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Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00611325
Recruitment Status : Completed
First Posted : February 8, 2008
Results First Posted : February 4, 2014
Last Update Posted : March 12, 2014
Sponsor:
Collaborators:
Millennium Pharmaceuticals, Inc.
Genentech, Inc.
Information provided by (Responsible Party):
Duke University

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Glioblastoma
Gliosarcoma
Interventions Drug: Avastin
Drug: Bortezomib
Enrollment 56
Recruitment Details  
Pre-assignment Details  
Arm/Group Title EIAED Non-EIAED
Hide Arm/Group Description Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle. Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Period Title: Overall Study
Started 28 28
Completed 28 28
Not Completed 0 0
Arm/Group Title EIAED Non-EIAED Total
Hide Arm/Group Description Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle. Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle. Total of all reporting groups
Overall Number of Baseline Participants 28 28 56
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 28 participants 28 participants 56 participants
52.73  (12.57) 55.03  (11.36) 53.88  (11.93)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants 28 participants 56 participants
Female
8
  28.6%
12
  42.9%
20
  35.7%
Male
20
  71.4%
16
  57.1%
36
  64.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 28 participants 28 participants 56 participants
28 28 56
1.Primary Outcome
Title 6-month Progression-free Survival (PFS)
Hide Description Percentage of participants surviving six months from the initiation of treatment without progression of disease. PFS was defined as the time from the initiation of treatment to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title EIAED Non-EIAED
Hide Arm/Group Description:
Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Overall Number of Participants Analyzed 28 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25
(9.0 to 41.0)
28.6
(11.9 to 45.3)
2.Secondary Outcome
Title Median Progression Free Survival (PFS)
Hide Description Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion, or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time Frame Time in months from the start of study treatment to the date of first progression or death. Assessed up to 60 months.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title EIAED Non-EIAED
Hide Arm/Group Description:
Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Overall Number of Participants Analyzed 28 28
Median (95% Confidence Interval)
Unit of Measure: months
2
(2 to 4)
2.5
(1 to 4)
3.Secondary Outcome
Title Median Overall Survival (OS)
Hide Description Time in months from the start of study treatment to the date of death. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time Frame Time in months from the start of study treatment to date of death due to any cause. Assessed up to 60 months.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title EIAED Non-EIAED
Hide Arm/Group Description:
Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Overall Number of Participants Analyzed 28 28
Median (95% Confidence Interval)
Unit of Measure: months
8
(5 to 11)
6
(4 to 10)
4.Secondary Outcome
Title Radiographic Response Rate
Hide Description The percentage of participants with a complete or partial response at any assessment as determined by the Macdonald criteria. A confirmation of response was not required. Per Macdonald criteria, complete response (CR) was the disappearance of all target lesions and partial response (PR) was a ≥50% decrease in the sum of the longest diameter of target lesions, no new lesions and stable or decreasing steroid dose. Objective response =CR+PR. Tumor assessments were done at baseline and at the end of each 6 week treatment cycle, and overall best response was recorded.
Time Frame 60 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title EIAED Non-EIAED
Hide Arm/Group Description:
Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Overall Number of Participants Analyzed 28 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
7.1
(0 to 16.6)
39.3
(21.2 to 57.4)
5.Secondary Outcome
Title Number of Patients With Grade 3 or Greater, Treatment-related, Non-hematologic Toxicities
Hide Description Number of patients with grade 3 or greater, treatment-related, non-hematologic toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Time Frame 60 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title EIAED Non-EIAED
Hide Arm/Group Description:
Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Overall Number of Participants Analyzed 28 28
Measure Type: Number
Unit of Measure: participants
27 24
Time Frame 60 months
Adverse Event Reporting Description The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.
 
Arm/Group Title EIAED Non-EIAED
Hide Arm/Group Description

Avastin: Avastin was administered intravenously at the dose 15 mg/kg every 3 weeks.

Bortezomib: Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, & 32 of a 42-day cycle. Bortezomib was 2.5 mg/m2 for patients taking EIAEDs.

Avastin: Avastin was administered intravenously at the dose 15 mg/kg every 3 weeks.

Bortezomib: Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, & 32 of a 42-day cycle. Bortezomib was 1.7 mg/m2 for patients not taking EIAEDs.

All-Cause Mortality
EIAED Non-EIAED
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
EIAED Non-EIAED
Affected / at Risk (%) Affected / at Risk (%)
Total   11/28 (39.29%)   5/28 (17.86%) 
Blood and lymphatic system disorders     
Anemia  1  1/28 (3.57%)  0/28 (0.00%) 
Gastrointestinal disorders     
Abdominal pain  1  4/28 (14.29%)  1/28 (3.57%) 
Colitis  1  1/28 (3.57%)  0/28 (0.00%) 
Diarrhea  1  2/28 (7.14%)  0/28 (0.00%) 
Nausea  1  2/28 (7.14%)  1/28 (3.57%) 
Vomiting  1  2/28 (7.14%)  1/28 (3.57%) 
General disorders     
Fatigue  1  1/28 (3.57%)  0/28 (0.00%) 
Fever  1  2/28 (7.14%)  0/28 (0.00%) 
Infections and infestations     
Enterocolitis infectious  1  0/28 (0.00%)  1/28 (3.57%) 
Lung infection  1  1/28 (3.57%)  0/28 (0.00%) 
Urinary tract infection  1  1/28 (3.57%)  2/28 (7.14%) 
Injury, poisoning and procedural complications     
Fracture  1  2/28 (7.14%)  0/28 (0.00%) 
Investigations     
Platelet count decreased  1  2/28 (7.14%)  1/28 (3.57%) 
Metabolism and nutrition disorders     
Dehydration  1  1/28 (3.57%)  0/28 (0.00%) 
Hypokalemia  1  1/28 (3.57%)  0/28 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  0/28 (0.00%)  1/28 (3.57%) 
Generalized muscle weakness  1  1/28 (3.57%)  2/28 (7.14%) 
Musculoskeletal and connective tissue disorder - Other, specify  1  0/28 (0.00%)  1/28 (3.57%) 
Myositis  1  1/28 (3.57%)  0/28 (0.00%) 
Neck pain  1  0/28 (0.00%)  1/28 (3.57%) 
Nervous system disorders     
Ataxia  1  3/28 (10.71%)  2/28 (7.14%) 
Cognitive disturbance  1  1/28 (3.57%)  1/28 (3.57%) 
Hydrocephalus  1  1/28 (3.57%)  0/28 (0.00%) 
Memory impairment  1  0/28 (0.00%)  1/28 (3.57%) 
Seizure  1  2/28 (7.14%)  0/28 (0.00%) 
Syncope  1  0/28 (0.00%)  1/28 (3.57%) 
Psychiatric disorders     
Confusion  1  1/28 (3.57%)  2/28 (7.14%) 
Respiratory, thoracic and mediastinal disorders     
Epistaxis  1  1/28 (3.57%)  0/28 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, specify  1  0/28 (0.00%)  1/28 (3.57%) 
Vascular disorders     
Hypertension  1  1/28 (3.57%)  0/28 (0.00%) 
Hypotension  1  1/28 (3.57%)  1/28 (3.57%) 
Thromboembolic event  1  2/28 (7.14%)  0/28 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
EIAED Non-EIAED
Affected / at Risk (%) Affected / at Risk (%)
Total   28/28 (100.00%)   28/28 (100.00%) 
Blood and lymphatic system disorders     
Anemia  1  2/28 (7.14%)  2/28 (7.14%) 
Eye disorders     
Blurred vision  1  1/28 (3.57%)  3/28 (10.71%) 
Extraocular muscle paresis  1  2/28 (7.14%)  0/28 (0.00%) 
Eye disorders - Other, specify  1  0/28 (0.00%)  3/28 (10.71%) 
Eye pain  1  1/28 (3.57%)  0/28 (0.00%) 
Gastrointestinal disorders     
Abdominal distension  1  1/28 (3.57%)  2/28 (7.14%) 
Abdominal pain  1  13/28 (46.43%)  6/28 (21.43%) 
Constipation  1  3/28 (10.71%)  8/28 (28.57%) 
Diarrhea  1  13/28 (46.43%)  11/28 (39.29%) 
Fecal incontinence  1  1/28 (3.57%)  1/28 (3.57%) 
Gastrointestinal disorders - Other, specify  1  3/28 (10.71%)  4/28 (14.29%) 
Hemorrhoids  1  0/28 (0.00%)  1/28 (3.57%) 
Lower gastrointestinal hemorrhage  1  1/28 (3.57%)  0/28 (0.00%) 
Mucositis oral  1  5/28 (17.86%)  6/28 (21.43%) 
Nausea  1  12/28 (42.86%)  7/28 (25.00%) 
Pancreatitis  1  1/28 (3.57%)  0/28 (0.00%) 
Stomach pain  1  1/28 (3.57%)  0/28 (0.00%) 
Toothache  1  1/28 (3.57%)  0/28 (0.00%) 
Vomiting  1  9/28 (32.14%)  5/28 (17.86%) 
General disorders     
Edema limbs  1  2/28 (7.14%)  6/28 (21.43%) 
Fatigue  1  18/28 (64.29%)  21/28 (75.00%) 
Fever  1  2/28 (7.14%)  2/28 (7.14%) 
Gait disturbance  1  3/28 (10.71%)  5/28 (17.86%) 
Non-cardiac chest pain  1  0/28 (0.00%)  1/28 (3.57%) 
Pain  1  1/28 (3.57%)  2/28 (7.14%) 
Infections and infestations     
Device related infection  1  1/28 (3.57%)  0/28 (0.00%) 
Eye infection  1  0/28 (0.00%)  1/28 (3.57%) 
Infections and infestations - Other, specify  1  2/28 (7.14%)  6/28 (21.43%) 
Kidney infection  1  1/28 (3.57%)  0/28 (0.00%) 
Sinusitis  1  1/28 (3.57%)  2/28 (7.14%) 
Skin infection  1  1/28 (3.57%)  0/28 (0.00%) 
Tooth infection  1  0/28 (0.00%)  1/28 (3.57%) 
Upper respiratory infection  1  1/28 (3.57%)  1/28 (3.57%) 
Urinary tract infection  1  2/28 (7.14%)  5/28 (17.86%) 
Investigations     
Alanine aminotransferase increased  1  0/28 (0.00%)  3/28 (10.71%) 
Alkaline phosphatase increased  1  1/28 (3.57%)  0/28 (0.00%) 
Aspartate aminotransferase increased  1  1/28 (3.57%)  1/28 (3.57%) 
Lipase increased  1  1/28 (3.57%)  0/28 (0.00%) 
Neutrophil count decreased  1  5/28 (17.86%)  6/28 (21.43%) 
Platelet count decreased  1  11/28 (39.29%)  14/28 (50.00%) 
Weight loss  1  1/28 (3.57%)  1/28 (3.57%) 
White blood cell decreased  1  3/28 (10.71%)  8/28 (28.57%) 
Metabolism and nutrition disorders     
Anorexia  1  1/28 (3.57%)  10/28 (35.71%) 
Dehydration  1  4/28 (14.29%)  5/28 (17.86%) 
Hyperglycemia  1  4/28 (14.29%)  3/28 (10.71%) 
Hypoalbuminemia  1  0/28 (0.00%)  1/28 (3.57%) 
Hypocalcemia  1  0/28 (0.00%)  1/28 (3.57%) 
Hyponatremia  1  3/28 (10.71%)  2/28 (7.14%) 
Hypophosphatemia  1  0/28 (0.00%)  1/28 (3.57%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/28 (3.57%)  3/28 (10.71%) 
Arthritis  1  0/28 (0.00%)  1/28 (3.57%) 
Avascular necrosis  1  0/28 (0.00%)  1/28 (3.57%) 
Back pain  1  0/28 (0.00%)  3/28 (10.71%) 
Bone pain  1  0/28 (0.00%)  1/28 (3.57%) 
Generalized muscle weakness  1  10/28 (35.71%)  13/28 (46.43%) 
Muscle weakness left-sided  1  0/28 (0.00%)  4/28 (14.29%) 
Muscle weakness lower limb  1  2/28 (7.14%)  3/28 (10.71%) 
Muscle weakness right-sided  1  1/28 (3.57%)  0/28 (0.00%) 
Musculoskeletal and connective tissue disorder - Other, specify  1  1/28 (3.57%)  0/28 (0.00%) 
Neck pain  1  0/28 (0.00%)  1/28 (3.57%) 
Pain in extremity  1  0/28 (0.00%)  4/28 (14.29%) 
Nervous system disorders     
Ataxia  1  13/28 (46.43%)  9/28 (32.14%) 
Cognitive disturbance  1  4/28 (14.29%)  6/28 (21.43%) 
Depressed level of consciousness  1  4/28 (14.29%)  7/28 (25.00%) 
Dizziness  1  3/28 (10.71%)  2/28 (7.14%) 
Dysphasia  1  4/28 (14.29%)  4/28 (14.29%) 
Headache  1  7/28 (25.00%)  9/28 (32.14%) 
Memory impairment  1  1/28 (3.57%)  5/28 (17.86%) 
Nervous system disorders - Other, specify  1  1/28 (3.57%)  0/28 (0.00%) 
Peripheral motor neuropathy  1  1/28 (3.57%)  4/28 (14.29%) 
Peripheral sensory neuropathy  1  18/28 (64.29%)  15/28 (53.57%) 
Seizure  1  7/28 (25.00%)  11/28 (39.29%) 
Syncope  1  0/28 (0.00%)  2/28 (7.14%) 
Tremor  1  1/28 (3.57%)  2/28 (7.14%) 
Trigeminal nerve disorder  1  0/28 (0.00%)  1/28 (3.57%) 
Psychiatric disorders     
Agitation  1  1/28 (3.57%)  3/28 (10.71%) 
Anxiety  1  0/28 (0.00%)  4/28 (14.29%) 
Confusion  1  4/28 (14.29%)  5/28 (17.86%) 
Depression  1  2/28 (7.14%)  5/28 (17.86%) 
Insomnia  1  1/28 (3.57%)  5/28 (17.86%) 
Personality change  1  0/28 (0.00%)  1/28 (3.57%) 
Renal and urinary disorders     
Proteinuria  1  3/28 (10.71%)  4/28 (14.29%) 
Urinary incontinence  1  1/28 (3.57%)  1/28 (3.57%) 
Reproductive system and breast disorders     
Erectile dysfunction  1  0/28 (0.00%)  1/28 (3.57%) 
Reproductive system and breast disorders - Other, specify  1  0/28 (0.00%)  3/28 (10.71%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  1/28 (3.57%)  1/28 (3.57%) 
Dyspnea  1  6/28 (21.43%)  3/28 (10.71%) 
Epistaxis  1  1/28 (3.57%)  1/28 (3.57%) 
Laryngeal edema  1  0/28 (0.00%)  1/28 (3.57%) 
Skin and subcutaneous tissue disorders     
Dry skin  1  0/28 (0.00%)  1/28 (3.57%) 
Rash maculo-papular  1  3/28 (10.71%)  6/28 (21.43%) 
Vascular disorders     
Hypertension  1  5/28 (17.86%)  6/28 (21.43%) 
Hypotension  1  3/28 (10.71%)  2/28 (7.14%) 
Thromboembolic event  1  4/28 (14.29%)  2/28 (7.14%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Katherine B. Peters
Organization: Duke University Medical Center
Phone: (919) 684-6173
EMail: katherine.peters@duke.edu
Layout table for additonal information
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00611325    
Other Study ID Numbers: Pro00003596
First Submitted: January 28, 2008
First Posted: February 8, 2008
Results First Submitted: December 18, 2013
Results First Posted: February 4, 2014
Last Update Posted: March 12, 2014