A Phase I Study of Metronomic Temozolomide With Abexinostat (PCI-24781) for Patients With Recurrent High Grade Glioma

Trial ID: NCT05698524

Interventional - Phase 1 - Recruiting

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.

Conditions

• Recurrent High Grade Glioma
• Anaplastic Astrocytoma
• Anaplastic Oligodendroglioma
• Glioblastoma
• Gliosarcoma

Interventions

• PCI 24781
• 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

• Pimozide (Orap)
• Procainamide (Procan, Pronestyl)
• Quinidine (Cardioquin, Quinaglute)
• Sotalol (Betapace)
• Thioridazine (Mellaril)
• Vandetanib (Zactima)
• Pentamidine (Pentam, Nebupent)
• 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)

Sponsor

University of Nebraska, Xynomic Pharmaceuticals, Inc.

Source: ClinicalTrials.gov

Search more clinical trials on myTomorrows