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

Primary Purpose

Glioblastoma, Gliosarcoma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Bevacizumab and Erlotinib

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring Glioblastoma, Gliosarcoma, Recurrent MG, Malignant glioma, Glioma, Glioblastoma multiforme (GBM), GBM, Brain tumor, Anaplastic astrocytoma, Anaplastic oligodendroglioma, Anaplastic oligoastrocytoma, Bevacizumab, Avastin, Erlotinib, Tarceva

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Duke University Health System

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bevacizumab + Erlotinib

Arm Description

Bevacizumab + Erlotinib

Outcomes

Primary Outcome Measures

6 Month Progression-free Survival

The proportion of patients alive and progression free at 6 months

Secondary Outcome Measures

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.

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

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

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

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

Association of Biomarkers and One-year Survival - EGFR vIII

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)

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)

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)

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)

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

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.

Full Information

NCT ID

NCT00671970

First Posted

January 29, 2008

Last Updated

March 29, 2013

Sponsor

Duke University

Collaborators

Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT00671970

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2013

Overall Recruitment Status

Completed

Study Start Date

February 2007 (undefined)

Primary Completion Date

November 2008 (Actual)

Study Completion Date

April 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Duke University

Collaborators

Genentech, Inc.

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

57 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bevacizumab + Erlotinib

Arm Type

Experimental

Arm Description

Bevacizumab + Erlotinib

Intervention Type

Drug

Intervention Name(s)

Bevacizumab and Erlotinib

Other Intervention Name(s)

Bevacizumab, Erlotitnib, Avastin, Tarceva

Intervention Description

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.

Primary Outcome Measure Information:

Title

6 Month Progression-free Survival

Description

The proportion of patients alive and progression free at 6 months

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Radiographic Response

Description

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

Title

Pharmacokinetics of Erlotinib: Cmax

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

Title

Pharmacokinetics of Erlotinib: AUC

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

Title

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

Description

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

Time Frame

1 year

Title

Association of Biomarkers and One-year Survival - EGFR vIII

Description

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

Time Frame

1 year

Title

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

Description

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

Time Frame

1 year

Title

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

Description

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

Time Frame

1 year

Title

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

Description

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

Time Frame

1 year

Title

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

Description

Time Frame

1 year

Title

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

Description

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David A. Reardon, MD

Organizational Affiliation

Duke Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

Duke University Health System

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

20716591

Citation

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.

Results Reference

derived

Links:

URL

http://www.cancer.duke.edu/btc/

Description

The Preston Robert Tisch Brain Tumor Center at DUKE

Learn more about this trial

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

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