Glioblastoma (GBM), WHO grade IV glioma, represents the majority of adult malignant primary brain tumors, with an incidence of 2-3 per 100,000 person-years. The survival for GBM has increased in the last decade but is still low with a median survival of 15-18 months. Recurrence after initial standard therapy, radiation therapy and chemotherapy with temozolomide, few options are available. Even with further therapy, median progression free survival at 6 months after first relapse (PFS-6) is only 15%. Similarly, anaplastic astrocytoma and anaplastic oligodendroglioma, grade III gliomas, once recurrent after radiation therapy and first-line chemotherapy, have identical therapeutic options and poor outcomes with PFS-6 of 31%. Temozolomide (TMZ) has a favorable side effect profile and is available orally, however, cytotoxicity occurs. Metronomic temozolomide at low doses on a continuous schedule, have demonstrated better survival in studies. This study will determine the recommended dose and the side effects of PCI-24781/Abexinostat with metronomic temozolomide.
Pathologically proven diagnosis of high grade (aka grade III or IV) glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, gliosarcoma)
Prior radiation therapy and standard temozolomide; additional therapies for previous progressions are eligible (prior bevacizumab and Optune are allowed)
Three or more months from the end of chemoradiotherapy or have biopsy or imaging consistent with disease progression
19 years of age or older (the age of consent in Nebraska)
Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of oral PCI-24781/Abexinostat, or put the study outcomes at undue risk
Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmia, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
Immunotherapy, chemotherapy, radiotherapy, corticosteroids (at dosages equivalent to prednisone > 20 mg/day) or experimental therapy (other than PCI-24781/Abexinostat PO) within 4 weeks before first dose of study drug
Single group
PCI 24781
DrugParticipants will take PCI-24781/Abexinostat on days 1 - 4, 8 - 11, and 15 - 18 of each 28-day cycle.
Temozolomide
DrugParticipants will receive temozolomide at a dose of 50 mg/mg2, taken by mouth once daily.
Toxicities Associated with PCI-24781/Abexinostat and Metronomic Temozolomide Therapy - Adverse Events and Serious Adverse Events
The incidence of adverse events (AEs) and serious adverse events (SAEs) will be recorded for each dose level cohort. Toxicities will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicities will be graded on from 1 to 5, with higher numbers indicating a higher severity grade.
Toxicities Associated With PCI-24781/Abexinostat and Metronomic Temozolomide Therapy - Overall
The frequency of overall toxicity occurrence will be categorized by toxicity grades using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicities will be graded ranging from 1 to 5, with higher numbers indicating a higher severity grade.
Recommended Dose Determination of PCI-24781/Abexinostat
Participants who either complete the first cycle of treatment or experience a dose-limiting toxicity (DLT) within the first cycle of treatment will be considered evaluable. The target DLT rate for the maximum tolerated dose (MTD) is 0.25. The MTD determination will be based on isotonic regression. The MTD will be defined as the dose for which the isotonic estimate of the DLT rate is closest to the target DLT rate of 0.25. If a tie exists between potential doses the higher dose level will be selected when the isotonic estimate is lower than the target DLT rate and the lower dose level will be selected when the isotonic estimate is greater than or equal to the target DLT rate. If the observed DLT rate at the current dose is ≤ 0.197, escalate the dose to the next higher dose level. If the observed DLT rate at the current dose is \> 0.298, de-escalate the dose to the next lower dose level. Otherwise, stay at the current dose level.
Changes in Acetylation of Peripheral Blood Mononuclear Cell Histones, H3 and H4, During Treatment
Peripheral blood samples collected at baseline and during treatment will be analyzed for changes in acetylation of peripheral blood mononuclear cell (PBMC) histones H3 and H4.
Changes in Acetylation of Histones, H3 and H4, Using Peripheral Blood Exosomes
Peripheral blood samples collected at baseline and during treatment will be analyzed for changes in acetylation of peripheral blood mononuclear cell (PBMC) histones, H3 and H4, using peripheral blood exosomes.
Progression-free Survival
Progression-free survival (PFS), the time from treatment initiation to disease progression, will be estimated using the Kaplan-Meier method.
Overall Survival (OS)
Overall survival (OS), the time from treatment initiation to death from any cause, will be estimated using the Kaplan-Meier method.
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University of Nebraska
Lead sponsor
Xynomic Pharmaceuticals, Inc.
Collaborator
