2026-05-12)_ - `eligibility.criteria` — added _(2026-05-12)_ - `eligibility.minAge` — added _(2026-05-12)_ - `eligibility.sex` — added _(2026-05-12)_ - `outcomes.primary` — added _(2026-05-12)_ - `outcomes.secondary` — added _(2026-05-12)_ - `armsInterventions.arms` — added _(2026-05-12)_ - `armsInterventions.interventions` — added _(2026-05-12)_ - `sponsor.lead` — added _(2026-05-12)_ - `sponsor.collaborators` — added _(2026-05-12)_ - `results.hasResults` — added _(2026-05-12)_ - `locations.johns hopkins university/sidney kimmel cancer center|baltimore|maryland|united states` — added _(2026-05-12)_ - `locations.cleveland clinic foundation|cleveland|ohio|united states` — added _(2026-05-12)_ - `locations.m d anderson cancer center|houston|texas|united states` — added _(2026-05-12)_ --- *Canonical: https://parkinsonspathways.com/agent/trials/NCT03383575.md* *Source data (authoritative): https://clinicaltrials.gov/study/NCT03383575* *This page is a raw mirror with no AI summary, no editorial enrichment, and no Parkinson's-specific filtering.*