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

M.D. Anderson Cancer Center

Status and phase: Enrolling; Phase 2

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

Treatments: Drug: Azacitidine; Drug: Enasidenib; Other: Quality-of-Life Assessment

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT03383575

NCI-2018-00987 (Registry Identifier)

P30CA016672 (U.S. NIH Grant/Contract)

2016-0981 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 63 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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63 participants in 2 patient groups

Arm I (enasidenib, azacitidine)

Experimental group

Description:

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.

Treatment:

Other: Quality-of-Life Assessment

Drug: Enasidenib

Drug: Azacitidine

Arm II (enasidenib)

Experimental group

Description:

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.

Treatment:

Other: Quality-of-Life Assessment

Drug: Enasidenib