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

Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an <span class="go-doc-concept go-doc-biomarker">IDH1</span> and/or <span class="go-doc-concept go-doc-alteration">IDH2 Mutation</span>

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

    NCT ID: NCT02481154

    ORG ID: AG881-C-002

    Trial Conditions

    Cholangiocarcinoma

    Chondrosarcoma

    Glioma

    Trial Interventions

    Drug Synonyms Arms
    AG881 AG881

    Trial Purpose

    This study evaluates the safety, pharmacokinetics, pharmacodynamics and clinical activity of
    AG-881 in advanced solid tumors, including 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 advanced solid tumors, including
    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

    Name Type Description Interventions
    AG881 Experimental AG-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 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, 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 >38.5C 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 using Bazett's formula (QTcB) 480 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

    - 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 2 months of first dose

    - Glioma patients with evidence of intracranial or intratumoral hemorrhage either by
    MRI or CT scan

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Safety/Tolerability; incidence of adverse events

    Maximum Tolerated Dose and/or the recommended Phase II dose of AG881 in patients with advance solid tumors, including gliomas

    Secondary Outcome Measures

    Pharmacokinetic profiles including max concentration (Cmax), time to maximum concentration (Tmax), AUC, and elimination half-life

    Pharmacodynamic levels of AG-881

    Pharmacodynamic levels of 2-HG

    Clinical Activity according to RECIST v 1.1 (2009) for patients with solid tumors, by RANO (2010) criteria for patients with glioma

    Trial Keywords

    Chondrosarcoma

    Cholangiocarcinoma

    Advanced Solid Tumors

    Glioma

    IDH1

    IDH2

    Dual Mutation

    AG-881