Acute Myeloid LeukemiaPhase 2NCT03383575
Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome
A Phase 2 study testing Azacitidine, Enasidenib and Quality-of-Life Assessment in people with Acute Myeloid Leukemia and Blasts 20-30 Percent of Bone Marrow Nucleated Cells, run by M.D. Anderson Cancer Center at 3 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Acute Myeloid Leukemia, Blasts 20-30 Percent of Bone Marrow Nucleated Cells, Chronic Myelomonocytic Leukemia
- What is being tested?
- Azacitidine, Enasidenib and Quality-of-Life Assessment
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 63 participants
- Where
- 3 sitesUnited States
- Study dates
- 17 Jan 2018to 28 Feb 2027
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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 locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States3 sites, 1 recruiting
- Active, not recruiting
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
- Active, not recruiting
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
- Recruiting
M D Anderson Cancer Center
Houston, Texas, 77030
Courtney DiNardo, 713-794-1141
Courtney DiNardo
About this study
Official title: Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome
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.
Read the 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).
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:
- 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:
- 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.
- 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
- Being tested
- Azacitidine, Enasidenib, Quality-of-Life Assessment
- Medical subject headings
- Leukemia, Myeloid, Acute, Leukemia, Myelomonocytic, Chronic, Anemia, Refractory, with Excess of Blasts
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
Also called 5 AZC, 5-AC, 5-Azacytidine, 5-AZC
Given IV or SC
EnasidenibDrug
Also called AG-221, CC-90007
Given PO
Quality-of-Life AssessmentOther
Also called Quality of Life Assessment
Ancillary studies
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Azacitidine; Drug: Enasidenib; Other: Quality-of-Life Assessment |
| 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. Receives: Drug: Enasidenib; Other: Quality-of-Life Assessment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of adverse events
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.
Measured: Up to 3 years
Overall response rate
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.
Measured: Up to 3 years
Secondary outcomes (5)
Event-free survival (EFS)
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.
Measured: Up to 3 years
Overall survival (OS)
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.
Measured: Up to 3 years
Anti-tumor activity
Will be summarized graphically and with descriptive statistics.
Measured: Up to 3 years
Pharmadynamics (PDn) markers
PDn markers will be summarized graphically and with descriptive statistics.
Measured: Up to 3 years
Drug exposure levels
Will be summarized graphically and with descriptive statistics.
Measured: Up to 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Dec 2017
- Study start17 Jan 2018
- Primary completion28 Feb 2027 (estimated)
- Study completion28 Feb 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 63 participants (estimated)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI), Celgene
- Responsible party
- Sponsor
- Investigators
- Courtney DiNardo, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03383575
- Sponsor's protocol ID
- 2016-0981
- Other IDs
- NCI-2018-00987, 2016-0981, P30CA016672
- Status last verified
- Aug 2026
- First submitted
- 8 Dec 2017
- Last updated
- 4 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
DiNardo CD, Venugopal S, Lachowiez C, Takahashi K, Loghavi S, Montalban-Bravo G, Wang X, Carraway H, Sekeres M, Sukkur A, Hammond D, Chien K, Maiti A, Masarova L, Sasaki K, Alvarado Y, Kadia T, Short NJ, Daver N, Borthakur G, Ravandi F, Kantarjian HM, Patel B, Dezern A, Roboz G, Garcia-Manero G. Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome. Blood Adv. 2023 Jun 13;7(11):2378-2387. doi: 10.1182/bloodadvances.2022008378.
PubMed 35973199