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

Phase 2

Completed

Conditions: Glioblastoma
Gliosarcoma

Interventions: Drug: Bevacizumab and Erlotinib

Registration Number: NCT00671970

Lead Sponsor: Duke University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 57

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

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Bevacizumab + Erlotinib	Bevacizumab and Erlotinib	Bevacizumab + Erlotinib

Primary Outcome Measures

Name	Time	Method
6 Month Progression-free Survival	6 months	The proportion of patients alive and progression free at 6 months

Secondary Outcome Measures

Name	Time	Method
Radiographic Response	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	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	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)	1 year	Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
Association of Biomarkers and One-year Survival - EGFR vIII	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)	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)	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)	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)	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	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.