PCI-24781 in Combination with Temozolomide for the Treatment of High Grade Glioma

Inclusion Criteria

• Patients must have pathologically proven diagnosis of high grade (also known as [aka] grade III or IV) glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, gliosarcoma)
• Patients must have received prior radiation therapy and standard temozolomide. Patients who have received additional therapies for previous progressions will be considered eligible. Prior bevacizumab and Optune are allowed
• Patients must be three or more months from the end of chemoradiotherapy or have biopsy or imaging consistent with disease progression
• Physiologic Status/Age: Patients must be 19 years of age or older (the age of consent in Nebraska)
• Patients must have recovered from any toxicity of prior therapy that in the opinion of the investigator could impact tolerance to the study drug
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Hemoglobin > 8 g/dL
• Platelet count >= 100,000/mm^3
• Serum creatinine that is at or below 2.0 mg/dL
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 1.5 times the upper limits of normal
• Serum alkaline phosphatase less than 2.5 times the upper limits of normal
• The patient must willingly provide written, informed consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts
• Women of reproductive potential must be non-pregnant and non-nursing and must agree to employ an effective barrier method of birth control throughout the study and for up to 6 months following treatment
• Women of child-bearing potential must have a negative pregnancy test within 7 days of initiating study. (Non childbearing potential is defined as age 55 years or older and no menses for two years or any age with surgical removal of the uterus and/or both ovaries)

Exclusion Criteria

• 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 arrhythmias, 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
• Concurrent use of enzyme-inducing antiepileptic drugs (phenytoin, phenobarbital, carbamazepine, felbamate, topiramate and oxcarbazepine)
• Any other active malignancy other than nonmelanoma skin cancer or controlled prostate cancer
• Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection, no testing is required for eligibility
• Creatinine > 1.5 x institutional upper limit of normal (ULN)
• Total bilirubin > 1.5 x ULN (unless due to Gilbert's disease)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
• Lactating or pregnant
• Patients who are currently receiving treatment with any of the medications listed and cannot either discontinue this treatment or switch to a different medication prior to study enrollment will be excluded from the study
• If baseline electrocardiography (ECG) has corrected QT interval (QTc) interval prolongation based on Fridericia’s formula (> 450 ms in males, > 470 ms in females)
• Concomitant valproic acid use, or another HDAC inhibitor