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

Phase 2CompletedNCT00671970

Duke University57 enrolled

Overview

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

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

6 Month Progression-free Survival

The proportion of patients alive and progression free at 6 months

Time frame: 6 months

Secondary Outcomes

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.

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

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

Time frame: Day 1 and 42 of Dosing 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

Time frame: Day 1 and 42 of Dosing Erlotinib

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