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

This study has been completed.
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00671970
First received: January 29, 2008
Last updated: March 29, 2013
Last verified: March 2013
  Purpose

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


Condition Intervention Phase
Glioblastoma
Gliosarcoma
Drug: Bevacizumab and Erlotinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Trial of Bevacizumab Plus Erlotinib for Patients With Recurrent Malignant Glioma

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • 6 Month Progression-free Survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    The proportion of patients alive and progression free at 6 months


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 57
Study Start Date: February 2007
Study Completion Date: April 2010
Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bevacizumab + Erlotinib
Bevacizumab + Erlotinib
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00671970

Locations
United States, North Carolina
Duke University Health System
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
Genentech, Inc.
Investigators
Principal Investigator: David A. Reardon, MD Duke University Health System
  More Information

Additional Information:
No publications provided by Duke University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00671970     History of Changes
Other Study ID Numbers: Pro00000220
Study First Received: January 29, 2008
Results First Received: December 28, 2012
Last Updated: March 29, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
Glioblastoma
Gliosarcoma
Recurrent MG
Malignant glioma
Glioma
Glioblastoma multiforme (GBM)
GBM
Brain tumor
Anaplastic astrocytoma
Anaplastic oligodendroglioma
Anaplastic oligoastrocytoma
Bevacizumab
Avastin
Erlotinib
Tarceva

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Bevacizumab
Erlotinib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014