A Study of Temodar With Abexinostat (PCI-24781) for Patients With Recurrent Glioma

The goal of this clinical trial is to learn about treatment for a type of brain cancer called glioma. This clinical trial is for people with glioma who have been cancer-free for a period of time but their cancer has come back. The primary goals of this clinical trial are the following:

* To determine the recommended dose of PCI-24781/Abexinostat with metronomic temozolomide
* To evaluate side effects associated with using PCI-24781/Abexinostat with metronomic temozolomide

Patients will be enrolled to each dose level 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:

* Dose Level 1: 60 mg PCI-24781/Abexinostat two times daily (BID)
* Dose Level 2: 100 mg PCI-24781/Abexinostat BID
* Dose Level 3: 140 mg PCI-24781/Abexinostat BID

Primary Objectives

I. To evaluate the toxicities and determine the recommended dose of PCI-24781/Abexinostat with metronomic temozolomide in subjects with recurrent high grade glioma, \[grade III or IV glioma (glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma)\].

Secondary Objectives

I. To evaluate changes in the acetylation of peripheral blood mononuclear cell (PBMC) histones H3 and H4 during treatment II. To evaluate for acetylation of histones H3 and H4 using peripheral blood exosomes III. To evaluate progression-free and overall survival of subjects with recurrent high grade glioma treated with therapy with PCI-24781/Abexinostat with metronomic temozolomide. Subjects with stable or responsive disease after every 2 cycles will continue on therapy until intolerance or progressive disease.

IV. To descriptively examine quality of life (QOL) using EORTC QLQ-C30 questionnaire, QLQ-BN20 questionnaire during treatment.

V. To characterize the pharmacokinetics (PK) of PCI-24781/Abexinostat, temozolomide, and the combination of the 2 drugs.

VI. To measure tumor response. VII. To correlate molecular profiles with tumor response.

Eligibility Criteria:
Inclusion Criteria:

* Pathologically proven diagnosis of high grade (aka grade III or IV) glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, gliosarcoma).
* Received 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)
* Fully 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
* Adequate bone marrow reserve (ANC count ≥1,500/mm3, hemoglobin \> 8 g/dL, platelet count ≥100,000/mm3)
* Adequate renal function (a serum creatinine that is at or below 2.0 mg/dL)
* Adequate hepatic function (serum AST and ALT less than 1.5 times the upper limits of normal, serum alkaline phosphatase less than 2.5 times the upper limits of normal)
* Able to provide written, informed consent
* Females of child-bearing potential must have a negative pregnancy test within 7 days of initiating study. (Non-child bearing 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)
* Females of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and up to 6 months following treatment

Exclusion Criteria:

* Have 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 from Gilbert's disease), and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 x ULN
* Pregnant or breast-feeding
* Baseline ECG duration of the ventricular action potential corrected for heart rate (QTc interval) prolongation based on Fridericia's formula is \> 450 ms in males and \> 470 ms in females
* Concomitant valproic acid use, or another histone deacetylases (HDAC) inhibitor
* Receiving treatment with following medications and unable to discontinue treatment or switch medications prior to study enrollment:

  * Amiodarone (Cordarone, Pacerone)
  * Arsenic trioxide (Trisenox)
  * Chlorpromazine (Aralen)
  * Cisapride (Propulsid)
  * Clarithromycin (Biaxin)
  * Disopyramide (Norpace)
  * Dofetilide (Tikosyn)
  * Doperidol (Inapsine)
  * Erythromycin (EryTab, Erythrocin)
  * Flecanide (Tambocor)
  * Haloperidol (Haldol)
  * Ibutilide (Corvert)
  * Methadone (Methadose, Dolophine)
  * Moxifloxacin (Avelox)
  * Pentamidine (Pentam, Nebupent)
  * Pimozide (Orap)
  * Procainamide (Procan, Pronestyl)
  * Quinidine (Cardioquin, Quinaglute)
  * Sotalol (Betapace)
  * Thioridazine (Mellaril)
  * Vandetanib (Zactima)