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

March 29, 2013 updated by: Duke University

Phase II Trial of Bevacizumab Plus Erlotinib for Patients With Recurrent Malignant Glioma

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

57

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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:
  • Avastin
  • Tarceva
  • Bevacizumab
  • Erlotitnib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
6 Month Progression-free Survival
Time Frame: 6 months
The proportion of patients alive and progression free at 6 months
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
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
Day 1 and 42 of Dosing 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
Day 1 and 42 of Dosing 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.
1 year
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.
1 year
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.
1 year
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.
1 year
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.
1 year
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.
1 year
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.
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Duke University

Collaborators

Genentech, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2007

Primary Completion (Actual)

November 1, 2008

Study Completion (Actual)

April 1, 2010

Study Registration Dates

First Submitted

January 29, 2008

First Submitted That Met QC Criteria

May 5, 2008

First Posted (Estimate)

May 6, 2008

Study Record Updates

Last Update Posted (Estimate)

May 13, 2013

Last Update Submitted That Met QC Criteria

March 29, 2013

Last Verified

March 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00000220

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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