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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01342757
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 17
• Patients Per Site Per Month: 0.7

Study Details

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	Phase
Adult Glioblastoma; Depression; Recurrent Adult Brain Tumor	Drug: vorinostat; Drug: temozolomide; Procedure: magnetic resonance spectroscopic imaging; Other: survey administration	N/A

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

1. 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
• Actual Enrollment: 12 participants
• Allocation: N/A
• 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: Dec 1, 2010
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: May 1, 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 [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 [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)).

3. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jeffrey Olson, Emory University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01342757
• Other Study ID Numbers: NCI-2011-02569; EMORY IRB #00044064; WCI-44064; R21CA141836
• First Posted: Apr 27, 2011
• Last Update Posted: Jan 29, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Glioblastoma; Temozolomide; Vorinostat

Study Results

Participant Flow

Recruitment Details	Recruitment closed
Pre-assignment Detail	No events requiring changes in approach or enrollment criteria

Arm/Group Title	Vorinostat and Temozolomide
Arm/Group Description	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.
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	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.
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52 (10)
Sex: Female, Male (Count of Participants)
Female	4 33.3%
Male	8 66.7%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	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.
Measure Participants	12
Number [participants]	0 0%

2. Primary Outcome

Title	Proportion of Patients Who Experience Metabolic Restoration Between the Responders and Non-responder Groups by MRS Scans
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm I
Arm/Group Description	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.
Measure Participants	7
Metabolic Responders SRI Greater than 0	3 25%
Metabolic Responders SRI 0 or Less	0 0%
Metabolic Non-Responders SRI Greater than 0	0 0%
Metabolic Non-Responders SRI 0 or Less	4 33.3%

3. Primary Outcome

Title	Measurable Change on Magnetic Resonance Spectroscopy Imaging After Vorinostat Administration
Description	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

Outcome Measure Data

Analysis Population Description

Patients collected until measurable spectroscopic indexes were available in at least three cases with metabolic response and three without metabolic response

Arm/Group Title	Arm I
Arm/Group Description	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.
Measure Participants	12
Mean (Standard Deviation) [Spectroscopic index]	0 (1.4)

4. Secondary Outcome

Title	Mean Change in Metabolite Levels
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	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.
Measure Participants	7
Metabolic Responders	-0.15
Metabolic Non-Responders	0.29

Adverse Events

Time Frame	Until tumor progression by imaging
Adverse Event Reporting Description	Clinic visits, drug diary and patient reporting
Arm/Group Title	Arm I
Arm/Group Description	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.
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	5/12 (41.7%)
Blood and lymphatic system disorders
Thrombocytopenia	1/12 (8.3%)	1
Gastrointestinal disorders
Diarrhea	1/12 (8.3%)	1
Nausea	1/12 (8.3%)	1
Vomiting	1/12 (8.3%)	1
Nervous system disorders
Headache	1/12 (8.3%)	1
Psychiatric disorders
Agitation	1/12 (8.3%)	1
Vascular disorders
Thromboembolism	1/12 (8.3%)	1
Hypertension	2/12 (16.7%)	2
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	9/12 (75%)
Blood and lymphatic system disorders
Thrombocytopenia	3/12 (25%)	4
Bruising	1/12 (8.3%)	1
Leukopenia	2/12 (16.7%)	2
Anemia	2/12 (16.7%)	2
Prolonged APTT	1/12 (8.3%)	1
Ear and labyrinth disorders
Vertigo	1/12 (8.3%)	1
Gastrointestinal disorders
Diarrhea	3/12 (25%)	3
Abdominal Pain	1/12 (8.3%)	1
Vomiting	1/12 (8.3%)	1
Constipation	1/12 (8.3%)	1
Gastoesophageal Reflux disease	1/12 (8.3%)	1
General disorders
Fatigue	3/12 (25%)	3
Pain	1/12 (8.3%)	1
Nausea	4/12 (33.3%)	6
Anorexia	1/12 (8.3%)	1
Weight Loss	1/12 (8.3%)	1
Insomnia	1/12 (8.3%)	1
Syncope	1/12 (8.3%)	1
Infections and infestations
Skin infection-scalp	1/12 (8.3%)	1
Metabolism and nutrition disorders
Hyperglycemia	5/12 (41.7%)	6
ALT increased	1/12 (8.3%)	1
Hyponatremia	3/12 (25%)	3
Dehydration	1/12 (8.3%)	1
AST elevation	1/12 (8.3%)	1
Hyperkalemia	3/12 (25%)	3
Hypophosphatemia	1/12 (8.3%)	1
Hypoalbuminemia	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/12 (8.3%)	1
Nervous system disorders
Seizure	1/12 (8.3%)	1
Intracranial Hemorrhage	2/12 (16.7%)	2
Headache	1/12 (8.3%)	1
Confusion	1/12 (8.3%)	1
Weakness, left sided	1/12 (8.3%)	1
Cognitive Disturbances	1/12 (8.3%)	1
Agitation	1/12 (8.3%)	1
Renal and urinary disorders
Creatinine Increased	2/12 (16.7%)	2
Urinary Frequency	1/12 (8.3%)	1
Proteinuria	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Pruritis	1/12 (8.3%)	1
Vascular disorders
Edema in Limbs and Hands	1/12 (8.3%)	1
Hypertension	3/12 (25%)	3

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.