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

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03383575

Collaborator

National Cancer Institute (NCI) (NIH), Celgene (Industry)

105

Enrollment

Locations

Arms

61.4

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Azacitidine Drug: Enasidenib Other: Quality-of-Life Assessment	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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).
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:

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.
To assess overall survival, event-free survival and duration of response of enasidenib alone, and enasidenib in combination with azacitidine.

EXPLORATORY OBJECTIVES:

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.
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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

105 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome

Actual Study Start Date :

Jan 17, 2018

Anticipated Primary Completion Date :

Feb 28, 2022

Anticipated Study Completion Date :

Feb 28, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (enasidenib, azacitidine) 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.	Drug: Azacitidine Given IV or SC Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar U-18496 Vidaza Drug: Enasidenib Given PO Other Names: AG-221 CC-90007 Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment
Experimental: Arm II (enasidenib) 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.	Drug: Enasidenib Given PO Other Names: AG-221 CC-90007 Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment

Arm

Intervention/Treatment

Experimental: Arm I (enasidenib, azacitidine)

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.

Drug: Azacitidine

Given IV or SC

Other Names:

5 AZC

5-AC

5-Azacytidine

5-AZC

Azacytidine

Azacytidine, 5-

Ladakamycin

Mylosar

U-18496

Vidaza

Drug: Enasidenib

Given PO

Other Names:

AG-221

CC-90007

Other: Quality-of-Life Assessment

Ancillary studies

Other Names:

Quality of Life Assessment

Experimental: Arm II (enasidenib)

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.

Drug: Enasidenib

Given PO

Other Names:

AG-221

CC-90007

Other: Quality-of-Life Assessment

Ancillary studies

Other Names:

Quality of Life Assessment

Outcome Measures

Primary Outcome Measures

Incidence of adverse events [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 [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 Outcome Measures

Event-free survival (EFS) [Up to 3 years]
The Kaplan-Meier method will be used to estimate the probabilities of EFS. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.
Overall survival (OS) [Up to 3 years]
The Kaplan-Meier method will be used to estimate the probabilities of OS. Log-rank tests will be used to compare among subgroups of patients in terms of OS.
Anti-tumor activity [Up to 3 years]
Will be summarized graphically and with descriptive statistics.
Pharmadynamics (PDn) markers [Up to 3 years]
PDn markers will be summarized graphically and with descriptive statistics.
Drug exposure levels [Up to 3 years]
Will be summarized graphically and with descriptive statistics.

Other Outcome Measures

Biomarkers analysis [Up to 3 years]
The association between molecular and cellular markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
2	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
3	M D Anderson Cancer Center	Houston	Texas	United States	77030