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

Primary Purpose

Recurrent High Grade Glioma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PCI 24781
Temozolomide
Sponsored by
University of Nebraska
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent High Grade Glioma

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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. 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, 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 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 QTc interval prolongation based on Fridericia's formula (> 450 ms in males,> 470 ms in females) Concomitant valproic acid use, or another HDAC inhibitor

Sites / Locations

  • University of Nebraska Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single arm

Arm Description

Patients will receive a combination of PCI-24781 and temozolomide. Patients will receive a loading dose of PCI-24781 prior to the start of Cycle 1; patients will take PCI-24781 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 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-24781 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 and metronomic temozolomide regimen until disease progression or intolerance.

Outcomes

Primary Outcome Measures

Evaluation of toxicities associated with PCI-24781 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.
Evaluation of toxicities associated with PCI-24781 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.
Determine the recommended dose of PCI-24781
Patients who complete the first two cycles of treatment or patients experiencing a dose-limiting toxicity (DLT) within the first two cycles 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.

Secondary Outcome Measures

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.
Evaluation of acetylation of histones H3 and H4 using peripheral blood exosomes
Peripheral blood samples collected at baseline and during treatment will be analyzed.
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.
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.
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.
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."
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.
Correlation of molecular profiles with tumor response
Assessed using PMBCs and exosomes extracted from peripheral blood samples.

Full Information

First Posted
December 20, 2022
Last Updated
September 29, 2023
Sponsor
University of Nebraska
Collaborators
Xynomic Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT05698524
Brief Title
A Study of Temodar With PCI-24781 for Patients With Recurrent Glioma
Official Title
A Phase I Study of Metronomic Temozolomide With PCI-24781 for Patients With Recurrent High Grade Glioma
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 26, 2023 (Actual)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
June 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Nebraska
Collaborators
Xynomic Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 with metronomic temozolomide To evaluate side effects associated with using PCI-24781 with metronomic temozolomide
Detailed Description
Patients will be enrolled to each dose level in cohorts of 3. Dose level escalation/de-escalation will follow BOIN (Bayesian Optimal Interval) 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 BID (two times daily) Dose Level 2: 100 mg PCI-24781 BID Dose Level 3: 140 mg PCI-24781 BID Primary Objectives I. To evaluate the toxicities and determine the recommended dose of PCI-24781 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 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, QLQ-BN20 during treatment. V. To characterize the pharmacokinetics (PK) of PCI-24781, temozolomide, and the combination of the 2 drugs. VI. To measure tumor response. VII. To correlate molecular profiles with tumor response.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent High Grade Glioma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Glioblastoma, Gliosarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Single arm
Arm Type
Experimental
Arm Description
Patients will receive a combination of PCI-24781 and temozolomide. Patients will receive a loading dose of PCI-24781 prior to the start of Cycle 1; patients will take PCI-24781 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 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-24781 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 and metronomic temozolomide regimen until disease progression or intolerance.
Intervention Type
Drug
Intervention Name(s)
PCI 24781
Other Intervention Name(s)
Abexinostat
Intervention Description
Patients will take the PCI-24781 on days 1-4, 8-11, 15-18, and 22-25 of each 28-day cycle.
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
Temodar
Intervention Description
Patients will receive temozolomide at a dose of 50 mg/mg2, taken by mouth once daily.
Primary Outcome Measure Information:
Title
Evaluation of toxicities associated with PCI-24781 and metronomic temozolomide therapy (AEs & SAEs)
Description
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.
Time Frame
Up to 25 months
Title
Evaluation of toxicities associated with PCI-24781 and metronomic temozolomide therapy (overall, graded 1-5)
Description
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.
Time Frame
Up to 25 months
Title
Determine the recommended dose of PCI-24781
Description
Patients who complete the first two cycles of treatment or patients experiencing a dose-limiting toxicity (DLT) within the first two cycles 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.
Time Frame
Up to 20 months
Secondary Outcome Measure Information:
Title
Evaluation of changes in the acetylation of peripheral blood mononuclear cell (PBMC) histones H3 and H4 during treatment
Description
Peripheral blood samples collected at baseline and during treatment will be analyzed for changes over time.
Time Frame
Up to 20 months
Title
Evaluation of acetylation of histones H3 and H4 using peripheral blood exosomes
Description
Peripheral blood samples collected at baseline and during treatment will be analyzed.
Time Frame
Up to 20 months
Title
Evaluation of progression-free survival (PFS)
Description
PFS will be estimated using the Kaplan-Meier method. PFS is defined as the time from treatment initiation to disease progression.
Time Frame
36 months
Title
Evaluation of overall survival (OS)
Description
OS will be estimated using the Kaplan-Meier method. OS is defined as the time from treatment initiation to death from any cause.
Time Frame
36 months
Title
Descriptive examination of patient quality of life (QOL) during treatment - EORTC QLQ-C30 Questionnaire
Description
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.
Time Frame
24 months
Title
Descriptive examination of patient quality of life (QOL) during treatment - EORTC QLQ-BN20 Questionnaire
Description
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."
Time Frame
24 months
Title
Measurement of tumor response
Description
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.
Time Frame
Up to 36 months
Title
Correlation of molecular profiles with tumor response
Description
Assessed using PMBCs and exosomes extracted from peripheral blood samples.
Time Frame
Up to 36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
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. 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, 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 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 QTc interval prolongation based on Fridericia's formula (> 450 ms in males,> 470 ms in females) Concomitant valproic acid use, or another HDAC inhibitor
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michaela K Savine, RN
Phone
402-836-9488
Email
misavine@unmc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicole A Shonka, MD
Organizational Affiliation
University of Nebraska
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michaela K Savine, RN
Phone
402-836-9488
Email
misavine@unmc.edu

12. IPD Sharing Statement

Learn more about this trial

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

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