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CompletedNCT00671970Updated May 13, 2013Results posted

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

A Phase 2 interventional study of Bevacizumab and Erlotinib in Glioblastoma and Gliosarcoma, sponsored by Duke University. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2013-05-13.

Sponsored by Duke University · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
57
Allocation
Not applicable
Ages
18 Years and older
Sex
All
01

Study summary

Primary objective:

To estimate 6-month progression free survival probability of pts w recurrent malignant gliomas treated w erlotinib + bevacizumab.

Secondary Objectives:

To evaluate safety \& tolerability of erlotinib + bevacizumab among pts w recurrent malignant gliomas To evaluate radiographic response of pts w recurrent malignant gliomas treated w erlotinib + bevacizumab To evaluate pharmacokinetics of erlotinib when administered to pts w recurrent malignant gliomas; \& to examine relationship of clinical response to Epidermal Growth Factor (EGFR) expression, amplification, \& v-III mutation, phosphatase and tensin homolog (PTEN) expression, vascular endothelial growth factor (VEGF) expression, vascular endothelial growth factor receptor 2 (VEGFR-2) \& phosphorylated protein kinase B (PKB/Akt) in archival tumor samples

Read the detailed description

Exploratory, Phase II study designed to assess anti-tumor activity of combinatorial regimen consisting of erlotinib + bevacizumab among pts w recurrent malignant glioma. Signal transduction inhibitors, such as erlotinib, as well as anti-angiogenic agents, such as bevacizumab, are expected to exert a cytostatic anti-tumor effect. Primary endpoint of study is probability of progression-free survival at 6 months. An important secondary objective is to further assess the safety of erlotinib + bevacizumab for pts w RMG. Pharmacokinetic studies included in protocol will evaluate impact of enzyme-inducing anti-epileptic drugs (EIAEDs) on metabolism of erlotinib.

If study demonstrates that combo regimen of erlotinib + bevacizumab is associated w encouraging anti-tumor activity among pts w recurrent malignant glioma (RMG), further assessment of regimen in additional ph II \& possibly ph III studies, will be considered.

02

Conditions studied

  • Glioblastoma
  • Gliosarcoma

Keywords

  • Glioblastoma
  • Gliosarcoma
  • Recurrent MG
  • Malignant glioma
  • Glioma
  • Glioblastoma multiforme (GBM)
  • GBM
  • Brain tumor
  • Anaplastic astrocytoma
  • Anaplastic oligodendroglioma
  • Anaplastic oligoastrocytoma
  • Bevacizumab
  • Avastin
  • Erlotinib
  • Tarceva
03

In context

Glioblastoma

1,920 studies on the registry are indexed under Glioblastoma; 450 are open to participants now.

This study's enrollment of 57 is above the median of 36 across 1,618 interventional studies indexed under Glioblastoma.

Browse Glioblastoma studies →

Lead sponsor

Duke University is the lead sponsor of 2,025 studies on the registry; 275 are open to participants now.

Of its 194 completed or terminated interventional studies of FDA-regulated products, 159 (82%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Pts have histologically confirmed diagnosis of recurrent/progressive WHO gr III \& IV MG \& meet following inclusion criteria:
  • Age >18 yrs
  • Interval of >4 wks since prior surgery
  • Interval of >4 wks since prior external beam radiation therapy (XRT) or chemo, unless there is unequivocal evidence of progressive disease \& pts have recovered from all anticipated toxicity of most recent therapy
  • Karnofsky performance status score >60
  • Hematocrit > 29 percent, absolute neutrophil count (ANC) >1,500 cells/microliter, platelets >100,000 cells/microliter
  • Serum creatinine \<.5mg/dl, blood urea nitrogen (BUN) \<25 mg/dl, serum glutamate oxaloacetate transaminase (SGOT) \& bilirubin \<1.5 x upper limit of normal (ULN)
  • For pts on corticosteroids, they have been on stable dose for 1 wk prior to entry
  • Pts have had prior bevacizumab are eligible however interval of >6 wks must have elapsed since their last dose
  • Signed informed consent approved by Institutional Review Board (IRB) prior to patient entry;
  • If sexually active, pts must agree to take contraceptive measures for duration of treatments

Exclusion criteria

Exclusion Criteria:

  • Prior therapy w either bevacizumab/EGFR-directed agents
  • >3 prior recurrences
  • Pregnancy/breast feeding
  • Co-medication w immuno-suppressive agents other than corticosteroids including but not limited to cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil
  • Evidence of central nervous system (CNS) hemorrhage on baseline MRI on CT scan
  • Pts who require therapeutic anti-coagulation
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics \& psychiatric illness/social situations that would limit compliance w study requirements, or disorders associated w significant immunocompromised state
  • Pts w another primary malignancy that has required treatment within past year
  • Pts w acute/chronic renal insufficiency/those w acute renal insufficiency of any severity due to hepato-renal syndrome/in peri-operative liver transplantation period
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
57 participants (actual)

Study arms

  • Experimental
    Bevacizumab + Erlotinib

    Bevacizumab + Erlotinib

    Drug: Bevacizumab and Erlotinib

Interventions

  • DrugBevacizumab and Erlotinib

    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. Dose of erlotinib is based on prior erlotinib monotherapy trial in RMG. 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. It is possible that taking erlotinib w regular medications or supplements may change how erlotinib, subject's regular medications, or subject's regular supplements work. Treatment will continue until either evidence of progressive disease, unacceptable toxicity, non-compliance w study follow-up, or withdrawal of consent.

    Also known as: Bevacizumab, Erlotitnib, Avastin, Tarceva

06

What researchers measure

Primary outcomes

  1. 6 Month Progression-free Survival

    The proportion of patients alive and progression free at 6 months

    Time frame: 6 months

Secondary outcomes

  1. Radiographic Response

    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

  2. Pharmacokinetics of Erlotinib: Cmax

    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

  3. Pharmacokinetics of Erlotinib: AUC

    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

  4. Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR)

    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

    Time frame: 1 year

  5. Association of Biomarkers and One-year Survival - EGFR vIII

    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

    Time frame: 1 year

  6. Association of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN)

    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

    Time frame: 1 year

  7. Association of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT)

    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

    Time frame: 1 year

  8. Association of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK)

    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

    Time frame: 1 year

  9. Association of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF)

    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

  10. Association of Biomarkers and One-year Survival - VEGFR-2

    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

07

Results

Posted May 13, 2013

Participant flow

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).

Participant flow — Overall Study
MilestoneWHO Grade IIIWHO Grade IV
Started3225
Completed3225
Not completed00

Outcome measures

Primary6 Month Progression-free Survival

The proportion of patients alive and progression free at 6 months

Time frame:
6 months
Reported as:
Number · proportion of participants
6 Month Progression-free Survival
proportion of participantsWho Grade IIIWHO Grade IV
6 Month Progression-free Survival.438 (.265 to .598).292 (.130 to .476)
SecondaryRadiographic Response

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
Reported as:
Number · participants
Radiographic Response
participantsWho Grade IIIWHO Grade IV
Complete11
Partial911
SecondaryPharmacokinetics of Erlotinib: Cmax

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
Reported as:
Median · ng/ml
Pharmacokinetics of Erlotinib: Cmax
ng/mlWHO Grade IV
Day1 Cmax{ng/ml}200mg n=12794 (524 to 2200)
Day1 Cmax{ng/ml}500mg n=101323 (317 to 2990)
Day42 Cmax{ng/ml}200mg n=91320 (525 to 2940)
Day42 Cmax{ng/ml}500mg n=91400 (716 to 3955)
SecondaryPharmacokinetics of Erlotinib: AUC

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
Reported as:
Median · ng/ml.h
Pharmacokinetics of Erlotinib: AUC
ng/ml.hWHO Grade IV
Day1 AUC 0-24{ng/ml.h} 200mg n=1211072 (7850 to 30029)
Day1 AUC 0-24{ng/ml.h} 500mg n=1015611 (5295 to 40110)
Day42 AUC 0-24{ng/ml.h}200mg n=926072 (8308 to 42878)
Day42 AUC 0-24{ng/ml.h}500mg n=921421 (11680 to 55960)
SecondaryAssociation of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR)

Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

Time frame:
1 year
Reported as:
Number · participants
Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR)
participantsPositive ExpressionNegative Expression
Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR)70
Statistical analysis
  • Positive Expression vs Negative Expression · Fisher Exact · p = 1.0
SecondaryAssociation of Biomarkers and One-year Survival - EGFR vIII

Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

Time frame:
1 year
Reported as:
Number · participants
Association of Biomarkers and One-year Survival - EGFR vIII
participantsPositive ExpressionNegative Expression
Association of Biomarkers and One-year Survival - EGFR vIII17
Statistical analysis
  • Positive Expression vs Negative Expression · Fisher Exact · p = .613
SecondaryAssociation of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN)

Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

Time frame:
1 year
Reported as:
Number · participants
Association of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN)
participantsIntactLoss
Association of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN)17
Statistical analysis
  • Intact vs Loss · Fisher Exact · p = 1.0
SecondaryAssociation of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT)

Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

Time frame:
1 year
Reported as:
Number · participants
Association of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT)
participantsPositive ExpressionNegative Expression
Association of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT)61
Statistical analysis
  • Positive Expression vs Negative Expression · Fisher Exact · p = 1.0
SecondaryAssociation of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK)

Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.

Time frame:
1 year
Reported as:
Number · participants
Association of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK)
participantsPositive ExpressionNegative Expression
Association of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK)51
Statistical analysis
  • Positive Expression vs Negative Expression · Fisher Exact · p = 1.0
SecondaryAssociation of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF)

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
Reported as:
Median · IHC Expression Score
Association of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF)
IHC Expression ScorePatients Who Survived At Least 1 YearPatients Who Survived Less Than 1 Year
Association of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF)40 (4 to 120)60 (20 to 160)
Statistical analysis
  • Patients Who Survived At Least 1 Year vs Patients Who Survived Less Than 1 Year · Wilcoxon (Mann-Whitney) · p = .179
SecondaryAssociation of Biomarkers and One-year Survival - VEGFR-2

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
Reported as:
Median · IHC Expression Score
Association of Biomarkers and One-year Survival - VEGFR-2
IHC Expression ScorePatients Who Survived At Least 1 YearPatients Who Survived Less Than 1 Year
Association of Biomarkers and One-year Survival - VEGFR-250 (20 to 100)120 (40 to 160)
Statistical analysis
  • Patients Who Survived At Least 1 Year vs Patients Who Survived Less Than 1 Year · Wilcoxon (Mann-Whitney) · p = .008

Adverse events

Collected over The length of time that the subjects were receiving treatment and then 30 days after treatment termination.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
All Patients—20/57 (35.1%)52/57 (91.2%)
Most frequent serious events
Showing 10 of 36
Most frequent serious events
EventAll Patients
SeizureNervous system disorders5/57
HeadacheNervous system disorders3/57
Thromboembolic eventVascular disorders3/57
NauseaGastrointestinal disorders2/57
VomitingGastrointestinal disorders2/57
Death NOSGeneral disorders2/57
Device related infectionInfections and infestations2/57
Cognitive disturbanceNervous system disorders2/57
Intracranial hemorrhageNervous system disorders2/57
Pyramidal tract syndromeNervous system disorders2/57
Most frequent other events
Showing 10 of 54
Most frequent other events
EventAll Patients
Rash maculo-papularSkin and subcutaneous tissue disorders44/57
FatigueGeneral disorders40/57
DiarrheaGastrointestinal disorders28/57
Peripheral motor neuropathyNervous system disorders26/57
Memory impairmentNervous system disorders25/57
InsomniaPsychiatric disorders24/57
HyperglycemiaMetabolism and nutrition disorders23/57
Cognitive disturbanceNervous system disorders20/57
HeadacheNervous system disorders20/57
ConfusionPsychiatric disorders20/57

Baseline characteristics

Age Continuous
Age Continuous(years)Who Grade IIIWHO Grade IVTotal
Median48.8 ± 12.851.5 ± 13.449.98 ± 13.05
Sex: Female, Male
Sex: Female, Male(Participants)Who Grade IIIWHO Grade IVTotal
Female81220
Male241337
08

Study locations

1 site
  • Duke University Health System
    Durham, North Carolina 27710, United States
09

References and documents

Publications

  • Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE, Mathe A, Hamilton M, Rich JN, Norfleet JA, Gururangan S, Friedman HS, Reardon DA. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol. 2010 Dec;12(12):1300-10. doi: 10.1093/neuonc/noq099. Epub 2010 Aug 17. PubMed 20716591 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 13, 2013, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00671970
Lead sponsor
Duke University
Collaborators
Genentech, Inc.
Responsible party
Sponsor
First posted
May 6, 2008
Start date
Feb 2007
Primary completion
Nov 2008
Completion
Apr 2010
Results posted
May 13, 2013
Last update
May 13, 2013

Study contacts

David A. Reardon, MD
principal investigator · Duke Health

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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