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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00671970
• Other study ID #: Pro00000220
• Status: Completed
• Phase: Phase 2
• First received: January 29, 2008
• Last updated: March 29, 2013
• Start date: February 2007
• Est. completion date: April 2010

Study information

• Verified date: March 2013
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: April 2010
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Glioblastoma
• Gliosarcoma

Intervention

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.

Locations

Country	Name	City	State
United States	Duke University Health System	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	6 Month Progression-free Survival	The proportion of patients alive and progression free at 6 months	6 months	No
Secondary	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.	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	No
Secondary	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	Day 1 and 42 of Dosing Erlotinib	No
Secondary	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	Day 1 and 42 of Dosing Erlotinib	No
Secondary	Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR)	Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.	1 year	No
Secondary	Association of Biomarkers and One-year Survival - EGFR vIII	Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.	1 year	No
Secondary	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.	1 year	No
Secondary	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.	1 year	No
Secondary	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.	1 year	No
Secondary	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.	1 year	No
Secondary	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.	1 year	No

External Links

•   The Preston Robert Tisch Brain Tumor Center at DUKE