Adult Glioblastoma, Depression, Recurrent Adult Brain Tumor
Conditions
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.
Interventions
DRUGvorinostat
Given orally
DRUGtemozolomide
Given orally
PROCEDUREmagnetic resonance spectroscopic imaging
Undergo MRI
OTHERsurvey administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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)). |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment closed
Pre-assignment details
No events requiring changes in approach or enrollment criteria
Participants by arm
| Arm | Count |
|---|---|
| Arm I 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. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 12 |
| serious Total, serious adverse events | 5 / 12 |
Outcome results
Primary
Measurable Change on Magnetic Resonance Spectroscopy Imaging After Vorinostat Administration
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.
Time frame: 9 weeks
Population: Patients collected until measurable spectroscopic indexes were available in at least three cases with metabolic response and three without metabolic response
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I | Measurable Change on Magnetic Resonance Spectroscopy Imaging After Vorinostat Administration | 0 Spectroscopic index | Standard Deviation 1.4 |
Primary
Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans
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)).
Time frame: After 1 week
Population: In five of the twelve cases spectroscopic indices could not be calculated because the tumor volume was outside of reliably measured voxels. These were primarily accounted for by tumor closeness to the skull or the small size of residual tumor.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I | Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans | Metabolic Responders SRI Greater than 0 | 3 Participants |
| Arm I | Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans | Metabolic Responders SRI 0 or Less | 0 Participants |
| Arm I | Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans | Metabolic Non-Responders SRI Greater than 0 | 0 Participants |
| Arm I | Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans | Metabolic Non-Responders SRI 0 or Less | 4 Participants |
Primary
Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index
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.
Time frame: 9 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index | 0 participants |
Secondary
Mean Change in Metabolite Levels
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.
Time frame: Baseline to 1 week
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Arm I | Mean Change in Metabolite Levels | Metabolic Responders | -0.15 Cho/NAA Ratios |
| Arm I | Mean Change in Metabolite Levels | Metabolic Non-Responders | 0.29 Cho/NAA Ratios |