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

Not Applicable

Completed

Conditions: Adult Glioblastoma
Depression
Recurrent Adult Brain Tumor

Interventions: Drug: vorinostat
Drug: temozolomide
Procedure: magnetic resonance spectroscopic imaging
Other: survey administration

Registration Number: NCT01342757

Lead Sponsor: National Cancer Institute (NCI)

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	magnetic resonance spectroscopic imaging	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.
Arm I	survey administration	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.
Arm I	vorinostat	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.
Arm I	temozolomide	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.

Primary Outcome Measures

Name	Time	Method
Measurable Change on Magnetic Resonance Spectroscopy Imaging After Vorinostat Administration	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.
Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index	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.
Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans	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. A responder was defined as stable disease: determined in glioblastoma to be between a 25% volume increase and 50% volume decrease compared to baseline imaging at the therapy initiation at the 2 month follow-up visit. The spectroscopic restoration index was calculated (ΔN-acetyl aspartate + Δcreatine + Δmyo-inositol - Δcholine - Δ(lactate / lipids)).

Secondary Outcome Measures

Name	Time	Method
Mean Change in Metabolite Levels	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). The reported ratios represent the Cho-to-NAA ratio at day 7 compared with day 0.