Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial Summary
This study evaluates the safety, pharmacokinetics, pharmacodynamics and clinical activity of
AG-881 in Gliomas, that harbor an IDH1 and/or IDH2 mutation.
Phase
Phase 1
Funding Agency/Sponsor
Industrial
Disease
Neurological Cancer
Enrollment Eligibility
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