This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drug is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved ASTX727 as a treatment for
any disease.
ASTX727 is made up of the 2 study drugs cedazuridine and decitabine. Cedazuridine is believed
to work by slowing down how fast decitabine is broken down by the body. Decitabine is
believed to work by blocking abnormal cells or cancer cells from growing.
Inclusion Criteria:
- Participants must be ≥18 years of age.
- Participants must have histologically or cytologically confirmed glioma, with
documented IDH1 and/or IDH2 gene-mutation.
- Participants must have radiographic evidence of non-enhancing disease
progression/recurrence per RANO criteria for low grade gliomas (LGG).
- Patients who have received prior treatment with chemotherapy, radiation, or a
combination of both are eligible. Also, patients who have not received any prior
treatment for their glioma are also eligible.
- Participants must be ≥12 weeks from completion of radiation.
- Participants must have a baseline brain MRI scan within 28 days prior to Day 1 of
treatment.
- Participants must be on a stable or decreasing dose of glucocorticoids for 7 days
prior to registration.
- Participants must have archived primary tumor biopsies or surgical specimens for
additional exploratory translational studies. At least 100-micron length of FFPE
tissue or a tissue block should be available for enrollment and for shipment to the
Sponsor, or a laboratory designated by the Principal Investigator. If less material is
available, participants could still be eligible after discussion with the Principal
Investigator who will assess and confirm that there is sufficient material for key
evaluations.
- Participants must be able to understand and willing to sign an informed consent. A
legally authorized representative may consent on behalf of a participant who is
otherwise unable to provide informed consent, if acceptable to and approved by the
site and/or site's Institutional Review Board (IRB)/Independent Ethics Committee
(IEC).
- Participants must have KPS ≥ to 70
- Participants must have expected survival of ≥ 6 months.
- Participants must have adequate bone marrow function as evidenced by:
- Leukocytes ≥ 3,000/mcL
- Absolute neutrophil count ≥1500/mcL;
- Hemoglobin ≥10 g/dL
- Platelets ≥100,000/mcL
- Participants must have adequate hepatic function as evidenced by:
- Serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due
to Gilbert's disease
- Aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline
phosphatase (ALP) ≤3.0 x ULN.
- Participants must have adequate renal function as evidenced by:
- Serum creatinine ≤2.0 x ULN
- OR Creatinine clearance >40 mL/min based on the Cockroft-Gault glomerular
filtration rate (GFR) estimation: (140 - Age) × (weight in kg) × (0.85 if
female)/72 × serum creatinine
- Participants must be recovered from any clinically relevant toxic effects of any prior
surgery, radiotherapy, or other therapy intended for the treatment of cancer.
(Participants with residual Grade 1 toxicity due to prior chemotherapy are allowed).
- Female participants with reproductive potential must have a negative serum pregnancy
test within 14 days prior to the first study drug administration. Participants with
reproductive potential are defined as sexually mature women who have not undergone a
hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally
postmenopausal (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 2 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
ASTX727.
- Participants enrolling in the expansion cohort (Arm B) must meet all of the above
criteria and must have surgically accessible tumors and be surgical candidates.
Exclusion Criteria:
- Participants with enhancing disease on brain MRI.
- Participants who received systemic anticancer therapy <28 days prior to registration.
One exception: participants on lomustine/CCNU must wait at least 42 days from last
date of drug administration to registration.
- Participants who received an investigational agent <14 days prior to registration. In
addition, the first dose of ASTX727 should not occur before a period ≥5 half-lives of
the investigational agent has elapsed.
- Participants with prior treatment with bevacizumab (Avastin) are excluded.
- Participants who are pregnant or breast-feeding.
- Participants with an active severe infection that requires anti-infective therapy or
with an unexplained fever >38.5°C during screening visits or on their first day of
study drug administration.
- Participants with known additional malignancy that is progressing or requires active
treatment within 2 years of start of study drug. Exceptions include basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer
that has undergone potentially curative therapy, or surgically treated prostate
cancer.
- Participants with known hypersensitivity to any of the components of ASTX727.
- Participants with a history of myocardial infarction within the 6 months prior to
screening.
- Participants with a known history of severe and/or uncontrolled ventricular
arrhythmias.
- Participants with QTc interval ≥450 msec or with other factors that significantly
increase the risk of QT prolongation or arrhythmic events (e.g., family history of
long QT interval syndrome).
- Participants with known infection with human immunodeficiency virus (HIV) or active
hepatitis B or C.
- Participants with any other medical or psychological condition, deemed by the
Investigator to be likely to interfere with a participant's ability to sign informed
consent, cooperate, or participate in the study.
- Participants with known dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered orally.
- Participants with evidence of intracranial or intratumoral hemorrhage either by MRI or
CT scan. Participants with resolving post-surgical changes, punctate/micro-hemorrhage,
or hemosiderin are eligible.
- Participants enrolling in the expansion cohort will be excluded is they are deemed by
the treating physician or surgeon not to be suitable for surgery
