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Vorinostat and Temozolomide in Treating Patients With Malignant Gliomas

Primary Purpose

Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Pharmacological Study
Temozolomide
Vorinostat
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Anaplastic Astrocytoma

Eligibility Criteria

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

Inclusion Criteria: Patients with histologically proven intracranial malignant glioma will be eligible for this protocol; malignant gliomas include glioblastoma multiforme (GBM), gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified); patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made All patients must sign an informed consent indicating that they are aware of the investigational nature of this study; patients must have signed an authorization for the release of their protected health information; patients must be registered with the Adult Brain Tumor Consortium (ABTC) Central Office database prior to treatment with study drug Life expectancy > 8 weeks Karnofsky performance status of >= 60 White blood cell (WBC) >= 3,000/mm^3 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 10 g/dL; eligibility level for hemoglobin may be reached by transfusion Serum glutamic oxaloacetic transaminase (SGOT) < 2 times upper limit of normal (ULN) Bilirubin < 2 times ULN If liver function tests are above the institutional upper limit of normal but < 2 times institutional upper limit of normal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient Creatinine < 1.5 mg/dL A scan should be performed within 14 days prior to registration and on a steroid dose that has been stable for at least 5 days; if the steroid dose is increased between the date of imaging and registration a new baseline magnetic resonance (MR)/computed tomography (CT) is required; the same type of scan, i.e., magnetic resonance imaging (MRI) or CT must be used throughout the period of protocol treatment for tumor measurement Patients must have an interval of greater than or equal to 3 weeks (21) days from the completion of radiation therapy to study entry Women of childbearing potential must have a negative beta-human chorionic gonadotropin (HCG) pregnancy test documented within 7 days prior to registration; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of participation in the study Patients must be willing to participate in the pharmacokinetic studies ELIGIBILITY CRITERIA SPECIFIC FOR PATIENTS IN PART I OF THE STUDY Patients with either stable disease after radiation therapy or with progression are eligible (except if they have progressed on temozolomide; patients who have received prior treatment with temozolomide and have stable disease are eligible Patients with recurrent disease may have had treatment for any number of prior relapses; relapse is defined as progression following initial therapy (i.e. radiation +/- chemo if that was used as initial therapy) Patients must have recovered from the toxic effects of prior therapy: 28 days from any investigational agent, 28 days from prior cytotoxic therapy except 23 days from last dose of temozolomide for patients taking the standard 5 days every 28 day regimen of temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from procarbazine administration, and 7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count); any questions related to the definition of non-cytotoxic agents should be directed to the study chair Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: They have recovered from the effects of surgery Residual disease following resection is not mandated for eligibility into the study; to best assess the extent of residual disease post-operatively, a CT/MRI should be done no later than 96 hours in the immediate post-operative period or at least 4 weeks post-operatively, within 14 days prior to registration; if the 96-hour scan is more than 14 days before registration, the scan needs to be repeated; if the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon either positron emission tomography (PET) or thallium scanning, MR spectroscopy or surgical documentation of disease ELIGIBILITY CRITERIA SPECIFIC FOR PATIENTS IN PART II OF THE STUDY Only patients with stable disease after radiation therapy are eligible for part 2 of the study; patients with recurrent disease are ineligible The only prior therapy permitted for patients in part 2 of the study is concomitant temozolomide with radiation therapy or radiation therapy alone; patients that are stable on adjuvant temozolomide may also participate Patients with recurrent disease and prior chemotherapies (except concurrent or adjuvant temozolomide) will not be included in this part of the study Exclusion Criteria: Patients who have progressed on temozolomide are ineligible Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy; patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible Patients must not have active infection or serious intercurrent medical illness Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with vorinostat (SAHA); potential risks may also apply to temozolomide Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism Patients who are known to be human immunodeficiency virus (HIV) positive and are receiving combination antiretroviral therapy are ineligible Patients may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in study Patients should not have taken valproic acid (another histone deacetylase inhibitor) for at least 2 weeks prior to enrollment

Sites / Locations

  • University of Alabama at Birmingham Cancer Center
  • UCLA / Jonsson Comprehensive Cancer Center
  • UCSF Medical Center-Mount Zion
  • Moffitt Cancer Center
  • Emory University Hospital/Winship Cancer Institute
  • Johns Hopkins University/Sidney Kimmel Cancer Center
  • National Cancer Institute Neuro-Oncology Branch
  • Dana-Farber Cancer Institute
  • Henry Ford Hospital
  • Memorial Sloan Kettering Cancer Center
  • Duke University Medical Center
  • Wake Forest University Health Sciences
  • Cleveland Clinic Foundation
  • University of Pennsylvania/Abramson Cancer Center
  • University of Pittsburgh Cancer Institute (UPCI)
  • M D Anderson Cancer Center
  • University of Wisconsin Carbone Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (vorinostat, temozolomide)

Arm Description

PART I: Patients receive vorinostat PO QD or BID on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part I*. [Note: Beginning in course 2, some patients may receive a higher dose of temozolomide.]

Outcomes

Primary Outcome Measures

MTD of vorinostat with temozolomide defined as the dose at which less than one-third of patients experience dose-limiting toxicity based on the CTC severity grading (Part I)
For both parts of the study, treatment administration will be described for all cycles. Doses administered, dose modifications/delays, and duration of therapy will be evaluated. Safety variables summarized by descriptive statistics. Adverse events that occur will be reported for each dose level and described in terms of incidence and severity. Laboratory data will be presented by dose level at each observation time. Values outside of normal limits will be identified and their frequency calculated. Distribution by CTC severity grade (when applicable) and clinical relevance will be given.

Secondary Outcome Measures

Efficacy in terms of anti-tumor activity based on clinical, radiographic, and biologic assessments (Part II)
A descriptive analysis of evidence of anti-tumor activity will be provided based on clinical, radiographic, and biologic assessments of efficacy.
Plasma pharmacokinetic parameters of vorinostat
Presented in tabular and graphic form. Pharmacokinetic parameters of interest such as maximal plasma concentration (Cmax), time of maximal concentration (Tmax), area under the plasma concentration-time curve (AUCo-t and AUC-infinity), clearance (CL), apparent volume of distribution at steady state (Vdss), terminal half-life (t1/2), and tumor to plasma (whole blood) concentration ratio will be determined using non-compartmental methods. Dose proportionality in pharmacokinetic parameters will be determined by performing a one-way analysis of variance (ANOVA) on dose-normalized parameters.

Full Information

First Posted
December 20, 2005
Last Updated
September 12, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00268385
Brief Title
Vorinostat and Temozolomide in Treating Patients With Malignant Gliomas
Official Title
A Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]) in Combination With Temozolomide in Patients With Malignant Gliomas
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 16, 2005 (Actual)
Primary Completion Date
October 18, 2018 (Actual)
Study Completion Date
April 11, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial is studying the side effects and best dose of vorinostat when given together with temozolomide in treating patients with malignant gliomas. Drugs used in chemotherapy, such as vorinostat and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may help temozolomide work better by making tumor cells more sensitive to the drug. Giving vorinostat together with temozolomide may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of vorinostat (suberoylanilide hydroxamic acid [SAHA]) in combination with temozolomide in patients with malignant gliomas. II. To characterize the safety profile of vorinostat (SAHA) in combination with temozolomide. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics of vorinostat (SAHA) in combination with temozolomide. II. To determine efficacy of vorinostat (SAHA) in combination with temozolomide as measured by objective response. TERTIARY OBJECTIVES: I. To explore the association of response to treatment to the molecular phenotype of the tumor. II. To assess the effects of vorinostat (SAHA) on histone acetylation status in peripheral mononuclear cells. OUTLINE: This is a 2-part, dose-escalation study of vorinostat. PART I: Patients receive vorinostat orally (PO) once (QD) or twice daily (BID) on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Beginning in course 2, some patients may receive a higher dose of temozolomide. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part 1*. [Note: *Beginning in course 2, all patients receive a higher dose of temozolomide.] After completion of study treatment, patients are followed up periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Recurrent Adult Brain Neoplasm

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment (vorinostat, temozolomide)
Arm Type
Experimental
Arm Description
PART I: Patients receive vorinostat PO QD or BID on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part I*. [Note: Beginning in course 2, some patients may receive a higher dose of temozolomide.]
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
CCRG-81045, Gliotem, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temizole, Temodal, Temodar, Temomedac, TMZ
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
Vorinostat
Other Intervention Name(s)
L-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, Zolinza
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
MTD of vorinostat with temozolomide defined as the dose at which less than one-third of patients experience dose-limiting toxicity based on the CTC severity grading (Part I)
Description
For both parts of the study, treatment administration will be described for all cycles. Doses administered, dose modifications/delays, and duration of therapy will be evaluated. Safety variables summarized by descriptive statistics. Adverse events that occur will be reported for each dose level and described in terms of incidence and severity. Laboratory data will be presented by dose level at each observation time. Values outside of normal limits will be identified and their frequency calculated. Distribution by CTC severity grade (when applicable) and clinical relevance will be given.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Efficacy in terms of anti-tumor activity based on clinical, radiographic, and biologic assessments (Part II)
Description
A descriptive analysis of evidence of anti-tumor activity will be provided based on clinical, radiographic, and biologic assessments of efficacy.
Time Frame
Up to 4 years
Title
Plasma pharmacokinetic parameters of vorinostat
Description
Presented in tabular and graphic form. Pharmacokinetic parameters of interest such as maximal plasma concentration (Cmax), time of maximal concentration (Tmax), area under the plasma concentration-time curve (AUCo-t and AUC-infinity), clearance (CL), apparent volume of distribution at steady state (Vdss), terminal half-life (t1/2), and tumor to plasma (whole blood) concentration ratio will be determined using non-compartmental methods. Dose proportionality in pharmacokinetic parameters will be determined by performing a one-way analysis of variance (ANOVA) on dose-normalized parameters.
Time Frame
Baseline, 1, 2, 3, 4, 6, 8, and 24 hours post-dose day 1 of course 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with histologically proven intracranial malignant glioma will be eligible for this protocol; malignant gliomas include glioblastoma multiforme (GBM), gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified); patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made All patients must sign an informed consent indicating that they are aware of the investigational nature of this study; patients must have signed an authorization for the release of their protected health information; patients must be registered with the Adult Brain Tumor Consortium (ABTC) Central Office database prior to treatment with study drug Life expectancy > 8 weeks Karnofsky performance status of >= 60 White blood cell (WBC) >= 3,000/mm^3 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 10 g/dL; eligibility level for hemoglobin may be reached by transfusion Serum glutamic oxaloacetic transaminase (SGOT) < 2 times upper limit of normal (ULN) Bilirubin < 2 times ULN If liver function tests are above the institutional upper limit of normal but < 2 times institutional upper limit of normal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient Creatinine < 1.5 mg/dL A scan should be performed within 14 days prior to registration and on a steroid dose that has been stable for at least 5 days; if the steroid dose is increased between the date of imaging and registration a new baseline magnetic resonance (MR)/computed tomography (CT) is required; the same type of scan, i.e., magnetic resonance imaging (MRI) or CT must be used throughout the period of protocol treatment for tumor measurement Patients must have an interval of greater than or equal to 3 weeks (21) days from the completion of radiation therapy to study entry Women of childbearing potential must have a negative beta-human chorionic gonadotropin (HCG) pregnancy test documented within 7 days prior to registration; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of participation in the study Patients must be willing to participate in the pharmacokinetic studies ELIGIBILITY CRITERIA SPECIFIC FOR PATIENTS IN PART I OF THE STUDY Patients with either stable disease after radiation therapy or with progression are eligible (except if they have progressed on temozolomide; patients who have received prior treatment with temozolomide and have stable disease are eligible Patients with recurrent disease may have had treatment for any number of prior relapses; relapse is defined as progression following initial therapy (i.e. radiation +/- chemo if that was used as initial therapy) Patients must have recovered from the toxic effects of prior therapy: 28 days from any investigational agent, 28 days from prior cytotoxic therapy except 23 days from last dose of temozolomide for patients taking the standard 5 days every 28 day regimen of temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from procarbazine administration, and 7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count); any questions related to the definition of non-cytotoxic agents should be directed to the study chair Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: They have recovered from the effects of surgery Residual disease following resection is not mandated for eligibility into the study; to best assess the extent of residual disease post-operatively, a CT/MRI should be done no later than 96 hours in the immediate post-operative period or at least 4 weeks post-operatively, within 14 days prior to registration; if the 96-hour scan is more than 14 days before registration, the scan needs to be repeated; if the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon either positron emission tomography (PET) or thallium scanning, MR spectroscopy or surgical documentation of disease ELIGIBILITY CRITERIA SPECIFIC FOR PATIENTS IN PART II OF THE STUDY Only patients with stable disease after radiation therapy are eligible for part 2 of the study; patients with recurrent disease are ineligible The only prior therapy permitted for patients in part 2 of the study is concomitant temozolomide with radiation therapy or radiation therapy alone; patients that are stable on adjuvant temozolomide may also participate Patients with recurrent disease and prior chemotherapies (except concurrent or adjuvant temozolomide) will not be included in this part of the study Exclusion Criteria: Patients who have progressed on temozolomide are ineligible Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy; patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible Patients must not have active infection or serious intercurrent medical illness Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with vorinostat (SAHA); potential risks may also apply to temozolomide Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism Patients who are known to be human immunodeficiency virus (HIV) positive and are receiving combination antiretroviral therapy are ineligible Patients may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in study Patients should not have taken valproic acid (another histone deacetylase inhibitor) for at least 2 weeks prior to enrollment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick Y Wen
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham Cancer Center
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
UCLA / Jonsson Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
UCSF Medical Center-Mount Zion
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Emory University Hospital/Winship Cancer Institute
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
National Cancer Institute Neuro-Oncology Branch
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Pennsylvania/Abramson Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
University of Pittsburgh Cancer Institute (UPCI)
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Wisconsin Carbone Cancer Center
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

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Vorinostat and Temozolomide in Treating Patients With Malignant Gliomas

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