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.
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. Participants will be enrolled to one of each of four dose levels in cohorts of 3. Dose level escalation/de-escalation will follow Bayesian Optimal Interval (BOIN) design rules based on analysis of dose-limiting toxicities (DLTs) that occur within the first cycle of protocol treatment. Protocol treatment will continue until disease progression or intolerable toxicity. Dose Levels: 1 - 60 mg PCI-24781/Abexinostat two times daily (BID), 1.5 - 80 mg PCI-24781/Abexinostat BID, 2 - 100 mg PCI-24781/Abexinostat BID, and 3 - 140 mg PCI-24781/Abexinostat BID. The primary study objective is to evaluate the toxicities and determine the recommended dose of PCI-24781/Abexinostat with metronomic temozolomide in participants with recurrent high grade glioma, \[grade III or IV glioma (glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma)\]. Other objects are to evaluate changes in the acetylation of peripheral blood mononuclear cell (PBMC) histones H3 and H4 during treatment, evaluate acetylation of histones H3 and H4 using peripheral blood exosomes, evaluate progression-free and overall survival of participants with recurrent high grade glioma treated with therapy with PCI-24781/Abexinostat and metronomic temozolomide, descriptively examine quality of life (QOL) using EORTC QLQ-C30 questionnaire and QLQ-BN20 questionnaire during treatment, characterize the pharmacokinetics (PK) of PCI-24781/Abexinostat, temozolomide, and the combination of the 2 drugs, measure tumor response, and correlate molecular profiles with tumor response.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Participants will take PCI-24781/Abexinostat on days 1 - 4, 8 - 11, and 15 - 18 of each 28-day cycle.
Participants will receive temozolomide at a dose of 50 mg/mg2, taken by mouth once daily.
University of Nebraska Medical Center
Omaha, Nebraska, United States
RECRUITINGToxicities 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.
Time frame: Up to 25 months
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.
Time frame: Up to 25 months
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.
Time frame: Up to 20 months
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.
Time frame: Up to 20 months
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.
Time frame: Up to 20 months
Progression-free Survival
Progression-free survival (PFS), the time from treatment initiation to disease progression, will be estimated using the Kaplan-Meier method.
Time frame: 36 months
Overall Survival (OS)
Overall survival (OS), the time from treatment initiation to death from any cause, will be estimated using the Kaplan-Meier method.
Time frame: 36 months
Descriptive examination of patient quality of life during treatment (EORTC QLQ-C30)
Participant Quality of Life (QOL) will be measured throughout treatment using the European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-BN30) questionnaire. Question responses range from 1 (Not at All) to 4 (Quite a Bit). Higher scores indicate greater functioning. Two additional questions ask participants to rate overall health and quality of life using a scale ranging from 1 to 7, where higher numbers indicate more favorable outcomes.
Time frame: 24 months
Descriptive Examination of Participant Quality of Life During Treatment (EORTC QLQ-BN20)
Participant Quality of Life (QOL) will be measured throughout treatment using the European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-BN20) questionnaire. Question responses range from 1 (Not at All) to 4 (Quite a Bit). Higher scores indicate greater functioning.
Time frame: 24 months
Measurement of Tumor Response
Magnetic resonance imaging (MRI) and clinical features will be used to classify tumor response as one of four categories that range from complete response to disease progression. The overall response will be assessed using Response Assessment in Neuro-Oncology (RANO) Criteria.
Time frame: Up to 36 months
Correlation of Molecular Profiles With Tumor Response
The correlation of tumor response and peripheral blood mononuclear cells (PBMC) and exosomes extracted from peripheral blood samples will be determined.
Time frame: Up to 36 months
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