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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

Tracking Information
First Submitted Date  ICMJE January 29, 2008
First Posted Date  ICMJE May 6, 2008
Results First Submitted Date  ICMJE December 28, 2012
Results First Posted Date  ICMJE May 13, 2013
Last Update Posted Date May 13, 2013
Study Start Date  ICMJE February 2007
Actual Primary Completion Date November 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2013)
6 Month Progression-free Survival [ Time Frame: 6 months ]
The proportion of patients alive and progression free at 6 months
Original Primary Outcome Measures  ICMJE
 (submitted: May 5, 2008)
6 Month Progression-free Survival [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 29, 2013)
  • Radiographic Response [ 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 ]
    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.
  • Pharmacokinetics of Erlotinib: Cmax [ Time Frame: Day 1 and 42 of Dosing Erlotinib ]
    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
  • Pharmacokinetics of Erlotinib: AUC [ Time Frame: Day 1 and 42 of Dosing Erlotinib ]
    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
  • Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR) [ Time Frame: 1 year ]
    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
  • Association of Biomarkers and One-year Survival - EGFR vIII [ Time Frame: 1 year ]
    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
  • Association of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN) [ Time Frame: 1 year ]
    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
  • Association of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT) [ Time Frame: 1 year ]
    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
  • Association of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK) [ Time Frame: 1 year ]
    Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
  • Association of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF) [ Time Frame: 1 year ]
    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.
  • Association of Biomarkers and One-year Survival - VEGFR-2 [ Time Frame: 1 year ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 5, 2008)
  • a. Radiographic response b. Pharmacokinetics of Erlotinib c. Correlation of clinical response & pathological findings of EGFR expression, amplification & EGFR-vIII expression, VEGF expression, PTEN expression & PKB/Akt expression [ Time Frame: 6 months ]
  • Gr 3 or greater, treatment related, non-hematologic toxicities [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase (Ph) II Bevacizumab + Erlotinib for Patients (Pts) With Recurrent Malignant Glioma (MG)
Official Title  ICMJE Phase II Trial of Bevacizumab Plus Erlotinib for Patients With Recurrent Malignant Glioma
Brief 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Gliosarcoma
Intervention  ICMJE Drug: Bevacizumab 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.

Other Names:
  • Bevacizumab
  • Erlotitnib
  • Avastin
  • Tarceva
Study Arms  ICMJE Experimental: Bevacizumab + Erlotinib
Bevacizumab + Erlotinib
Intervention: Drug: Bevacizumab and Erlotinib
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 29, 2013)
57
Original Estimated Enrollment  ICMJE
 (submitted: May 5, 2008)
56
Actual Study Completion Date  ICMJE April 2010
Actual Primary Completion Date November 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00671970
Other Study ID Numbers  ICMJE Pro00000220
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Duke University
Study Sponsor  ICMJE Duke University
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Principal Investigator: David A. Reardon, MD Duke University Health System
PRS Account Duke University
Verification Date March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP