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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

NCT02273739

Description:

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.

Related Conditions:
  • Angioimmunoblastic T-Cell Lymphoma
  • Glioma
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

    <li>Brief Title: 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 Mutationli><li>Official Title: 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 Mutationli>

Clinical Trial IDs

    <li>ORG STUDY ID: AG221-C-003li><li>NCT ID: NCT02273739li>

Conditions

    <li>Solid Tumorli><li>Gliomali><li>Angioimmunoblastic T-cell Lymphomali><li>Intrahepatic Cholangiocarcinomali><li>Chondrosarcomali>

Interventions

<td>AG-221td><td/><td>AG-221td>
DrugSynonymsArms

Purpose

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.

Trial Arms

<td>AG-221td><td>Experimentaltd><td/><td>
    <li>AG-221li>
td>
NameTypeDescriptionInterventions

Eligibility Criteria

        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
      
<td>Maximum Eligible Age:td><td>N/Atd><td>Minimum Eligible Age:td><td>18 Yearstd><td>Eligible Gender:td><td>Alltd><td>Healthy Volunteers:td><td>Notd>

Primary Outcome Measures

<td>Measure:td><td>Safety/tolerability: incidence of adverse eventstd><td>Time Frame:td><td>up to 26 weeks, on averagetd><td>Safety Issue:td><td/><td>Description:td><td/>

Secondary Outcome Measures

<td>Measure:td><td>Identification and Description of Dose Limiting Toxicities associated with AG-221 in subjects with advanced solid tumors, including glioma, and with AITLtd><td>Time Frame:td><td>up to 26 weeks, on averagetd><td>Safety Issue:td><td/><td>Description:td><td/>
<td>Measure:td><td>Pharmacokinetic profiles including max concentration (Cmax), time to maximum concentration (Tmax), AUC, and elimination half-lifetd><td>Time Frame:td><td>up to 26 weeks, on averagetd><td>Safety Issue:td><td/><td>Description:td><td>Descriptive statistics will be used to summarize PK profile parameters for each dose group and, where appropriate, for the entire populationtd>
<td>Measure:td><td>Pharmacodynamic relationship between levels of AG-221 and 2-HGtd><td>Time Frame:td><td>up to 26 weeks, on averagetd><td>Safety Issue:td><td/><td>Description:td><td>Descriptive and graphical methods will be used to explore the potential relationship between levels of AG-221 and 2-HG levelstd>
<td>Measure:td><td>Clinical Activity according to RECIST v1.1 (2009), RANO (2010), and IWG for malignant lymphoma (2007)td><td>Time Frame:td><td>up to 26 weeks, on averagetd><td>Safety Issue:td><td/><td>Description:td><td>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 AITLtd>

Details

<td>Phase:td><td>Phase 1/Phase 2td><td>Primary Purpose:td><td>Interventionaltd><td>Overall Status:td><td>Completedtd><td>Lead Sponsor:td><td>Celgenetd>

Trial Keywords

    <li>solid tumorli><li>intrahepatic cholangiocarcinomali><li>ICCli><li>chondrosarcomali><li>angioimmunoblastic T-cell lymphomali><li>AITLli><li>IDHli><li>gliomali><li>solid tumor, including intrahepatic cholangiocarcinoma and chondrosarcomali>

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