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Magnetic Resonance Spectroscopy Imaging in Predicting Response to Vorinostat and Temozolomide in Patients With Recurrent or Progressive Glioblastoma

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ClinicalTrials.gov Identifier: NCT01342757
Recruitment Status : Completed
First Posted : April 27, 2011
Results First Posted : June 11, 2014
Last Update Posted : December 1, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
This clinical trial is studying magnetic resonance spectroscopy imaging in predicting response in patients to vorinostat and temozolomide in patients with recurrent, progressive, or newly diagnosed glioblastoma. 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. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may also help temozolomide work better by making tumor cells more sensitive to the drug. Imaging procedures, such as magnetic resonance spectroscopy imaging, may help measure the patient's response to vorinostat and temozolomide and allow doctors to plan better treatment.

Condition or disease Intervention/treatment
Adult Glioblastoma Depression Recurrent Adult Brain Tumor Drug: vorinostat Drug: temozolomide Procedure: magnetic resonance spectroscopic imaging Other: survey administration

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the strength of the association between magnetic resonance spectroscopy (MRS) imaging measurable biomarkers and response to vorinostat plus temozolomide.

SECONDARY OBJECTIVES:

I. To evaluate MRS-detected inositol and N-acetylaspartate (NAA) levels (at 3 tesla) as indicators of mood alterations as measured by a self-report depression survey (IDS-SR).

OUTLINE:

Patients receive vorinostat orally (PO) once daily (QD) on days -7 to -1 (course 1 only) and days 8-14 and 22-28 and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients previously treated with standard radiotherapy and temozolomide receive maintenance temozolomide PO on days 1-5.

Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicities. Patients undergo magnetic resonance spectroscopy imaging at baseline and at approximately 1 and 8 weeks on treatment. Patients also undergo an Inventory of Depression Symptomatology Self-Reported (IDS-SR) assessment at baseline and periodically during study.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Using Proton Magnetic Resonance Spectroscopy (MRS) to Predict Response of Vorinostat Treatment in Glioblastoma
Study Start Date : December 2010
Primary Completion Date : May 2012
Study Completion Date : May 2012


Arms and Interventions

Arm Intervention/treatment
Experimental: Arm I

Patients receive vorinostat once daily on days -7 to -1 (course 1 only) and days 8-14 and 22-28 and temozolomide on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo magnetic resonance spectroscopic imaging at baseline and at approximately 1 and 8 weeks on treatment. Patients also undergo a survey administration of Inventory of Depression Symptomatology Self-Reported (IDS-SR) assessment at baseline and periodically during study.

Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: temozolomide
Given orally
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Procedure: magnetic resonance spectroscopic imaging
Undergo MRI
Other Names:
  • 1H-nuclear magnetic resonance spectroscopic imaging
  • Proton Magnetic Resonance Spectroscopic Imaging
Other: survey administration
Ancillary studies


Outcome Measures

Primary Outcome Measures :
  1. Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index [ Time Frame: 9 weeks ]
    Changes in magnetic resonance spectroscopic imaging signal and semiquantitative analysis of inositol, choline, lactate, and N-acetylaspartate signal are measured. The values for each of these metabolites are normalized to baseline at one and nine weeks. The values of all the metabolites at one week are added and this is the magnetic resonance spectroscopic index for one week. This is done again at nine weeks. The number is unitless and there is no range limit. Positive values represent normalization of tumor metabolism and negative values suggest no improvement or worsening of metabolic character.

  2. Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans [ Time Frame: After 1 week ]
    Baseline MRS was performed 1-3 days before initiation of treatment. Follow-up MRS studies were performed at day 7. A standard quadrature head coil was used to collect MR data. The spectroscopic restoration index was calculated (ΔN-acetyl aspartate + Δcreatine + Δmyo-inositol − Δcholine − Δ(lactate / lipids)) and used to classify responders and nonresponders.

  3. Measurable Change on Magnetic Resonance Spectroscopy Imaging After Vorinostat Administration [ Time Frame: 9 weeks ]
    Changes in magnetic resonance spectroscopic imaging signal and semiquantitative analysis of inositol, choline, lactate, and N-acetyl aspartate (NAA) signal are measured. The values for each of these metabolites are normalized to baseline at one and nine weeks. The values of all the metabolites at one week are added and this is the magnetic resonance spectroscopic index for one week. This is done again at nine weeks. The number is unitless and there is no range limit. Positive values represent normalization of tumor metabolism and negative values suggest no improvement or worsening of metabolic character.


Secondary Outcome Measures :
  1. Mean (or Median) Change in Metabolite Levels [ Time Frame: Baseline to 1 week ]
    Baseline MRS was performed 1-3 days before initiation of treatment. Follow-up MRS studies were performed at day 7. A standard quadrature head coil was used to collect MR data. The change of metabolite level in choline (Cho) and N-acetyl aspartate (NAA) were calculated in ratio by (metabolite after treatment / metabolite before treatment − 1).


Eligibility Criteria

Information from the National Library of Medicine

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

Inclusion Criteria:

  • Patients must have 1 of the following:

    • Diagnosis of recurrent or progressive glioblastoma

      • Patients with recurrent disease may have had treatment for any number of prior relapses
    • Newly diagnosed glioblastoma and have completed radiation therapy and are receiving standard follow-up temozolomide
  • Must be able to have an MRI, and have a measurable contrast-enhancing supratentorial tumor of at least 1 cm by shortest diameter
  • Residual disease following resection measuring 1 cm in diameter or greater is mandated for eligibility into the study
  • Patients must have a stable or progressive disease as determined by serial brain MRI using the McDonald Criteria on a scan 14 days or fewer before registration and on a stable steroid dose for 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
  • White Blood Cell Count > 3,000/μL
  • Absolute Neutrophil Count > 1,500/μL
  • Platelet count > 100,000/μL
  • Hemoglobin > 10 g/dL (transfusion allowed)
  • Serum glutamate oxaloacetate transaminase < 2 times upper limit of normal (ULN)
  • Bilirubin < 2 times ULN
  • Creatinine < 1.5 mg/dL
  • Negative pregnancy test
  • Women of childbearing potential and men must agree to use adequate barrier contraception for the duration of study participation
  • Able to swallow capsules
  • No patients with pacemakers, non-titanium aneurysm clips, neurostimulators, cochlear implants, non-titanium metal in ocular structures, history of being a steel worker, or other incompatible implants
  • No 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
  • No history of any other cancer except non-melanoma skin cancer or carcinoma in-situ of the cervix, or cancer in complete remission and off all therapy for ≥ 3 years
  • No active infection or serious intercurrent medical illness
  • No disease that would obscure toxicity or dangerously alter drug metabolism
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in this study
  • No prolonged corrected QT interval waves on baseline EKG
  • No other anticancer therapy (including chemotherapy, radiation, hormonal treatment, or immunotherapy) of any kind is permitted during the study period
  • At least 3 weeks since prior radiotherapy
  • Patients must have recovered from the toxic effects of prior therapy, including surgery
  • At least 28 days since any prior investigational agent or prior cytotoxic therapy
  • At least 23 days since prior temozolomide
  • At least 14 days since prior vincristine (42 days for nitrosourea)
  • At least 21 days since prior procarbazine
  • At least 7 days since prior non-cytotoxic agents (e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.)
  • At least 2 weeks since prior valproic acid (or another histone deacetylase inhibitor)
  • No other concurrent investigational agents

Exclusion Criteria:

  • Diagnostic and Statistical Manual-IV Axis I or II diagnosis (as determined by PI), exclusive of nicotine dependence.
  • Pregnant.
  • Contraindications to MRI: pacemaker, aneurysm clips, neurostimulators, cochlear implants, metal in eyes, steel worker, or other implants.
  • Active medical or neurological disorder.
  • History of alcohol or drug dependence
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01342757


Locations
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jeffrey Olson Emory University
More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01342757     History of Changes
Other Study ID Numbers: NCI-2011-02569
EMORY IRB #00044064 ( Other Identifier: Emory University )
WCI-44064 ( Other Identifier: Winship Cancer Institute )
R21CA141836 ( U.S. NIH Grant/Contract )
First Posted: April 27, 2011    Key Record Dates
Results First Posted: June 11, 2014
Last Update Posted: December 1, 2017
Last Verified: October 2017

Additional relevant MeSH terms:
Glioblastoma
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
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors