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Valproic Acid With Temozolomide and Radiation Therapy to Treat Brain Tumors

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ClinicalTrials.gov Identifier: NCT00302159
Recruitment Status : Completed
First Posted : March 13, 2006
Results First Posted : June 24, 2014
Last Update Posted : August 18, 2016
Sponsor:
Information provided by (Responsible Party):
Kevin Camphausen, M.D., National Institutes of Health Clinical Center (CC)

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions High Grade Gliomas
Brain Tumors
Interventions Procedure: adjuvant therapy
Drug: Temozolomide
Drug: Valproic Acid
Radiation: Radiation therapy
Enrollment 43
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Valproic Acid
Hide Arm/Group Description

adjuvant therapy

Temozolomide Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Period Title: Overall Study
Started 43
Completed 41
Not Completed 2
Reason Not Completed
pt declined before treatment started             1
pt started Avastin             1
Arm/Group Title Valproic Acid
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adjuvant therapy

Temozolomide Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Overall Number of Baseline Participants 43
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 43 participants
52.88  (11.33)
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants
<=18 years
0
   0.0%
Between 18 and 65 years
39
  90.7%
>=65 years
4
   9.3%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants
Female
14
  32.6%
Male
29
  67.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   2.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
5
  11.6%
White
35
  81.4%
More than one race
0
   0.0%
Unknown or Not Reported
2
   4.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants
Hispanic or Latino
2
   4.7%
Not Hispanic or Latino
41
  95.3%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 43 participants
43
1.Primary Outcome
Title Median Progression Free Survival.
Hide Description Progression free survival is the interval from initiation of treatment on protocol to symptomatic or radiographic progression. Progressive disease is a >25% increase in contrast enhancing tumor volume documented at the initiation of treatment on protocol.
Time Frame up to 51 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valproic Acid
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adjuvant therapy

Temozolomide Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Overall Number of Participants Analyzed 43
Median (95% Confidence Interval)
Unit of Measure: months
10.5
(7 to 51)
2.Primary Outcome
Title Percentage of Participants With Progression Free Survival at 6, 12, and 24 Months
Hide Description Percentage of participants who were progression free by 6, 12, or 24 months. Progressive disease is a >25% increase in contrast enhancing tumor volume documented at the initiation of treatment on protocol.
Time Frame 6, 12, and 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valproic Acid
Hide Arm/Group Description:

Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

adjuvant therapy

Temozolomide: Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid: Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy: External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Overall Number of Participants Analyzed 43
Measure Type: Number
Unit of Measure: percentage of participants
6 months 70
12 months 43
24 months 38
3.Primary Outcome
Title Number of Participants With Best Response
Hide Description Best response recorded from the start of treatment until disease progression/recurrence. Complete response is complete resolution of all contrast enhancing tumor documented at initiation of treatment on protocol, with no appearance of new lesions. Partial response is a >50% reduction in the contrast enhancing tumor volume documented at the initiation of treatment on protocol. Minor response is a >25%, but <50% reduction in the contrast enhancing tumor volume documented at the initiation of treatment on protocol. Stable disease is a change in tumor size less than MR but not demonstrating progressive disease. Progressive disease is a >25% increase in contrast enhancing tumor volume documented at the initiation of treatment on protocol. Not evaluable means the participant cannot be evaluated (e.g., quality of scan).
Time Frame up to 63.8 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valproic Acid
Hide Arm/Group Description:

Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

adjuvant therapy

Temozolomide: Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid: Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy: External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Overall Number of Participants Analyzed 43
Measure Type: Number
Unit of Measure: participants
Complete Response 0
Partial Response 0
Minor Response 0
Stable Disease 27
Progressive Disease 7
Not Evaluable 9
4.Primary Outcome
Title Median Overall Survival
Hide Description Survival is the interval from the initiation of treatment on protocol to date of death.
Time Frame up to 63.8 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valproic Acid
Hide Arm/Group Description:

Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

adjuvant therapy

Temozolomide: Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid: Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy: External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Overall Number of Participants Analyzed 43
Median (95% Confidence Interval)
Unit of Measure: months
29.6
(21 to 63.8)
5.Primary Outcome
Title Percentage of Participants With Overall Survival at 6, 12, and 24 Months
Hide Description Percentage of participants who were alive at 6, 12, and 24 months.
Time Frame 6, 12, and 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valproic Acid
Hide Arm/Group Description:

Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

adjuvant therapy

Temozolomide: Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid: Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy: External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Overall Number of Participants Analyzed 43
Measure Type: Number
Unit of Measure: percentage of participants
6 months 97
12 months 86
24 months 56
6.Secondary Outcome
Title Number of Participants With Adverse Events
Hide Description Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Time Frame 6 years, 7 months and 27 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valproic Acid
Hide Arm/Group Description:

adjuvant therapy

Temozolomide Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Overall Number of Participants Analyzed 43
Measure Type: Number
Unit of Measure: participants
43
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Valproic Acid
Hide Arm/Group Description

adjuvant therapy

Temozolomide Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

All-Cause Mortality
Valproic Acid
Affected / at Risk (%)
Total   --/--    
Hide Serious Adverse Events
Valproic Acid
Affected / at Risk (%) # Events
Total   17/43 (39.53%)    
Blood and lymphatic system disorders   
Lymphopenia  1  1/43 (2.33%)  1
Platelets  1  2/43 (4.65%)  3
Eye disorders   
Vision-blurred vision  1  1/43 (2.33%)  1
Gastrointestinal disorders   
Dehydration  1  1/43 (2.33%)  1
General disorders   
Death not associated with CTCAE term::Disease progression NOS  1  1/43 (2.33%)  1
Fatigue (asthenia, lethargy, malaise)  1  1/43 (2.33%)  1
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)  1  1/43 (2.33%)  1
Infections and infestations   
Infection - Other (Specify, pneumonia)  1  1/43 (2.33%)  1
Metabolism and nutrition disorders   
Amylase  1  1/43 (2.33%)  1
Metabolic/Laboratory - Other (Specify, high ammonia)  1  1/43 (2.33%)  1
Nervous system disorders   
Ataxia (incoordination)  1  3/43 (6.98%)  3
Confusion  1  2/43 (4.65%)  2
Encephalopathy  1  1/43 (2.33%)  1
Hemorrhage, CNS  1  2/43 (4.65%)  2
Mood alteration::Agitation  1  2/43 (4.65%)  2
Neuropathy: motor  1  3/43 (6.98%)  3
Pain::Head/headache  1  1/43 (2.33%)  1
Seizure  1  4/43 (9.30%)  4
Speech impairment (e.g., dysphasia or aphasia)  1  2/43 (4.65%)  2
Respiratory, thoracic and mediastinal disorders   
Dyspnea (shortness of breath)  1  1/43 (2.33%)  1
Hypoxia  1  1/43 (2.33%)  2
Pulmonary/Upper Respiratory - Other (Specify, PE)  1  1/43 (2.33%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Valproic Acid
Affected / at Risk (%) # Events
Total   39/43 (90.70%)    
Blood and lymphatic system disorders   
Edema: head and neck  1  4/43 (9.30%)  4
Edema: limb  1  4/43 (9.30%)  5
Hemoglobin  1  13/43 (30.23%)  23
INR (International Normalized Ratio of prothrombin time)  1  1/43 (2.33%)  1
Leukocytes (total WBC)  1  14/43 (32.56%)  42
Lymphatics - Other (Specify)  1 [1]  2/43 (4.65%)  3
Lymphopenia  1  27/43 (62.79%)  79
Neutrophils/granulocytes (ANC/AGC)  1  8/43 (18.60%)  16
Petechiae/purpura (hemorrhage/bleeding into skin or mucosa)  1  1/43 (2.33%)  1
Platelets  1  27/43 (62.79%)  63
Cardiac disorders   
Cardiac General - Other (Specify, systolic ejection murmur noted)  1  1/43 (2.33%)  1
Supraventricular and nodal arrhythmia::Sinus tachycardia  1  1/43 (2.33%)  1
Ear and labyrinth disorders   
Auditory/Ear - Other (Specify, decreased hearing)  1  1/43 (2.33%)  1
Hearing: patients without baseline audiogram and not enrolled in a monitoring program  1  2/43 (4.65%)  2
Otitis, middle ear (non-infectious)  1  1/43 (2.33%)  2
Pain::External ear  1  1/43 (2.33%)  1
Tinnitus  1  4/43 (9.30%)  4
Endocrine disorders   
Cushingoid appearance (e.g., moon face, buffalo hump, centripetal obesity, cutaneous striae)  1  2/43 (4.65%)  2
Eye disorders   
Eyelid dysfunction  1  1/43 (2.33%)  2
Nystagmus  1  2/43 (4.65%)  2
Ocular/Visual - Other (Specify)  1 [2]  3/43 (6.98%)  3
Vision-blurred vision  1  4/43 (9.30%)  4
Vision-flashing lights/floaters  1  1/43 (2.33%)  1
Vision-photophobia  1  1/43 (2.33%)  1
Watery eye (epiphora, tearing)  1  2/43 (4.65%)  2
Gastrointestinal disorders   
Anorexia  1  6/43 (13.95%)  7
Constipation  1  17/43 (39.53%)  19
Dehydration  1  2/43 (4.65%)  2
Diarrhea  1  2/43 (4.65%)  3
Dry mouth/salivary gland (xerostomia)  1  1/43 (2.33%)  1
Dysphagia (difficulty swallowing)  1  2/43 (4.65%)  2
Flatulence  1  2/43 (4.65%)  2
Gastritis (including bile reflux gastritis)  1  1/43 (2.33%)  1
Gastrointestinal - Other (Specify, GERD)  1  1/43 (2.33%)  1
Heartburn/dyspepsia  1  1/43 (2.33%)  1
Hemorrhage, GI::Anus  1  1/43 (2.33%)  1
Hemorrhoids  1  1/43 (2.33%)  1
Mucositis/stomatitis (clinical exam)::Oral cavity  1  2/43 (4.65%)  2
Mucositis/stomatitis (functional/symptomatic)::Oral cavity  1  1/43 (2.33%)  1
Nausea  1  23/43 (53.49%)  30
Pain::Abdomen NOS  1  3/43 (6.98%)  4
Pain::Dental/teeth/peridontal  1  1/43 (2.33%)  1
Pain::Esophagus  1  1/43 (2.33%)  1
Taste alteration (dysgeusia)  1  3/43 (6.98%)  3
Vomiting  1  8/43 (18.60%)  8
General disorders   
Fatigue (asthenia, lethargy, malaise)  1  25/43 (58.14%)  34
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)  1  2/43 (4.65%)  2
Insomnia  1  7/43 (16.28%)  7
Pain - Other (Specify,jaw; right shoulder; whole body)  1  2/43 (4.65%)  3
Pain::Pain NOS  1  1/43 (2.33%)  2
Sweating (diaphoresis)  1  1/43 (2.33%)  1
Weight gain  1  1/43 (2.33%)  1
Weight loss  1  2/43 (4.65%)  2
Hepatobiliary disorders   
Pancreatitis  1  2/43 (4.65%)  2
Immune system disorders   
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)  1  4/43 (9.30%)  4
Infections and infestations   
Infection with normal ANC or Grade 1 or 2 neutrophils::Conjunctiva  1  1/43 (2.33%)  1
Infection with normal ANC or Grade 1 or 2 neutrophils::Middle ear (otitis media)  1  1/43 (2.33%)  1
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)  1  2/43 (4.65%)  2
Infection with unknown ANC::Bronchus  1  1/43 (2.33%)  1
Infection with unknown ANC::Paranasal  1  1/43 (2.33%)  1
Infection with unknown ANC::Skin (cellulites)  1  1/43 (2.33%)  1
Metabolism and nutrition disorders   
ALT, SGPT (serum glutamic pyruvic transaminase)  1  15/43 (34.88%)  19
AST, SGOT(serum glutamic oxaloacetic transaminase)  1  6/43 (13.95%)  7
Albumin, serum-low (hypoalbuminemia)  1  27/43 (62.79%)  41
Alkaline phosphatase  1  2/43 (4.65%)  2
Amylase  1  6/43 (13.95%)  9
Bilirubin (hyperbilirubinemia)  1  7/43 (16.28%)  10
Calcium, serum-high (hypercalcemia)  1  5/43 (11.63%)  5
Calcium, serum-low (hypocalcemia)  1  4/43 (9.30%)  6
Creatinine  1  5/43 (11.63%)  6
Glucose, serum-high (hyperglycemia)  1  4/43 (9.30%)  8
Lipase  1  6/43 (13.95%)  10
Magnesium, serum-high (hypermagnesemia)  1  15/43 (34.88%)  18
Magnesium, serum-low (hypomagnesemia)  1  3/43 (6.98%)  3
Metabolic/Laboratory - Other (Specify)  1 [3]  4/43 (9.30%)  6
Phosphate, serum-low (hypophosphatemia)  1  2/43 (4.65%)  3
Potassium, serum-high (hyperkalemia)  1  14/43 (32.56%)  26
Sodium, serum-high (hypernatremia)  1  11/43 (25.58%)  16
Sodium, serum-low (hyponatremia)  1  11/43 (25.58%)  20
Uric acid, serum-high (hyperuricemia)  1  6/43 (13.95%)  9
Musculoskeletal and connective tissue disorders   
Arthritis (non-septic)  1  1/43 (2.33%)  1
Extremity-upper (function)  1  1/43 (2.33%)  1
Muscle weakness, generalized or specific area (not due to neuropathy)::Extremity-upper  1  2/43 (4.65%)  3
Muscle weakness, generalized or specific area (not due to neuropathy)::Facial  1  1/43 (2.33%)  1
Muscle weakness, generalized or specific area (not due to neuropathy)::Left-sided  1  1/43 (2.33%)  1
Muscle weakness, generalized or specific area (not due to neuropathy)::Right-sided  1  2/43 (4.65%)  2
Musculoskeletal/Soft Tissue - Other (Specify, ® rotator cuff injury)  1  1/43 (2.33%)  1
Pain::Back  1  2/43 (4.65%)  2
Pain::Extremity-limb  1  2/43 (4.65%)  3
Pain::Joint  1  4/43 (9.30%)  4
Pain::Muscle  1  2/43 (4.65%)  3
Nervous system disorders   
Ataxia (incoordination)  1  10/43 (23.26%)  15
Cognitive disturbance  1  1/43 (2.33%)  1
Confusion  1  16/43 (37.21%)  19
Dizziness  1  5/43 (11.63%)  7
Encephalopathy  1  2/43 (4.65%)  2
Extrapyramidal/involuntary movement/restlessness  1  2/43 (4.65%)  3
Memory impairment  1  8/43 (18.60%)  8
Mental status  1  1/43 (2.33%)  1
Mood alteration::Agitation  1  6/43 (13.95%)  7
Mood alteration::Anxiety  1  5/43 (11.63%)  7
Mood alteration::Depression  1  4/43 (9.30%)  4
Mood alteration::Euphoria  1  1/43 (2.33%)  2
Neurology - Other (Specify)  1 [4]  5/43 (11.63%)  5
Neuropathy: cranial::CN II Vision  1  1/43 (2.33%)  1
Neuropathy: cranial::CN V Motor-jaw muscles; Sensory-facial  1  2/43 (4.65%)  2
Neuropathy: cranial::CN VII Motor-face; Sensory-taste  1  1/43 (2.33%)  1
Neuropathy: cranial::CN VIII Hearing and balance  1  1/43 (2.33%)  2
Neuropathy: motor  1  11/43 (25.58%)  12
Neuropathy: sensory  1  6/43 (13.95%)  10
Pain::Head/headache  1  14/43 (32.56%)  20
Psychosis (hallucinations/delusions)  1  2/43 (4.65%)  2
Pyramidal tract dysfunction  1 [5]  1/43 (2.33%)  1
Seizure  1  11/43 (25.58%)  18
Somnolence/depressed level of consciousness  1  6/43 (13.95%)  6
Speech impairment (e.g., dysphasia or aphasia)  1  4/43 (9.30%)  5
Tremor  1  4/43 (9.30%)  6
Renal and urinary disorders   
Incontinence, urinary  1  2/43 (4.65%)  2
Reproductive system and breast disorders   
Hemorrhage, GU::Vagina  1  1/43 (2.33%)  1
Respiratory, thoracic and mediastinal disorders   
Bronchospasm, wheezing  1  1/43 (2.33%)  1
Cough  1  4/43 (9.30%)  4
Pain::Chest/thorax NOS  1  1/43 (2.33%)  1
Pain::Throat/pharynx/larynx  1  2/43 (4.65%)  2
Pulmonary/Upper Respiratory - Other (Specify, pulomonary embolism)  1  1/43 (2.33%)  1
Skin and subcutaneous tissue disorders   
Dermatology/Skin - Other (Specify, cyst R axilla)  1  1/43 (2.33%)  1
Dry skin  1  1/43 (2.33%)  1
Hair loss/alopecia (scalp or body)  1  23/43 (53.49%)  23
Hyperpigmentation  1  2/43 (4.65%)  2
Hypopigmentation  1  1/43 (2.33%)  1
Pain::Scalp  1  2/43 (4.65%)  2
Pruritus/itching  1  2/43 (4.65%)  2
Rash/desquamation  1  4/43 (9.30%)  5
Rash: acne/acneiform  1  2/43 (4.65%)  3
Rash: dermatitis associated with radiation::Chemoradiation  1  4/43 (9.30%)  4
Rash: dermatitis associated with radiation::Radiation  1  5/43 (11.63%)  6
Vascular disorders   
Hypertension  1  2/43 (4.65%)  2
Hypotension  1  1/43 (2.33%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
L facial edema; Tonsillar edema; Mobile node L axilla
[2]
"Seeing shapes" in cloth; Eye irritation; Problems seeing bright lights
[3]
Elevated LD; Hypokalemia; Low protein; Phosphorus elevated
[4]
Dizziness; Hyperreflexivity; Decreased affect; Decreased attention span; Pronator drift
[5]
(e.g., increased tone, hyperreflexia, positive Babinski, decreased fine motor coordination)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Kevin Camphausen, M.D.
Organization: National Cancer Institute, national Institutes of Health
Phone: 301-496-5457
EMail: camphauk@mail.nih.gov
Layout table for additonal information
Responsible Party: Kevin Camphausen, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00302159    
Obsolete Identifiers: NCT00313664
Other Study ID Numbers: 060112
06-C-0112
First Submitted: March 11, 2006
First Posted: March 13, 2006
Results First Submitted: May 22, 2014
Results First Posted: June 24, 2014
Last Update Posted: August 18, 2016