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

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ClinicalTrials.gov Identifier: NCT03383575
Recruitment Status : Recruiting
First Posted : December 26, 2017
Last Update Posted : May 17, 2019
Sponsor:
Collaborator:
Celgene
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to learn if enasidenib (AG-221) alone or in combination with azacitidine can help to control myelodysplastic syndrome (MDS). The safety of this drug will also be studied.

If you are reading and signing this form on behalf of a potential participant, please note: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.

This is an investigational study. Enasidenib is not FDA approved or commercially available. It is currently being used for research purposes only. Azacitidine is FDA approved and commercially available for the treatment of MDS. It is considered investigational to give enasidenib and azacitidine in combination for the treatment of MDS. The study doctor can explain how the study drug(s) are designed to work.

Up to 105 participants will be enrolled in this multicenter study. Up to 75 will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Myelodysplastic Syndrome Drug: Azacitidine Drug: Enasidenib Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
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 7, 2018
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: Azacitidine + Enasidenib

Participants that have never received a hypomethylating drug (such as azacitidine or decitabine), assigned to Arm A.

Participants in Arm A receive Azacitidine and Enasidenib.

Drug: Azacitidine
75 mg/m2/day by vein or subcutaneously on Days 1-7 of each 28-day cycle.
Other Names:
  • Azacytidine
  • 5-azacytidine
  • 5-AZA
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816

Drug: Enasidenib
Enasidenib starting dose of 100 mg by mouth daily on Days 1-28 of each 28-day cycle,
Other Names:
  • AG-221
  • IDHIFA

Experimental: Arm B: Enasidenib

Participants that have received a hypomethylating drug (such as azacitidine or decitabine) and have relapsed or refractory MDS, assigned to Arm B.

Participants in Arm B receive Enasidenib alone.

Drug: Enasidenib
Enasidenib starting dose of 100 mg by mouth daily on Days 1-28 of each 28-day cycle,
Other Names:
  • AG-221
  • IDHIFA




Primary Outcome Measures :
  1. Adverse Events [ Time Frame: Every third cycle of 28 days up to 3 years ]
    Adverse events determined by the overall incidence and severity of all reported adverse events using Common Toxicity Criteria v 4.0.

  2. Efficacy determined by clinical activity assessed based on Modified IWG Response Criteria for MDS [ Time Frame: Every third cycle of 28 days up to 3 years ]
    Efficacy determined by clinical activity assessed based on Modified IWG Response Criteria for MDS (Cheson et al, 2006).


Secondary Outcome Measures :
  1. Evaluation of Molecular and Cellular Markers That May be Predictive of Antitumor Activity [ Time Frame: Cycle 2 Day 1 and on Cycle 3 Day 1 where each cycle is 28 days ]
    Blood samples to be collected for analysis.

  2. Overall Survival [ Time Frame: Baseline up to three years ]
    Overall survival determined by death from any cause.

  3. Event-Free Survival [ Time Frame: Baseline up to 3 years ]
    Event-free survival defined as the number of days from the date of treatment initiation to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, and calculated for all patients.

  4. Duration of Response [ Time Frame: Baseline up to 3 years ]
    Duration of response is defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed, informed consent must be obtained prior to any study specific procedures.
  2. Subjects must be >/= 12 years of age at the time of informed consent
  3. Subjects with a histologically confirmed diagnosis of MDS, including both MDS and RAEB-T (AML with 20-30% blasts and multilineage dysplasia by FAB criteria) by World Health Organization (WHO), and chronic myelomonocytic leukemia (CMML) are eligible.
  4. Subjects must have an IDH2 gene mutation (IDH2-R140 or R172) as determined by local laboratory result.
  5. (Arm A only): Subject must be hypomethylating agent naïve (i.e. prior azacitidine, decitabine, SGI-110 is exclusionary). Receipt of other MDS-directed therapy such as lenalidomide is allowed
  6. (Arm A only): Subjects with high-risk MDS (i.e. IPSS Intermediate-2 or high-risk; or 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.
  7. (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
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
  9. Adequate liver function, as evidenced by a serum bilirubin </= 2x the ULN (except for patients with Gilbert's disease), ALT and/or AST </= 3x the laboratory ULN
  10. Serum creatinine </= 2x the ULN
  11. Able to understand and voluntarily sign a written informed consent, and willing and able to comply with protocol requirements
  12. 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
  13. 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:

  1. 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.
  2. Subject has received a prior targeted IDH2 inhibitor
  3. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
  4. Active uncontrolled infection at study enrollment including known diagnosis of human immunodeficiency virus or chronic active Hepatitis B or C infection
  5. Clinically significant gastrointestinal conditions or disorders that may interfere with study drug absorption, including prior gastrectomy
  6. Patients with known active CNS disease, including leptomeningeal involvement
  7. 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
  8. Subjects with a QTc > 480 ms (QTc > 510 msec for subjects with a bundle branch block at baseline
  9. Nursing or pregnant women
  10. Subjects with known hypersensitivity to study drugs or their excipients

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03383575


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

Locations
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United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Rami Komrokji, MD         
United States, Maryland
John Hopkins Recruiting
Baltimore, Maryland, United States, 21218
Contact: Amy DeZern, MD         
United States, Massachusetts
Dana Farber Recruiting
Boston, Massachusetts, United States, 02215
Contact: David Steensma, MD         
United States, New York
Weill Cornell Medicin Recruiting
New York, New York, United States, 10065
Contact: Gail Roboz, MD         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Mikkael Sekeres, MD         
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research Operations       cdinardo@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Celgene
Investigators
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Principal Investigator: Courtney DiNardo, MD M.D. Anderson Cancer Center

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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03383575     History of Changes
Other Study ID Numbers: 2016-0981
NCI-2018-00987 ( Registry Identifier: NCI CTRP )
First Posted: December 26, 2017    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Myelodysplastic Syndrome
MDS
Enasidenib
AG-221
IDHIFA
Azacitidine
5-Azacytidine
Azacytidine
5-aza
Vidaza
5-AZC
AZA-CR
Ladakamycin
NSC-102816

Additional relevant MeSH terms:
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Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors