Vorinostat and Temozolomide in Treating Patients With Malignant Gliomas

• ClinicalTrials.gov Identifier: NCT00268385
• Recruitment Status: Active, not recruiting
• First Posted: December 22, 2005
• Last Update Posted: November 19, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

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.

Condition or disease	Intervention/treatment	Phase
Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Neoplasm	Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Temozolomide; Drug: Vorinostat	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 83 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]) in Combination With Temozolomide in Patients With Malignant Gliomas
• Actual Study Start Date: December 16, 2005
• Actual Primary Completion Date: October 15, 2011

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (vorinostat, temozolomide); 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.]

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Temozolomide; Given orally; Other Names: CCRG-81045; 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; Temodal; Temodar; Temomedac; TMZ; Drug: Vorinostat; Given orally; Other Names: L-001079038; MSK-390; SAHA; Suberanilohydroxamic Acid; Suberoylanilide Hydroxamic Acid; Zolinza

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: 28 days ]
   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 :

1. Efficacy in terms of anti-tumor activity based on clinical, radiographic, and biologic assessments (Part II) [ Time Frame: Up to 4 years ]
   A descriptive analysis of evidence of anti-tumor activity will be provided based on clinical, radiographic, and biologic assessments of efficacy.
2. Plasma pharmacokinetic parameters of vorinostat [ Time Frame: Baseline, 1, 2, 3, 4, 6, 8, and 24 hours post-dose day 1 of course 1 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States, 35233

United States, California

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, United States, 90095

UCSF Medical Center-Mount Zion

San Francisco, California, United States, 94115

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33612

United States, Georgia

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Maryland

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States, 21287

National Cancer Institute Neuro-Oncology Branch

Bethesda, Maryland, United States, 20892

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

Henry Ford Hospital

Detroit, Michigan, United States, 48202

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

University of Pennsylvania/Abramson Cancer Center

Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, United States, 15232

United States, Texas

M D Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Wisconsin

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Patrick Y Wen; National Cancer Institute (NCI)

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00268385 History of Changes
• Other Study ID Numbers: NCI-2009-00675; NCI-2009-00675 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NABTC 04-03; CDR0000450762; NABTC04-03 ( Other Identifier: Adult Brain Tumor Consortium ); NABTC-04-03 ( Other Identifier: CTEP ); U01CA137443 ( U.S. NIH Grant/Contract ); U01CA062399 ( U.S. NIH Grant/Contract )
• First Posted: December 22, 2005
• Last Update Posted: November 19, 2019
• Last Verified: November 2019

Additional relevant MeSH terms:

Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Brain Neoplasms; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Temozolomide; Vorinostat; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Histone Deacetylase Inhibitors; Enzyme Inhibitors