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Drug Interventions

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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 06/01/2020.

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

Clinicaltrials.gov identifier NCT03383575

Recruitment Status Recruiting

First Posted December 26, 2017

Last update posted March 6, 2020

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: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
  • Intervention/Treatment: Drug: Azacitidine
    Drug: Enasidenib
    Other: Quality-of-Life Assessment
  • Phase: Phase 2
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.

Study Design
  • Study Type: Interventional
  • Estimated 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: January 2018
  • Estimated Primary Completion Date: February 2022
  • Estimated Study Completion Date: February 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

Drug: Enasidenib
Given PO

Other: Quality-of-Life Assessment
Ancillary studies
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: Quality-of-Life Assessment
Ancillary studies
Outcome Measures
  • Primary Outcome Measures: 1. 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.
  • 2. 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 Outcome Measures: 1. Event-free survival (EFS) [ Time Frame: 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.
  • 2. Overall survival (OS) [ Time Frame: 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.
  • 3. Anti-tumor activity [ Time Frame: Up to 3 years ]
    Will be summarized graphically and with descriptive statistics.
  • 4. Pharmadynamics (PDn) markers [ Time Frame: Up to 3 years ]
    PDn markers will be summarized graphically and with descriptive statistics.
  • 5. Drug exposure levels [ Time Frame: Up to 3 years ]
    Will be summarized graphically and with descriptive statistics.
  • Other Outcome Measures: 1. Biomarkers analysis [ Time Frame: 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
  • Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
Criteria

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 = 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
Contacts

Contact: Courtney DiNardo, MD 713-794-1141 cdinardo@mdanderson.org

Locations

United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore

United States, Ohio
Cleveland Clinic Foundation
Cleveland

United States, Texas
M D Anderson Cancer Center
Houston

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Celgene

Investigators

Principal Investigator: Courtney DiNardo M.D. Anderson Cancer Center

More Information
  • Responsible Party: M.D. Anderson Cancer Center
  • ClinicalTrials.gov Identifier: NCT03383575 History of Changes
  • Other Study ID Numbers: 2016-0981, NCI-2018-00987, 2016-0981, P30CA016672
  • First Posted: December 26, 2017 Key Record Dates
  • Last Update Posted: March 6, 2020
  • Last Verified: March 2020
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Additional relevant MeSH terms: Leukemia
    Preleukemia
    Leukemia, Myelomonocytic, Chronic
    Leukemia, Myelomonocytic, Juvenile
    Myelodysplastic Syndromes
    Anemia, Refractory, with Excess of Blasts
    Syndrome