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NCT05698524 | Recruiting | Recurrent High Grade Glioma

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

University of Nebraska

Brief Summary:

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

Condition or disease

Recurrent High Grade Glioma

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Glioblastoma

Gliosarcoma

Intervention/treatment

PCI 24781

Temozolomide

Phase

Phase 1

Detailed Description:

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.}}

Study Type : Interventional
Estimated Enrollment : 18 participants
Masking : None (Open Label)
Primary Purpose : Treatment
Official Title : A Phase I Study of Metronomic Temozolomide With Abexinostat (PCI-24781) for Patients With Recurrent High Grade Glioma
Actual Study Start Date : June 26, 2023
Estimated Primary Completion Date : February 2025
Estimated Study Completion Date : June 2027
Arm Intervention/treatment

Experimental: Single arm

Patients will receive a combination of PCI-24781/Abexinostat and temozolomide. Patients will receive a loading dose of PCI-24781/Abexinostat prior to the start of Cycle 1; patients will take PCI-24781/Abexinostat by mouth twice a day starting 7 days prior to Cycle 1, Day 1 and ending 4 days prior to Cycle 1, Day 1. Patients will continue taking PCI-24781/Abexinostat on days 1-4, 8-11, 15-18, and 22-25 of each 28 day cycle, starting with Cycle 1, Day 1. The initial dose level is 60 mg of PCI-2478/Abexinostat 1 by mouth twice daily. The dose level may be escalated based on results of interim data analysis. Patients will additionally initiate metronomic temozolomide on Cycle 1, Day 1 at a dose of 50 mg/m2, taken by mouth twice daily. Patients will continue the PCI-24781/Abexinostat and metronomic temozolomide regimen until disease progression or intolerance.

Mate: PCI 24781

Drug: Temozolomide
Ages Eligible for Study: 19 Years
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria
  • Patients must have pathologically proven diagnosis of high grade (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.
  • Patients must have an adequate bone marrow reserve (ANC count ≥1,500/mm3, hemoglobin > 8 g/dL, platelet count ≥100,000/mm3).
  • Patients must have adequate renal function (a serum creatinine that is at or below 2.0 mg/dL).
  • Patients must have 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).
  • 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 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).
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); and 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 in Appendix I and cannot either discontinue this treatment or switch to a different medication prior to study enrollment will be excluded from the study.
  • If baseline ECG has duration of the ventricular action potential corrected for heart rate (QTc interval) prolongation based on Fridericia's formula (> 450 ms in males,> 470 ms in females)
  • Concomitant valproic acid use, or another histone deacetylases (HDAC) inhibitor
A Study of Temodar With Abexinostat (PCI-24781) for Patients With Recurrent Glioma

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

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Locations

Recruiting

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68198