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Study of Orally Administered AG-221 in Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation

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ClinicalTrials.gov Identifier: NCT02273739
Recruitment Status : Completed
First Posted : October 24, 2014
Last Update Posted : October 30, 2018
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE October 16, 2014
First Posted Date  ICMJE October 24, 2014
Last Update Posted Date October 30, 2018
Actual Study Start Date  ICMJE October 24, 2014
Actual Primary Completion Date June 30, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2014)
  • Safety/tolerability: incidence of adverse events [ Time Frame: up to 26 weeks, on average ]
  • Maximum Tolerated Dose and/or the recommended Phase II dose of AG-221 in subjects with advanced solid tumors, including glioma, and AITL [ Time Frame: up to 26 weeks, on average ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2014)
  • Identification and Description of Dose Limiting Toxicities associated with AG-221 in subjects with advanced solid tumors, including glioma, and with AITL [ Time Frame: up to 26 weeks, on average ]
  • Pharmacokinetic profiles including max concentration (Cmax), time to maximum concentration (Tmax), AUC, and elimination half-life [ Time Frame: up to 26 weeks, on average ]
    Descriptive statistics will be used to summarize PK profile parameters for each dose group and, where appropriate, for the entire population
  • Pharmacodynamic relationship between levels of AG-221 and 2-HG [ Time Frame: up to 26 weeks, on average ]
    Descriptive and graphical methods will be used to explore the potential relationship between levels of AG-221 and 2-HG levels
  • Clinical Activity according to RECIST v1.1 (2009), RANO (2010), and IWG for malignant lymphoma (2007) [ Time Frame: up to 26 weeks, on average ]
    Clinical activity will be assessed based on 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Orally Administered AG-221 in Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation
Official Title  ICMJE A Phase 1/2, Multicenter, Open-Label, Dose-Escalation Study of AG-221 in Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, That Harbor an IDH2 Mutation
Brief Summary The purpose of this Phase 1/2, multi-center study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-221 in subjects with advanced solid tumors, including glioma, and with angioimmunoblastic T-cell lymphoma (AITL), with an IDH2 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-221 to determine maximum tolerated dose (MTD) and/or the recommended Phase 2 dose. The second portion of the study is a planned dose expansion phase where three cohorts of patients will receive AG-221 to further evaluate the safety, tolerability, and clinical activity. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumor
  • Glioma
  • Angioimmunoblastic T-cell Lymphoma
  • Intrahepatic Cholangiocarcinoma
  • Chondrosarcoma
Intervention  ICMJE Drug: AG-221
AG-221 administered orally on every day of 28 day cycles until disease progression or unacceptable toxicities. Multiple doses.
Study Arms  ICMJE Experimental: AG-221
Intervention: Drug: AG-221
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 21, 2016)
21
Original Estimated Enrollment  ICMJE
 (submitted: October 23, 2014)
45
Actual Study Completion Date  ICMJE June 30, 2016
Actual Primary Completion Date June 30, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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 ECOG PS of 0 to 2
  • Adequate bone marrow function (subjects other than those with AITL) as evidenced by: absolute neutrophil count ≥1.0 ×109/L;hemoglobin >9 g/dL (Subjects may be transfused red blood cells to this level.); platelets ≥50 × 109/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; AST, ALT, 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 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

Exclusion Criteria:

  • 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 LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1
  • 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
  • Heart-rate corrected QT (QTc) interval >450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with right bundle branch block and a prolonged QTc interval should be reviewed by the Medical Monitor for potential inclusion
  • Subjects taking medications that are known to prolong the QT interval
  • Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
  • 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
  • Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
  • Subjects with brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy, including to control symptoms, within 2 months of first dose. Subjects with glioma who are on a stable, steroid-dosing regimen prior to screening MRI may be permitted to enroll with Medical Monitor approval
  • In subjects with AITL, evidence of meningeal or cerebral disease or a history of progressive multifocal leukoencephalopathy
  • Radiotherapy involving <25% of the hematopoietically active bone marrow within 21 days preceding first dose of study treatment
  • Radiotherapy involving ≥25% of the hematopoietically active bone marrow within 42 days preceding first dose of study treatment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02273739
Other Study ID Numbers  ICMJE AG221-C-003
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Celgene Corporation
Investigators  ICMJE
Study Director: Clinical Development Agios Pharmaceuticals, Inc.
PRS Account Celgene
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP