Trial Outcomes & Findings for Magnetic Resonance Spectroscopy Imaging in Predicting Response to Vorinostat and Temozolomide in Patients With Recurrent or Progressive Glioblastoma (NCT NCT01342757)

Last Updated: 2018-01-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

Target enrollment

12 participants

Primary outcome timeframe

9 weeks

Results posted on

2018-01-29

Participant Flow

Recruitment closed

No events requiring changes in approach or enrollment criteria

Participant milestones

Participant milestones
Measure	Vorinostat and Temozolomide 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 Study STARTED	12
Overall Study COMPLETED	12
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I n=12 Participants 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.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	12 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	52 years STANDARD_DEVIATION 10 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Region of Enrollment United States	12 participants n=5 Participants

PRIMARY outcome

Timeframe: 9 weeks

Outcome measures

Outcome measures
Measure	Arm I n=12 Participants 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.
Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index	0 participants

PRIMARY outcome

Timeframe: 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.

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)).

Outcome measures

Outcome measures
Measure	Arm I n=7 Participants 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.
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
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
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
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 outcome

Timeframe: 9 weeks

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

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.

Outcome measures

Outcome measures
Measure	Arm I n=12 Participants 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.
Measurable Change on Magnetic Resonance Spectroscopy Imaging After Vorinostat Administration	0 Spectroscopic index Standard Deviation 1.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm I n=7 Participants 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.
Mean Change in Metabolite Levels Metabolic Responders	-0.15 Cho/NAA Ratios Interval -0.32 to -0.04
Mean Change in Metabolite Levels Metabolic Non-Responders	0.29 Cho/NAA Ratios Interval 0.0 to 0.94

Adverse Events

Arm I

Serious events: 5 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm I n=12 participants at risk 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.
Vascular disorders Thromboembolism	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Blood and lymphatic system disorders Thrombocytopenia	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Diarrhea	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Nausea	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Vomiting	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Vascular disorders Hypertension	16.7% 2/12 • Number of events 2 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Headache	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Psychiatric disorders Agitation	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting

Other adverse events

Other adverse events
Measure	Arm I n=12 participants at risk 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.
Skin and subcutaneous tissue disorders Pruritis	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Vascular disorders Edema in Limbs and Hands	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
General disorders Fatigue	25.0% 3/12 • Number of events 3 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
General disorders Pain	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Diarrhea	25.0% 3/12 • Number of events 3 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders Hyperglycemia	41.7% 5/12 • Number of events 6 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Infections and infestations Skin infection-scalp	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Blood and lymphatic system disorders Thrombocytopenia	25.0% 3/12 • Number of events 4 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Blood and lymphatic system disorders Bruising	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Respiratory, thoracic and mediastinal disorders Dyspnea	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders ALT increased	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Abdominal Pain	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
General disorders Nausea	33.3% 4/12 • Number of events 6 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Vomiting	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Renal and urinary disorders Creatinine Increased	16.7% 2/12 • Number of events 2 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders Hyponatremia	25.0% 3/12 • Number of events 3 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders Dehydration	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Blood and lymphatic system disorders Leukopenia	16.7% 2/12 • Number of events 2 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Seizure	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
General disorders Anorexia	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Intracranial Hemorrhage	16.7% 2/12 • Number of events 2 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
General disorders Weight Loss	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
General disorders Insomnia	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Renal and urinary disorders Urinary Frequency	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Blood and lymphatic system disorders Anemia	16.7% 2/12 • Number of events 2 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders AST elevation	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders Hyperkalemia	25.0% 3/12 • Number of events 3 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Vascular disorders Hypertension	25.0% 3/12 • Number of events 3 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Headache	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Confusion	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Weakness, left sided	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Blood and lymphatic system disorders Prolonged APTT	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders Hypophosphatemia	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Cognitive Disturbances	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Constipation	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Nervous system disorders Agitation	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Gastrointestinal disorders Gastoesophageal Reflux disease	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
General disorders Syncope	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Musculoskeletal and connective tissue disorders Generalized muscle weakness	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Ear and labyrinth disorders Vertigo	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Renal and urinary disorders Proteinuria	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting
Metabolism and nutrition disorders Hypoalbuminemia	8.3% 1/12 • Number of events 1 • Until tumor progression by imaging Clinic visits, drug diary and patient reporting

Additional Information

Jeffrey J. Olson, MD

Emory University School of Medicine

Phone: 404-778-3091

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60