Vorinostat, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00731731
First received: August 8, 2008
Last updated: March 5, 2014
Last verified: December 2013
  Purpose

This phase I/II trial studies the side effects and best dose of vorinostat when given together with temozolomide and radiation therapy and to see how well they work in treating patients with newly diagnosed glioblastoma multiforme. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with temozolomide and radiation therapy may kill more tumor cells.


Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Cognitive/Functional Effects
Radiation: 3-dimensional conformal radiation therapy
Drug: temozolomide
Drug: vorinostat
Procedure: cognitive assessment
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of vorinostat, defined as the dose at which fewer than one-third of patients experience DLTs, graded according to NCI CTCAE version 3.0 (Phase I) [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
  • Overall survival (Phase II) [ Time Frame: Time from study registration to the date of death from any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    Survival will be estimated using a Kaplan-Meier curve.


Secondary Outcome Measures:
  • Incidence of adverse events, based on CTC severity grade (Phase I) [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Safety variables will be summarized by descriptive statistics. AEs that occur will be reported for each dose level and described in terms of incidence and severity. Parameters will be described based on the CTC severity grading. Distribution by CTC severity grade and clinical relevance will be given.

  • Time to tumor progression (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Incidence of adverse events, as per NCI CTCAE version 3.0 (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing.


Other Outcome Measures:
  • Molecular characteristics of the tumor [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Correlated with expression profile of response, survival, and safety. For each test in the group of tests, a standard error of measurement will be used to derive the Reliable Change Index (RCI) which will be used to represent the 90% confidence interval for the difference in raw scores from baseline to follow-up assessment will be coded as 1 (deterioration), 2 (no change), and 3 (improved) according to the RCI. Percentage of patients in each treatment arm who show meaningful losses or gains in the various tests or test domains over the course of the study will be provided by frequency tables.

  • Time to neurocognitive progression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be estimated by Kaplan-Meier method and analyzed by Cox regression model adjusting all stratification factors.

  • Baseline neurocognitive test scores [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Baseline neurocognitive test scores will be correlated with overall survival. Will be analyzed using Cox proportional hazards model. Changes in cognitive function scores in each domain (memory, executive function and visual motor) among visits will be explored graphically and by repeated measurement models.


Enrollment: 51
Study Start Date: July 2009
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (radiation therapy, vorinostat, temozolomide)
Patients undergo radiotherapy and receive vorinostat PO QD on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD on days 1-5. Treatment with vorinostat and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Radiation: 3-dimensional conformal radiation therapy
Undergo radiotherapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Procedure: cognitive assessment
Ancillary studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of vorinostat in patients with newly diagnosed glioblastoma multiforme (GBM) and gliosarcomas, who are also receiving concomitant radiation therapy (RT) and temozolomide (TMZ). (Phase I) II. To define the safety of vorinostat with RT and TMZ in this population. (Phase II) III. To determine the efficacy of vorinostat in combination with RT and TMZ followed by vorinostat in combination with TMZ in patients with newly-diagnosed GBM and gliosarcomas as measured by overall survival at 15 months (OS15). (Phase II)

SECONDARY OBJECTIVES:

I. To determine progression-free survival in newly diagnosed GBM and gliosarcoma patients treated with the study regimen. (Phase II) II. To further evaluate the safety profile of vorinostat in combination with RT and TMZ in this patient population. (Phase II) III. Determine the neurocognitive effects in patients treated on this protocol and correlate these results with outcome endpoints. (Phase II)

TERTIARY OBJECTIVES:

I. To explore the extent to which the tumor's molecular characteristics and expression profile correlate with outcome.

II. Evaluate potential mechanisms of therapy resistance in tumor samples obtained at the time of tumor progression.

OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients undergo radiotherapy and receive vorinostat orally (PO) once daily (QD) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD on days 1-5. Treatment with vorinostat and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year, every 3 months for 1 year and then every 6 months for 3 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRE-REGISTRATION:
  • Central pathology review submission; this review is mandatory prior to registration to confirm eligibility; it should be initiated as soon after surgery as possible
  • Treatment should begin >= 2 weeks and =< 5 weeks following surgery
  • REGISTRATION:
  • Histologically confirmed glioblastoma multiforme as determined by pre-registration central pathology review; Note: gliosarcomas and other grade 4 astrocytoma variants (e.g., giant cell) are eligible
  • Measurable or evaluable disease by gadolinium magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) scan; Note: patients who have had a gross total resection (GTR) are eligible on the basis of evaluable disease

    • Must begin partial brain radiotherapy on the same day that vorinostat and temozolomide begin
  • Karnofsky performance status of >= 60
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • White blood cell (WBC) >= 3,000/mm^3
  • Hemoglobin >= 10.0 g/dL; Note: this level may be reached by transfusion
  • Total bilirubin =< 2.0 x institutional upper limit of normal (ULN)
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.0 x ULN
  • Creatinine =< 1.5 mg/dL
  • Life expectancy >= 12 weeks
  • Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • For Phase I established MTD and Phase II patients only: Willing and able to complete neurocognitive testing
  • Ability to provide informed written consent
  • Willing to return to Alliance or Adult Brain Tumor Consortium (ABTC) enrolling institution for follow-up
  • Phase I established MTD patients and Phase II patients: Willing to provide mandatory tissue samples (slides or blocks) for research purposes
  • Willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with vorinostat and temozolomide

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the duration of the study and for 12 weeks after treatment has ended
  • Prior cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors
  • Prior cranial RT
  • Prior Gliadel wafers
  • Known hypersensitivity to any of the components of vorinostat or other agents used in study
  • Valproic acid, another histone deacetylase inhibitor, =< 2 weeks prior to registration and during treatment
  • Other active malignancy =< 3 years prior to registration; Exception: non-melanotic skin cancer or carcinoma in situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer
  • Uncontrolled infection
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; Note: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Co-morbid systemic illness or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with proper assessment of safety and adverse events of the prescribed regimens
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
  • History of myocardial infarction or unstable angina =< 6 months prior to registration or congestive heart failure (CHF) requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • New York Heart Association (NYHA) >= Class II Congestive Heart Failure
  • Inability to take oral medications
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Congenital long QT syndrome
  • Prolonged corrected (QTc) interval (> 450 msec)
  • Any of the following Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes =< 7 days prior to registration

    • Quinidine, procainamide, disopyramide
    • Amiodarone, sotalol, ibutilide, dofetilide
    • Erythromycin, clarithromycin
    • Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
    • Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00731731

  Show 108 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Evanthia Galanis North Central Cancer Treatment Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00731731     History of Changes
Other Study ID Numbers: NCI-2009-00672, NCI-2009-00672, CDR0000609743, ABTC 0902, N0874, N0874, U10CA025224
Study First Received: August 8, 2008
Last Updated: March 5, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Vorinostat
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Histone Deacetylase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 16, 2014