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Vorinostat and Bortezomib in Treating Patients With Progressive, Recurrent Glioblastoma Multiforme

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ClinicalTrials.gov Identifier: NCT00641706
Recruitment Status : Completed
First Posted : March 24, 2008
Results First Posted : July 10, 2013
Last Update Posted : May 14, 2014
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Interventions Drug: vorinostat
Procedure: therapeutic conventional surgery
Drug: bortezomib
Enrollment 44
Recruitment Details 45 patients were enrolled from 28 medical clinics between July 4, 2008 and February 16, 2010.
Pre-assignment Details One patient cancelled prior to treatment initiation and is excluded in the analysis.
Arm/Group Title Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Hide Arm/Group Description

Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

bortezomib : Given IV

vorinostat : Given orally

Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.

surgery : Patient undergoes therapeutic conventional surgery

bortezomib : Given IV

vorinostat : Given orally

Period Title: Overall Study
Started 37 7
Completed 28 4
Not Completed 9 3
Reason Not Completed
Adverse Event             2             1
Withdrawal by Subject             6             1
Clinical Decline             1             0
Lead Investigator Decision             0             1
Arm/Group Title Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery) Total
Hide Arm/Group Description

Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

bortezomib : Given IV

vorinostat : Given orally

Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.

surgery : Patient undergoes therapeutic conventional surgery

bortezomib : Given IV

vorinostat : Given orally

Total of all reporting groups
Overall Number of Baseline Participants 37 7 44
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 37 participants 7 participants 44 participants
52
(33 to 80)
51
(39 to 60)
52
(33 to 80)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 37 participants 7 participants 44 participants
Female
10
  27.0%
1
  14.3%
11
  25.0%
Male
27
  73.0%
6
  85.7%
33
  75.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 37 participants 7 participants 44 participants
37 7 44
1.Primary Outcome
Title Progression-free Survival at 6 Months
Hide Description Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. For patients with bidimensionally measurable disease (measurable disease), progression is defined as > 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients without bidimensionally measurable disease (evaluable disease), progression is defined as unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.
Time Frame At 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients that started treatment.
Arm/Group Title Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Hide Arm/Group Description:

Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

bortezomib : Given IV

vorinostat : Given orally

Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.

surgery : Patient undergoes therapeutic conventional surgery bortezomib : Given IV vorinostat : Given orally

Overall Number of Participants Analyzed 37 7
Measure Type: Number
Unit of Measure: percentage of patients
0 29
2.Secondary Outcome
Title Overall Survival
Hide Description Estimated using Kaplan-Meier survival curve.
Time Frame From study registration to date of death due to any cause or last follow-up (up to 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients that started treatment.
Arm/Group Title Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Hide Arm/Group Description:

Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

bortezomib : Given IV

vorinostat : Given orally

Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.

surgery : Patient undergoes therapeutic conventional surgery bortezomib : Given IV vorinostat : Given orally

Overall Number of Participants Analyzed 37 7
Median (Full Range)
Unit of Measure: months
3.2
(0.7 to 24.8)
8.7
(3.0 to 16.4)
3.Secondary Outcome
Title Time to Progression
Hide Description Estimated using Kaplan-Meier survival curve. Patients who died were considered to have disease progression at the time of death unless there was documented evidence that no progression occurred before death. For patients with bidimensionally measurable disease (measurable disease), progression is defined as > 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients without bidimensionally measurable disease (evaluable disease), progression is defined as unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.
Time Frame From study registration to date of progression (up to 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients that started treatment.
Arm/Group Title Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Hide Arm/Group Description:

Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

bortezomib : Given IV

vorinostat : Given orally

Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.

surgery : Patient undergoes therapeutic conventional surgery bortezomib : Given IV vorinostat : Given orally

Overall Number of Participants Analyzed 37 7
Median (Full Range)
Unit of Measure: months
1.5
(0.5 to 5.6)
4.2
(0.6 to 9.3)
4.Secondary Outcome
Title Proportion of Confirmed Tumor Response Defined as an Objective Status of Confirmed Response (CR), Partial Response (PR), or Regression (REGR) on Two Consecutive Evaluations
Hide Description

Confidence intervals for the true proportion will be calculated using the exact binomial method.

Measurable patients must achieve at least a 50% reduction in the product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose.

Evaluable patients must achieve unequivocal reduction in size of contrast-enhancement or decrease in mass effect as agreed upon independently by primary physician and quality control physicians; no new lesions. Patient should be on stable or decreased steroid dose.

Time Frame Assessed up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Arm A patients that started treatment. Arm B patients were not analyzed for this outcome because they received surgery and hence response was not measured.
Arm/Group Title Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Hide Arm/Group Description:

Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

bortezomib : Given IV

vorinostat : Given orally

Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.

surgery : Patient undergoes therapeutic conventional surgery bortezomib : Given IV vorinostat : Given orally

Overall Number of Participants Analyzed 37 0
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of patients
0.027
(0.0007 to 0.14)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Hide Arm/Group Description vorinostat : Given orally vorinostat : Given orally
All-Cause Mortality
Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   18/37 (48.65%)      0/7 (0.00%)    
Gastrointestinal disorders     
Diarrhea  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Infections and infestations     
Opportunistic infection  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Sepsis  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Sinusitis  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Skin infection  1  1/37 (2.70%)  2 0/7 (0.00%)  0
Urinary tract infection  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Investigations     
Lymphocyte count decreased  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Platelet count decreased  1  12/37 (32.43%)  13 0/7 (0.00%)  0
Metabolism and nutrition disorders     
Blood glucose increased  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Dehydration  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Serum sodium decreased  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscle weakness lower limb  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Nervous system disorders     
Ataxia  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Depressed level of consciousness  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Facial nerve disorder  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Intracranial hemorrhage  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Memory impairment  1  1/37 (2.70%)  2 0/7 (0.00%)  0
Neurological disorder NOS  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Peripheral motor neuropathy  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Peripheral sensory neuropathy  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Seizure  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Speech disorder  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Psychiatric disorders     
Confusion  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Personality change  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Aspiration  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Vascular disorders     
Hypotension  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm A (Not Undergoing Surgery) Arm B (Undergoing Surgery)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   36/37 (97.30%)      7/7 (100.00%)    
Blood and lymphatic system disorders     
Hemoglobin decreased  1  23/37 (62.16%)  45 5/7 (71.43%)  6
Cardiac disorders     
Sinus bradycardia  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Eye disorders     
Dry eye syndrome  1  0/37 (0.00%)  0 1/7 (14.29%)  3
Vision blurred  1  2/37 (5.41%)  4 0/7 (0.00%)  0
Watering eyes  1  2/37 (5.41%)  5 0/7 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Constipation  1  10/37 (27.03%)  16 1/7 (14.29%)  1
Diarrhea  1  9/37 (24.32%)  13 3/7 (42.86%)  6
Dry mouth  1  2/37 (5.41%)  3 0/7 (0.00%)  0
Dyspepsia  1  1/37 (2.70%)  1 2/7 (28.57%)  3
Dysphagia  1  0/37 (0.00%)  0 1/7 (14.29%)  1
Ear, nose and throat examination abnormal  1  4/37 (10.81%)  5 0/7 (0.00%)  0
Mucositis oral  1  2/37 (5.41%)  3 0/7 (0.00%)  0
Nausea  1  14/37 (37.84%)  24 4/7 (57.14%)  6
Vomiting  1  8/37 (21.62%)  9 1/7 (14.29%)  1
General disorders     
Edema limbs  1  4/37 (10.81%)  7 0/7 (0.00%)  0
Fatigue  1  31/37 (83.78%)  70 5/7 (71.43%)  15
Pain  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Infections and infestations     
Catheter related infection  1  0/37 (0.00%)  0 1/7 (14.29%)  2
Investigations     
Alanine aminotransferase increased  1  3/37 (8.11%)  8 0/7 (0.00%)  0
Creatinine increased  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Leukocyte count decreased  1  11/37 (29.73%)  16 1/7 (14.29%)  2
Lymphocyte count decreased  1  5/37 (13.51%)  6 2/7 (28.57%)  3
Neutrophil count decreased  1  7/37 (18.92%)  7 1/7 (14.29%)  1
Platelet count decreased  1  31/37 (83.78%)  55 5/7 (71.43%)  11
Weight gain  1  0/37 (0.00%)  0 1/7 (14.29%)  1
Weight loss  1  3/37 (8.11%)  3 0/7 (0.00%)  0
Metabolism and nutrition disorders     
Anorexia  1  8/37 (21.62%)  12 2/7 (28.57%)  3
Blood glucose increased  1  4/37 (10.81%)  10 0/7 (0.00%)  0
Dehydration  1  7/37 (18.92%)  8 0/7 (0.00%)  0
Serum calcium decreased  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Serum calcium increased  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Serum glucose decreased  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Serum potassium decreased  1  1/37 (2.70%)  2 0/7 (0.00%)  0
Serum potassium increased  1  2/37 (5.41%)  4 0/7 (0.00%)  0
Serum sodium decreased  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Serum sodium increased  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Muscle weakness  1  3/37 (8.11%)  3 0/7 (0.00%)  0
Muscle weakness left-sided  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Muscle weakness lower limb  1  3/37 (8.11%)  7 0/7 (0.00%)  0
Myalgia  1  0/37 (0.00%)  0 2/7 (28.57%)  4
Nervous system disorders     
Acoustic nerve disorder NOS  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Ataxia  1  3/37 (8.11%)  3 0/7 (0.00%)  0
Cognitive disturbance  1  1/37 (2.70%)  2 0/7 (0.00%)  0
Depressed level of consciousness  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Dizziness  1  4/37 (10.81%)  4 0/7 (0.00%)  0
Facial nerve disorder  1  1/37 (2.70%)  2 0/7 (0.00%)  0
Headache  1  5/37 (13.51%)  6 0/7 (0.00%)  0
Hydrocephalus  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Memory impairment  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Mini mental status examination abnormal  1  2/37 (5.41%)  3 0/7 (0.00%)  0
Peripheral motor neuropathy  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Peripheral sensory neuropathy  1  7/37 (18.92%)  11 0/7 (0.00%)  0
Seizure  1  2/37 (5.41%)  2 1/7 (14.29%)  1
Speech disorder  1  2/37 (5.41%)  3 0/7 (0.00%)  0
Taste alteration  1  5/37 (13.51%)  15 1/7 (14.29%)  1
Psychiatric disorders     
Confusion  1  2/37 (5.41%)  5 0/7 (0.00%)  0
Depression  1  1/37 (2.70%)  2 0/7 (0.00%)  0
Insomnia  1  3/37 (8.11%)  4 0/7 (0.00%)  0
Libido decreased  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Renal and urinary disorders     
Urinary incontinence  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Cough  1  3/37 (8.11%)  3 0/7 (0.00%)  0
Dyspnea  1  3/37 (8.11%)  6 0/7 (0.00%)  0
Hemorrhage nasal  1  2/37 (5.41%)  2 0/7 (0.00%)  0
Hiccough  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Skin and subcutaneous tissue disorders     
Alopecia  1  5/37 (13.51%)  9 0/7 (0.00%)  0
Erythema multiforme  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Nail disorder  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Rash acneiform  1  3/37 (8.11%)  5 0/7 (0.00%)  0
Rash desquamating  1  2/37 (5.41%)  5 0/7 (0.00%)  0
Vascular disorders     
Hypertension  1  4/37 (10.81%)  4 0/7 (0.00%)  0
Hypotension  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Thrombosis  1  1/37 (2.70%)  1 0/7 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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
Name/Title: Evanthia Galanis, M.D.
Organization: Mayo Clinic
Phone: (507) 284-3902
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00641706     History of Changes
Other Study ID Numbers: NCI-2009-00668
NCI-2009-00668 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000590113
NCCTG-N0779
N0779 ( Other Identifier: North Central Cancer Treatment Group )
N0779 ( Other Identifier: CTEP )
U10CA025224 ( U.S. NIH Grant/Contract )
First Submitted: March 21, 2008
First Posted: March 24, 2008
Results First Submitted: March 6, 2013
Results First Posted: July 10, 2013
Last Update Posted: May 14, 2014