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Phase (Ph) II Bevacizumab + Erlotinib for Patients (Pts) With Recurrent Malignant Glioma (MG)

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: NCT00671970
Recruitment Status : Completed
First Posted : May 6, 2008
Results First Posted : May 13, 2013
Last Update Posted : May 13, 2013
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Duke University

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Glioblastoma
Gliosarcoma
Intervention Drug: Bevacizumab and Erlotinib
Enrollment 57
Recruitment Details Open for recruitment from February 2007 to May 2008. Subjects recruited in the Preston Robert Tisch Brian Tumor Center at Duke University Medical Center (DUMC).
Pre-assignment Details  
Arm/Group Title WHO Grade III WHO Grade IV
Hide Arm/Group Description

WHO Grade III Malignant Glioma

Bevacizumab administered intravenously at dose 10 mg/kg every 2 wks. Erlotinib administered orally, continuously once daily in fasting state for each 42-day cycle. It will be 200 mg/day for pts not on cytochrome P450 3A4 (CYP3A4)-enzyme inducing anti-epileptic drugs & 500 mg/day for pts on EIAEDs.

WHO Grade IV Malignant Glioma

Bevacizumab administered intravenously at dose 10 mg/kg every 2 wks. Erlotinib administered orally, continuously once daily in fasting state for each 42-day cycle. It will be 200 mg/day for pts not on cytochrome P450 3A4 (CYP3A4)-enzyme inducing anti-epileptic drugs & 500 mg/day for pts on EIAEDs.

Period Title: Overall Study
Started 32 25
Completed 32 25
Not Completed 0 0
Arm/Group Title Who Grade III WHO Grade IV Total
Hide Arm/Group Description Who Grade III Malignant Glioma WHO Grade IV Malignant Glioma Total of all reporting groups
Overall Number of Baseline Participants 32 25 57
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Median (Standard Deviation)
Unit of measure:  Years
Number Analyzed 32 participants 25 participants 57 participants
48.8  (12.8) 51.5  (13.4) 49.98  (13.05)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants 25 participants 57 participants
Female
8
  25.0%
12
  48.0%
20
  35.1%
Male
24
  75.0%
13
  52.0%
37
  64.9%
1.Primary Outcome
Title 6 Month Progression-free Survival
Hide Description The proportion of patients alive and progression free at 6 months
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Who Grade III WHO Grade IV
Hide Arm/Group Description:
Who Grade III Malignant Glioma
WHO Grade IV Malignant Glioma
Overall Number of Participants Analyzed 32 25
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
.438
(.265 to .598)
.292
(.130 to .476)
2.Secondary Outcome
Title Radiographic Response
Hide Description

The number of participants with complete or partial response as determined by the following criteria:

  • Complete response (CR): Disappearance of all enhancing tumor on contrast enhanced MRI scan. Patient must be off steroids or only on adrenal maintenance doses.
  • Partial response (PR): Greater than or equal to a 50% reduction in the size (products of the largest perpendicular diameters) for all enhancing lesions. No new lesions may arise. Steroids must be stable or decreasing dose.
Time Frame Patients were followed for the duration of the study, with a median follow-up of 103 weeks for grade III participants and 141.8 weeks for grade IV participants
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Who Grade III WHO Grade IV
Hide Arm/Group Description:
Who Grade III Malignant Glioma
WHO Grade IV Malignant Glioma
Overall Number of Participants Analyzed 32 25
Measure Type: Number
Unit of Measure: participants
Complete 1 1
Partial 9 11
3.Secondary Outcome
Title Pharmacokinetics of Erlotinib: Cmax
Hide Description Day 1 and Day 42 of Dosing Erlotinib in Cycle 1: Maximum Concentration (ng/mL) (Cmax) for subjects receiving 500 mg (Enzyme-Inducing Anti-epileptic Drug, EIAED) or 200 mg (non-EIAED) Erlotinib
Time Frame Day 1 and 42 of Dosing Erlotinib
Hide Outcome Measure Data
Hide Analysis Population Description
22 WHO Grade IV participants were available for pharmacokinetics studies of erlotinib
Arm/Group Title WHO Grade IV
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WHO Grade IV Malignant Glioma
Overall Number of Participants Analyzed 22
Median (Full Range)
Unit of Measure: ng/ml
Day1 Cmax{ng/ml}200mg n=12
794
(524 to 2200)
Day1 Cmax{ng/ml}500mg n=10
1323
(317 to 2990)
Day42 Cmax{ng/ml}200mg n=9
1320
(525 to 2940)
Day42 Cmax{ng/ml}500mg n=9
1400
(716 to 3955)
4.Secondary Outcome
Title Pharmacokinetics of Erlotinib: AUC
Hide Description Day 1 and Day 42 of Dosing Erlotinib in Cycle 1: Area under the Curve (ng/mL.h) (AUC) for subjects receiving 500 mg (Enzyme-Inducing Anti-epileptic Drug, EIAED) or 200 mg (non-EIAED) Erlotinib
Time Frame Day 1 and 42 of Dosing Erlotinib
Hide Outcome Measure Data
Hide Analysis Population Description
22 WHO Grade IV participants were available for pharmacokinetics studies of erlotinib
Arm/Group Title WHO Grade IV
Hide Arm/Group Description:
WHO Grade IV Malignant Glioma
Overall Number of Participants Analyzed 22
Median (Full Range)
Unit of Measure: ng/ml.h
Day1 AUC 0-24{ng/ml.h} 200mg n=12
11072
(7850 to 30029)
Day1 AUC 0-24{ng/ml.h} 500mg n=10
15611
(5295 to 40110)
Day42 AUC 0-24{ng/ml.h}200mg n=9
26072
(8308 to 42878)
Day42 AUC 0-24{ng/ml.h}500mg n=9
21421
(11680 to 55960)
5.Secondary Outcome
Title Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR)
Hide Description Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. One tumor had an insufficient measurement for analysis
Arm/Group Title Positive Expression Negative Expression
Hide Arm/Group Description:
EGFR positive expression
EGFR negative expression
Overall Number of Participants Analyzed 20 1
Measure Type: Number
Unit of Measure: participants
7 0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Positive Expression, Negative Expression
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
6.Secondary Outcome
Title Association of Biomarkers and One-year Survival - EGFR vIII
Hide Description Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit.
Arm/Group Title Positive Expression Negative Expression
Hide Arm/Group Description:
EGFR vIII positive expression
EGFR vIII negative expression
Overall Number of Participants Analyzed 5 17
Measure Type: Number
Unit of Measure: participants
1 7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Positive Expression, Negative Expression
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .613
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
7.Secondary Outcome
Title Association of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN)
Hide Description Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. One tumor had an insufficient measurement for analysis.
Arm/Group Title Intact Loss
Hide Arm/Group Description:
PTEN Intact
PTEN Loss
Overall Number of Participants Analyzed 2 19
Measure Type: Number
Unit of Measure: participants
1 7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Intact, Loss
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
8.Secondary Outcome
Title Association of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT)
Hide Description Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. Four tumors had an insufficient measurement for analysis.
Arm/Group Title Positive Expression Negative Expression
Hide Arm/Group Description:
pAKT positive expression
pAKT negative expression
Overall Number of Participants Analyzed 16 2
Measure Type: Number
Unit of Measure: participants
6 1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Positive Expression, Negative Expression
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
9.Secondary Outcome
Title Association of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK)
Hide Description Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. Six tumors had an insufficient measurement for analysis.
Arm/Group Title Positive Expression Negative Expression
Hide Arm/Group Description:
pMAPK positive expression
pMAPK negative expression
Overall Number of Participants Analyzed 12 4
Measure Type: Number
Unit of Measure: participants
5 1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Positive Expression, Negative Expression
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
10.Secondary Outcome
Title Association of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF)
Hide Description Archival tumor samples from grade IV participants were examined by immunohistochemistry (IHC) for biomarkers. The IHC expression score is the product of the percentage of cancer cells positive for VEGF multiplied by the overall intensity of staining, ranging from 0 to 3+. This produces a score ranging from 0 to 300.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Patients Who Survived At Least 1 Year Patients Who Survived Less Than 1 Year
Hide Arm/Group Description:
Patients who survived at least 1 year
Patients who survived less than 1 year
Overall Number of Participants Analyzed 8 14
Median (Full Range)
Unit of Measure: IHC Expression Score
40
(4 to 120)
60
(20 to 160)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patients Who Survived At Least 1 Year, Patients Who Survived Less Than 1 Year
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .179
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
11.Secondary Outcome
Title Association of Biomarkers and One-year Survival - VEGFR-2
Hide Description Archival tumor samples from grade IV participants were examined by immunohistochemistry (IHC) for biomarkers. The IHC score is the product of the percentage of cancer cells positive for VEGFR-2 multiplied by the overall intensity of staining, ranging from 0 to 3+. This produces a score ranging from 0 to 300.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Patients Who Survived At Least 1 Year Patients Who Survived Less Than 1 Year
Hide Arm/Group Description:
Patients who survived at least 1 year
Patients who survived less than 1 year
Overall Number of Participants Analyzed 8 14
Median (Full Range)
Unit of Measure: IHC Expression Score
50
(20 to 100)
120
(40 to 160)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patients Who Survived At Least 1 Year, Patients Who Survived Less Than 1 Year
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .008
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Time Frame The length of time that the subjects were receiving treatment and then 30 days after treatment termination.
Adverse Event Reporting Description Adverse events were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, but were converted to CTCAE version 4.0 for entry into ClinicalTrials.gov
 
Arm/Group Title All Patients
Hide Arm/Group Description All Patients
All-Cause Mortality
All Patients
Affected / at Risk (%)
Total   --/-- 
Hide Serious Adverse Events
All Patients
Affected / at Risk (%)
Total   20/57 (35.09%) 
Gastrointestinal disorders   
Colonic ulcer  1  1/57 (1.75%) 
Diarrhea  1  1/57 (1.75%) 
Duodenal hemorrhage  1  1/57 (1.75%) 
Duodenal ulcer  1  1/57 (1.75%) 
Gastric ulcer  1  1/57 (1.75%) 
Nausea  1  2/57 (3.51%) 
Vomiting  1  2/57 (3.51%) 
General disorders   
Death NOS  1  2/57 (3.51%) 
Edema limbs  1  1/57 (1.75%) 
Gait disturbance  1  1/57 (1.75%) 
Infections and infestations   
Device related infection  1  2/57 (3.51%) 
Lung infection  1  1/57 (1.75%) 
Meningitis  1  1/57 (1.75%) 
Skin infection  1  1/57 (1.75%) 
Injury, poisoning and procedural complications   
Wound dihiscence  1  1/57 (1.75%) 
Metabolism and nutrition disorders   
Dehydration  1  1/57 (1.75%) 
Hyponatremia  1  1/57 (1.75%) 
Musculoskeletal and connective tissue disorders   
Avascular necrosis  1  1/57 (1.75%) 
Nervous system disorders   
Cognitive disturbance  1  2/57 (3.51%) 
Headache  1  3/57 (5.26%) 
Intracranial hemorrhage  1  2/57 (3.51%) 
Ischemia cerebrovascular  1  1/57 (1.75%) 
Nervous system disorders-Other, specify: Visual Hallucinations  1  1/57 (1.75%) 
Pyramidal tract syndrome  1  2/57 (3.51%) 
Seizure  1  5/57 (8.77%) 
Tremor  1  1/57 (1.75%) 
Psychiatric disorders   
Confusion  1  1/57 (1.75%) 
Insomnia  1  1/57 (1.75%) 
Personality change  1  1/57 (1.75%) 
Psychosis  1  1/57 (1.75%) 
Renal and urinary disorders   
Urinary tract obstruction  1  1/57 (1.75%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnea  1  1/57 (1.75%) 
Epistaxis  1  1/57 (1.75%) 
Skin and subcutaneous tissue disorders   
Alopecia  1  1/57 (1.75%) 
Rash maculo-papular  1  2/57 (3.51%) 
Vascular disorders   
Thromboembolic event  1  3/57 (5.26%) 
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 5%
All Patients
Affected / at Risk (%)
Total   52/57 (91.23%) 
Blood and lymphatic system disorders   
Anemia  1  10/57 (17.54%) 
Eye disorders   
Blurred vision  1  14/57 (24.56%) 
Gastrointestinal disorders   
Constipation  1  13/57 (22.81%) 
Diarrhea  1  28/57 (49.12%) 
Mucositis oral  1  15/57 (26.32%) 
Nausea  1  14/57 (24.56%) 
Vomiting  1  5/57 (8.77%) 
General disorders   
Edema limbs  1  4/57 (7.02%) 
Fatigue  1  40/57 (70.18%) 
Fever  1  3/57 (5.26%) 
Infections and infestations   
Skin infection  1  7/57 (12.28%) 
Urinary tract infection  1  5/57 (8.77%) 
Investigations   
Alanine aminotransferase increased  1  10/57 (17.54%) 
Alkaline phosphatase increased  1  10/57 (17.54%) 
Aspartate aminotransferase increased  1  8/57 (14.04%) 
Blood bilirubin increased  1  6/57 (10.53%) 
Investigations-Other, specify: Total protein, low  1  15/57 (26.32%) 
Platelet count decreased  1  6/57 (10.53%) 
Weight loss  1  4/57 (7.02%) 
White blood cell decreased  1  7/57 (12.28%) 
Metabolism and nutrition disorders   
Anorexia  1  11/57 (19.30%) 
Hyperglycemia  1  23/57 (40.35%) 
Hypoalbuminemia  1  16/57 (28.07%) 
Hypocalcemia  1  10/57 (17.54%) 
Hypoglycemia  1  4/57 (7.02%) 
Hypokalemia  1  13/57 (22.81%) 
Hypomagnesemia  1  3/57 (5.26%) 
Hyponatremia  1  11/57 (19.30%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  3/57 (5.26%) 
Pain in extremity  1  3/57 (5.26%) 
Nervous system disorders   
Ataxia  1  17/57 (29.82%) 
Cognitive disturbance  1  20/57 (35.09%) 
Dizziness  1  17/57 (29.82%) 
Dysphasia  1  13/57 (22.81%) 
Headache  1  20/57 (35.09%) 
Memory impairment  1  25/57 (43.86%) 
Nervous system disorders-Other, specify: Mood Alteration, NOS  1  8/57 (14.04%) 
Peripheral motor neuropathy  1  26/57 (45.61%) 
Peripheral sensory neuropathy  1  15/57 (26.32%) 
Pyramidal tract syndrome  1  4/57 (7.02%) 
Seizure  1  13/57 (22.81%) 
Tremor  1  14/57 (24.56%) 
Psychiatric disorders   
Agitation  1  8/57 (14.04%) 
Anxiety  1  14/57 (24.56%) 
Confusion  1  20/57 (35.09%) 
Depression  1  9/57 (15.79%) 
Insomnia  1  24/57 (42.11%) 
Libido decreased  1  3/57 (5.26%) 
Renal and urinary disorders   
Urinary incontinence  1  5/57 (8.77%) 
Reproductive system and breast disorders   
Reproductive system and breast disorders-Other, specify: Sexual Dysfunction  1  11/57 (19.30%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnea  1  15/57 (26.32%) 
Epistaxis  1  5/57 (8.77%) 
Skin and subcutaneous tissue disorders   
Rash maculo-papular  1  44/57 (77.19%) 
Vascular disorders   
Hypertension  1  8/57 (14.04%) 
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. David Reardon
Organization: Dana Farber Cancer Institute
Phone: (617) 632-2166
EMail: David_Reardon@DFCI.HARVARD.EDU
Layout table for additonal information
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00671970    
Other Study ID Numbers: Pro00000220
First Submitted: January 29, 2008
First Posted: May 6, 2008
Results First Submitted: December 28, 2012
Results First Posted: May 13, 2013
Last Update Posted: May 13, 2013