Study of Orally Administered Enasidenib (AG-221) in Adults With Advanced Solid Tumors, Including Glioma, or Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation

NCT02273739 | Completed Phase 1 Results

• 2 other identifiers: AG221-C-0032014-003424-47
• Study Type: interventional
• Target: 21
• Locations: 2 countries
• Sites: 12

Brief Summary

The purpose of this study is to evaluate the safety, pharmacokinetics, and clinical activity of enasidenib in adults with advanced solid tumors, including glioma, or with angioimmunoblastic T-cell lymphoma (AITL), with an isocitrate dehydrogenase-2 (IDH2) mutation.

Conditions

Solid Tumor; Glioma; Angioimmunoblastic T-cell Lymphoma; Intrahepatic Cholangiocarcinoma; Chondrosarcoma

Keywords

solid tumor; intrahepatic cholangiocarcinoma; chondrosarcoma; angioimmunoblastic T-cell lymphoma; AITL; IDH; glioma; solid tumor, including intrahepatic cholangiocarcinoma and chondrosarcoma

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  Treatment-emergent adverse events included any adverse events (AEs) occurring or worsening on or after the first dose of study drug and within 28 days after the last dose of the study drug. Severity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03 or according to the following scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5= Fatal, death related to AE. A serious AE is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required or prolonged existing inpatient hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event. Relationship to study drug administration was determined by the investigator as not related, possibly related, or probably related; all AEs classified as possibly or probably related were considered treatment-related.

  From first dose of study drug to 28 days after last dose; median (minimum, maximum) duration of exposure was 66 (8, 197) days across all cohorts.

• Number of Participants With Dose-limiting Toxicities

  Toxicities were graded and documented according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. A dose-limiting toxicity (DLT) was defined as an event considered related to enasidenib and meeting 1 of the following criteria: Non-hematologic: \- All clinically significant non-hematologic toxicities CTCAE ≥ Grade 3, considered not related to underlying disease or intercurrent illness, with the exception of ≥ Grade 3 blood bilirubin increases in participants with a uridine diphosphate-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) mutation. In participants with a UGT1A1 mutation, blood bilirubin increases of \> 5 × upper limit of normal (ULN) were considered a DLT. Hematologic: \- Drug-related, prolonged myelosuppression of ≥ Grade 4 neutropenia or thrombocytopenia lasting beyond Day 28 of Cycle 1 unless related to bone marrow involvement by AITL.

  Cycle 1 (28 days)

• Eastern Cooperative Oncology Group (ECOG) Performance Status at Each Visit

  ECOG performance status is used by doctors and researchers to assess how a subjects disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. * 0 = Fully active (most favorable activity); * 1 = Restricted activity but ambulatory; * 2 = Ambulatory but unable to carry out work activities; * 3 = Limited self-care; * 4 = Completely disabled, no self-care (least favorable activity).

  Baseline, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and at end of treatment

Secondary Outcomes (17)

• Maximum Observed Plasma Concentration (Cmax) After a Single Dose of Enasidenib on Day -3

  Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

• Time of Maximum Plasma Concentration (Tmax) of Enasidenib After a Single Dose on Day -3

  Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

• Area Under the Plasma Concentration Time Curve From Time Zero to 10 Hours Postdose (AUC0-10) of Enasidenib After a Single Oral Dose on Day -3

  Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, and 10 hours post-dose.

• Area Under the Plasma Concentration Time Curve From Time Zero to 72 Hours Postdose (AUC0-72) of Enasidenib After a Single Dose on Day -3

  Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

• Maximum Observed Plasma Concentration (Cmax) of Metabolite AGI-16903 After a Single Dose of Enasidenib on Day -3

  Day -3 pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

Other Outcomes (1)

• Maximum Increase From Baseline in Corrected QT Interval Based on Fridericia's Formula (QTcF) by Category

  Baseline, Cycle 1 Days 1, 8, 15, and 22, Cycle 2 Days 1 and 15 and Day 1 of every cycle thereafter.

Study Arms (1)

Enasidenib

EXPERIMENTAL

During the dose escalation phase, consented eligible participants will be enrolled into sequential cohorts of increasing doses of enasidenib.The starting dose for this study is 100 mg administered every 24 hours,

Drug: Enasidenib

Interventions

Enasidenib DRUG

Enasidenib tablets administered orally once a day in 28-day treatment cycles until disease progression or unacceptable toxicities.

Also known as: AG-221, IDHIFA®

Enasidenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be ≥ 18 years of age
• Histologically or cytologically confirmed advanced solid tumor, including glioma, or angioimmunoblastic T-cell lymphoma (AITL) that has recurred or progressed following standard therapy, or that has not responded to standard therapy
• Subjects must be amenable to peripheral blood sampling, urine sampling, and biopsies during the study. Subjects with AITL must also be amenable to serial bone marrow biopsies
• Documented IDH2 gene-mutated disease based on local site testing
• Measurable disease by RECIST v1.1 for subjects with solid tumors without glioma, by modified RANO criteria for subjects with glioma, or by the revised IWG criteria for subjects with AITL
• Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Adequate bone marrow function (subjects other than those with AITL) as evidenced by: absolute neutrophil count ≥ 1.0 ×10\^9/L; hemoglobin \> 9 g/dL (subjects may be transfused red blood cells to this level.); platelets ≥ 50 × 10\^9/L
• Adequate hepatic function as evidenced by: serum total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease, a gene mutation in UGT1A1, or disease involvement, following approval by the Medical Monitor; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤ 2.5 × ULN, with the exception of subjects with bone metastases and/or suspected disease-related liver or biliary involvement, where ALP must be ≤ 5 × ULN
• Adequate renal function as evidenced by: serum creatinine ≤ 2.0 × ULN; OR creatinine clearance \> 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine
• Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of AG-221
• Previous allogeneic stem cell transplant is allowed only if subjects are \>100 days from stem cell transplant and do not have uncontrolled acute or chronic graft-vs-host disease

You may not qualify if:

• Received systemic anticancer therapy or radiotherapy \< 21 days prior to their first day of study drug administration
• Received an 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 prior to enrolling: 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 prior to enrolling. study unless they can be transferred to other medications prior to enrolling
• Subjects for whom potentially curative anticancer therapy is available
• Pregnant or breastfeeding
• 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)
• 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 1Day 1
• History of myocardial infarction within the last 6 months
• Subjects with uncontrolled hypertension (systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 100 mmHg) are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval.
• Known unstable or uncontrolled angina pectoris
• Known history of severe and/or uncontrolled ventricular arrhythmias
• Subjects taking medications that are known to prolong the QT interval
• Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C

Sponsors & Collaborators

• Celgene: lead
• Celgene Corporation: collaborator

Study Sites (12)

Unknown Facility

Los Angeles, California, 90095, United States

Location

Unknown Facility

Los Angeles, California, 91010, United States

Location

Unknown Facility

Miami, Florida, 33136, United States

Location

Unknown Facility

Baltimore, Maryland, 21287, United States

Location

Unknown Facility

Boston, Massachusetts, 02114, United States

Location

Unknown Facility

Omaha, Nebraska, 68198, United States

Location

Unknown Facility

New York, New York, 10065, United States

Location

Unknown Facility

Cleveland, Ohio, 44195, United States

Location

Unknown Facility

Nashville, Tennessee, 37203, United States

Location

Unknown Facility

Dallas, Texas, 75390, United States

Location

Unknown Facility

Bordeaux, 61283 33076, France

Location

Unknown Facility

Villejuif, 94805, France

Location

MeSH Terms

Conditions

Glioma; Immunoblastic Lymphadenopathy; Cholangiocarcinoma; Chondrosarcoma

Interventions

enasidenib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Lymphadenopathy; Lymphatic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma

Limitations and Caveats

The study was to be conducted in 2 parts: a dose-escalation and an expansion phase. Enrollment was closed after entry into Cohort 4 to focus resources on the development of other pipeline IDH inhibitors in other tumors; there were no safety concerns.

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please email:

Study Officials

• Clinical Development

  Agios Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 16, 2014
• First Posted: October 24, 2014
• Study Start: December 8, 2014
• Primary Completion: June 3, 2016
• Study Completion: June 3, 2016
• Last Updated: February 23, 2021
• Results First Posted: February 23, 2021

Record last verified: 2021-02

Locations

US (10); FR (2)