Phase 1/2 Study of Enasidenib (AG-221) in Adults With Advanced Hematologic Malignancies With an Isocitrate Dehydrogenase Isoform 2 (IDH2) Mutation

Completed · Phase 1/Phase 2

Conditions studied: Hematologic Neoplasms

In brief

The primary objectives of Phase 1 Dose Escalation/Part 1 Expansion are: * To assess the safety and tolerability of treatment with enasidenib administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in participants with advanced hematologic malignancies. * To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and/or the recommended Phase 2 dose (RP2D) of enasidenib in participants with advanced hematologic malignancies. The primary objective of Phase 2 is: • To assess the efficacy of enasidenib as treatment for participants with relapsed or refractory (R/R) acute myelogenous leukemia (AML) with an IDH2 mutation.

Key facts

Study ID

NCT01915498

Run by

Celgene

People needed

345

Starts

2013-08-27

Expected to finish

2023-10-31

Last updated by the study team

2024-10-22

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Subject must be greater than or equal to 18 years of age.
• Subjects must have an advanced hematologic malignancy including:
• Phase 1/ Dose escalation:
• Diagnosis of acute myelogenous leukemia (AML) according to World Health Organization (WHO) criteria;
• Disease refractory or relapsed (defined as the reappearance of > 5% blasts in the bone marrow).
• Untreated AML, greater than or equal to 60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor;
• Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor.
• Phase 1/Part 1 Expansion:
• Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any subject with AML regardless of age who has relapsed following a bone marrow transplant (BMT).
• Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML who have relapsed following a BMT.
• Arm 3: Untreated AML and age greater than or equal to 60 years that decline standard of care chemotherapy.
• Arm 4: Isocitrate dehydrogenase protein, 2 (IDH2)-mutated advanced hematologic malignancies not eligible for Arms 1 to 3.
• Phase 2:
• Diagnosis of AML according to World Health Organization (WHO) criteria and disease relapsed or refractory as defined by:
• Subjects who relapse after allogeneic transplantation;
• Subjects in second or later relapse;
• Subjects who are refractory to initial induction or re-induction treatment
• Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-risk status according to National Comprehensive Cancer Network (NCCN) Guidelines. Favorable-risk cytogenetics: inv(16), t(16;16), t(8;21), t(15;17)
• Subjects must have documented IDH2 gene-mutated disease:
• For subjects in the dose escalation phase and Part 1 Expansion, IDH2 mutation may be based on local evaluation. (Centralized testing will be performed retrospectively.)
• For subjects in the Phase 2 portion of the trial, central testing of IDH2 mutation of bone marrow aspirate and peripheral blood, is required during screening to confirm eligibility
• Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling and urine sampling during the study.
• The diagnosis and evaluation of AML or MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a "dry tap"), the diagnosis may be made from the core biopsy.
• Screening bone marrow aspirate and peripheral blood samples are required of all subjects. A bone marrow biopsy must be collected if adequate aspirate is not attainable unless:
• A bone marrow aspirate and biopsy was performed as part of the standard of care within 28 days prior to the start of the study treatment; and

You may not qualify if…

• Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-221, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). (The use of a stable dose of oral steroids post GVHD and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval.)
• Subjects who received systemic anticancer therapy or radiotherapy < 14 days prior to their first day of study drug administration. (Hydroxyurea is allowed for up to 28 days after the start of AG-221 for the control of peripheral leukemic blasts in subjects with white blood cell [WBC] counts > 30,000/μL as well as prior to enrollment).
• Subjects who received a small molecule investigational agent < 14 days prior to their first day of study drug administration. In addition, the first dose of AG-221 should not occur before a period ≥ 5 half-lives of the investigational agent has elapsed.
• Subjects taking the following sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2).
• Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the study unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.
• Subjects for whom potentially curative anticancer therapy is available.
• Subjects who are pregnant or lactating.
• Subjects with an active severe infection that required anti-infective therapy or with an unexplained fever > 38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
• Subjects with known hypersensitivity to any of the components of AG-221.
• Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of Cycle 1, Day 1 (C1D1).
• Subjects with a history of myocardial infarction within the last 6 months of screening.
• Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP > 100 mmHg) at screening are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval.
• Subjects with known unstable or uncontrolled angina pectoris.
• Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
• Subjects with heart-rate corrected QT (QTc) interval ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening.
• Subjects taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.
• Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
• Subjects with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study.
• Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
• Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia.
• Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
• In the Phase 2 portion of the trial only, subjects who have previously received treatment with an inhibitor of Isocitrate dehydrogenase ( IDH).

Where it is running

• City Of Hope — Duarte, California, United States
• Stanford Cancer Center — Stanford, California, United States
• University Of Colorado Cancer Center — Aurora, Colorado, United States
• University of Miami Sylvester Cancer Center — Miami, Florida, United States
• Florida Cancer Specialists — Sarasota, Florida, United States
• Moffitt Cancer Center — Tampa, Florida, United States
• Northwestern University — Chicago, Illinois, United States
• Massachusetts General Hospital — Boston, Massachusetts, United States
• Dana-Farber/Mass General Brigham Cancer Care, Inc — Boston, Massachusetts, United States
• Mayo Clinic — Rochester, Minnesota, United States
• Washington University — St Louis, Missouri, United States
• Cornell University Weill Medical College — New York, New York, United States
• Memorial Sloan-Kettering Cancer Center - NYC — New York, New York, United States
• Cleveland Clinic — Cleveland, Ohio, United States
• Ohio State University — Gahanna, Ohio, United States
• Oregon Health and Science University OHSU — Portland, Oregon, United States
• Sarah Cannon Research Institute Drug Development Unit — Nashville, Tennessee, United States
• Ut Southwestern Medical Center At Dallas — Dallas, Texas, United States
• MD Anderson Cancer Center — Houston, Texas, United States
• Local Institution - 202 — Bordeaux, France
• Local Institution - 204 — Paris, France
• Local Institution - 203 — Pessac, France
• Local Institution - 205 — Toulouse, France
• Local Institution - 201 — Villejuif, France

Full record on ClinicalTrials.gov

Trial information comes from ClinicalTrials.gov and is refreshed daily. TrialsForMe does not provide medical care and does not run the studies it lists.