Clinical Trials /

Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation

NCT02481154

Description:

This study evaluates the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in Gliomas, that harbor an IDH1 and/or IDH2 mutation.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation
  • Official Title: A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation

Clinical Trial IDs

  • ORG STUDY ID: AG881-C-002
  • NCT ID: NCT02481154

Conditions

  • Glioma

Interventions

DrugSynonymsArms
AG881AG881

Purpose

This study evaluates the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in Gliomas, that harbor an IDH1 and/or IDH2 mutation.

Detailed Description

      The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics,
      pharmacodynamics and clinical activity of AG-881 in gliomas, that harbor an IDH1and/or IDH2
      mutation. The first portion of the study is a dose escalation phase where cohorts of patients
      will receive ascending oral doses of AG-881 to determine the maximum tolerated dose (MTD)
      and/or the recommended Phase II dose. The second portion of the study is a dose expansion
      phase where patients will receive AG-881 to further evaluate the safety, tolerability, and
      clinical activity of the recommended Phase II dose. The anticipated time on study treatment
      is until disease progression, unacceptable toxicity occurs or the patient is removed at the
      discretion of the investigator
    

Trial Arms

NameTypeDescriptionInterventions
AG881ExperimentalAG-881 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with AG-881 until disease progression, development of other unacceptable toxicity or Investigator discretion
  • AG881

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must be ≥18 years of age

          -  Patient must have histologically or cytologically confirmed solid tumor, including
             glioma, with documented IDH1 and/or IDH2 gene-mutation. Patients in the dose
             escalation phase must have disease that has recurred or progressed following standard
             therapy and/or therapy with an inhibitor of mutant IDH1 and/or IDH2, or that has not
             responded to this therapy. Patients in the expansion phase may have previously
             untreated disease

          -  Patient must have evaluable disease by RECIST v1.1 for patients without glioma or by
             RANO or RANO LGG criteria for patients with glioma

          -  Patients with glioma must have a baseline brain MRI scan

          -  Patient must have archived primary tumor biopsies or surgical specimens, or biopsies
             of recurrent or metastatic samples

          -  Patient must be amenable to serial peripheral blood sampling, urine sampling, and
             tumor biopsies during the study

          -  Patient must be able to understand and willing to sign an informed consent

          -  Patient must have ECOG PS of 0 to 2

          -  Patient must have expected survival of ≥3 months

          -  Patient must have adequate bone marrow function as evidenced by absolute neutrophil
             count ≥1.5 ×10^9/L; hemoglobin >9 g/dL (Patients are allowed to be transfused to this
             level); platelets ≥75 × 10^9/L

          -  Patient must have adequate hepatic function as evidenced by: Serum total bilirubin
             ≤1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease or
             disease involvement; Aspartate aminotransferase (AST), alanine aminotransferase (ALT),
             and alkaline phosphatase (ALP) ≤2.5 × ULN. For patients with bone metastases and/or
             suspected disease-related liver or biliary involvement, AST, ALT and ALP must be ≤5 ×
             ULN

          -  Patient must have 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) estimated: (140-Age) x (weight in kg) x (0.85 if female)/72 x serum
             creatinine

          -  Patient must be recovered from any clinically relevant toxic effects of any prior
             surgery, radiotherapy, or other therapy intended for the treatment of cancer

          -  Female patients with reproductive potential must have a negative serum pregnancy test
             within 7 days prior to first study drug administration. Patients with reproductive
             potential are defined as sexually mature women who have not undergone a hysterectomy,
             bilateral oophorectomy or tubal occlusion or who have not experienced natural
             menopause (i.e., who have not menstruated at all) for at least 24 consecutive months
             (i.e., have had menses at any time in the preceding 24 consecutive months). Women with
             reproductive potential as well as fertile men and their partners who are female with
             reproductive potential must agree to abstain from sexual intercourse or to use two
             highly effective forms of contraception from the time of giving informed consent,
             during the study, and for 90 days (females and males) following the last dose of AG
             881

        Exclusion Criteria:

          -  Patients who received systemic anticancer therapy or radiotherapy <21 days prior to
             their first day of study drug administration

          -  Patients who received an investigational agent (including AG-120 or AG-221) <14 days
             prior to their first day of study drug administration. In addition, the first dose of
             AG-881 should not occur before a period ≥5 half-lives of the investigational agent
             (other than AG-120 or AG-221) has elapsed.

          -  Patients with gliomas who have had prior treatment with bevacizumab (Avastin) are
             excluded

          -  Patients who are pregnant or breast feeding

          -  Patients 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, patients with tumor fever
             may be enrolled)

          -  Patients 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
             obtained within approximately 28 days of C1D1

          -  Patients with a history of myocardial infarction within the 6 months prior to
             screening

          -  Patients with known unstable or uncontrolled angina pectoris

          -  Patients with a known history of severe and/or uncontrolled ventricular arrhythmias

          -  Patients with 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)

          -  Patients 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, or unless
             the medications can be properly monitored during the study.

          -  Patients with known infection with human immunodeficiency virus (HIV) or active
             hepatitis B or C

          -  Patients with known dysphagia, short-gut syndrome, gastroparesis, or other conditions
             that limit the ingestion or gastrointestinal absorption of drugs administered orally

          -  Patients with brain metastases that are untreated, symptomatic, or require therapy to
             control symptoms; or any radiation, surgery, or other therapy, including those used to
             control symptoms, within 1 month of first dose

          -  Glioma patients with evidence of intracranial or intratumoral hemorrhage either by MRI
             or CT scan
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety/Tolerability; incidence of adverse events
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Pharmacokinetic profiles including max concentration (Cmax), time to maximum concentration (Tmax), AUC, and elimination half-life
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:
Measure:Pharmacodynamic levels of AG-881
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:
Measure:Pharmacodynamic levels of 2-HG
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:
Measure:Clinical Activity according to RECIST v 1.1 (2009) for patients with solid tumors, by RANO (2010) criteria for patients with glioma
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Agios Pharmaceuticals, Inc.

Trial Keywords

  • Glioma
  • IDH1
  • IDH2
  • Dual Mutation
  • AG-881

Last Updated

May 25, 2021