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

Study Overview
=================
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

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 two cycles 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.

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

Conditions
-----------------
Recurrent High Grade Glioma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Glioblastoma, Gliosarcoma

Intervention / Treatment
-----------------
* Drug: PCI 24781
* Drug: Temozolomide


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>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. | Drug: PCI 24781<br>* Patients will take the PCI-24781/Abexinostat on days 1-4, 8-11, 15-18, and 22-25 of each 28-day cycle.<br>* Other names: Abexinostat;Drug: Temozolomide<br>* Patients will receive temozolomide at a dose of 50 mg/mg2, taken by mouth once daily.<br>* Other names: Temodar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of toxicities associated with PCI-24781/Abexinostat and metronomic temozolomide therapy (AEs & SAEs) | The incidence of adverse events (AEs) and serious adverse events (SAEs) will be described for each dose level cohort. Toxicities will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicities will be graded on a scale ranging from 1 to 5, with higher numbers indicating a higher severity grade. | Up to 25 months | 
| Evaluation of toxicities associated with PCI-24781/Abexinostat and metronomic temozolomide therapy (overall, graded 1-5) | The frequency of the occurrence of overall toxicity will be categorized by toxicity grades. Toxicity will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicities will be graded on a scale ranging from 1 to 5, with higher numbers indicating a higher severity grade. | Up to 25 months | 
| Determine the recommended dose of PCI-24781/Abexinostat | Patients who complete the first cycle of treatment or patients experiencing a dose-limiting toxicity (DLT) within the first cycle of treatment will be considered evaluable. The target DLT rate for the maximum tolerated dose (MTD) is 0.25. If the observed DLT rate at the current dose is ≤ 0.197, escalate the dose to the next higher dose level If the observed DLT rate at the current dose is > 0.298, de-escalate the dose to the next lower dose level Otherwise, stay at the current dose level The MTD determination will be based on isotonic regression. The MTD will be defined as the dose for which the isotonic estimate of the DLT rate is closest to the target DLT rate of 0.25. If a tie exists between potential doses the higher dose level will be selected when the isotonic estimate is lower than the target DLT rate and the lower dose level will be selected when the isotonic estimate is greater than or equal to the target DLT rate. | Up to 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of changes in the acetylation of peripheral blood mononuclear cell (PBMC) histones H3 and H4 during treatment | Peripheral blood samples collected at baseline and during treatment will be analyzed for changes over time. | Up to 20 months | 
| Evaluation of acetylation of histones H3 and H4 using peripheral blood exosomes | Peripheral blood samples collected at baseline and during treatment will be analyzed. | Up to 20 months | 
| Evaluation of progression-free survival (PFS) | PFS will be estimated using the Kaplan-Meier method. PFS is defined as the time from treatment initiation to disease progression. | 36 months | 
| Evaluation of overall survival (OS) | OS will be estimated using the Kaplan-Meier method. OS is defined as the time from treatment initiation to death from any cause. | 36 months | 
| Descriptive examination of patient quality of life (QOL) during treatment - EORTC QLQ-C30 Questionnaire | Patient QOL will be measured throughout treatment using the EORTC QLQ-C30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire). Patients respond using a scale that ranges from 1 to 4, with 1 meaning Not at All and 4 meaning Quite a Bit. The final two questions ask patients to rate their overall health and quality of life using a scale ranging from 1 to 7, where higher numbers indicate more favorable outcomes. | 24 months | 
| Descriptive examination of patient quality of life (QOL) during treatment - EORTC QLQ-BN20 Questionnaire | Patient QOL will be measured throughout treatment using the EORTC QLQ-BN20 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire). Patients respond using a scale that ranges from 1 to 4, with 1 meaning Not at All and 4 meaning Quite a Bit. | 24 months | 
| Measurement of tumor response | Overall response will be assessed using Response Assessment in Neuro-Oncology (RANO) Criteria. MRI and clinical features are used to classify response as one of four categories that range from complete response to disease progression. | Up to 36 months | 
| Correlation of molecular profiles with tumor response | Assessed using PMBCs and exosomes extracted from peripheral blood samples. | Up to 36 months |