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

Summary

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.

Eligibility

Inclusion Criteria:

* 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)
* 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:

* 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
* 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)

Conditions6

Locations1 site

Browse More Trials