Glioblastoma, Gliosarcoma
Conditions
Keywords
Glioblastoma, Gliosarcoma, Recurrent MG, Malignant glioma, Glioma, Glioblastoma multiforme (GBM), GBM, Brain tumor, Anaplastic astrocytoma, Anaplastic oligodendroglioma, Anaplastic oligoastrocytoma, Bevacizumab, Avastin, Erlotinib, Tarceva
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.
Interventions
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.
Sponsors
Genentech, Inc.
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Month Progression-free Survival | 6 months | The proportion of patients alive and progression free at 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Open for recruitment from February 2007 to May 2008. Subjects recruited in the Preston Robert Tisch Brian Tumor Center at Duke University Medical Center (DUMC).
Participants by arm
| Arm | Count |
|---|---|
| Who Grade III Who Grade III Malignant Glioma | 32 |
| WHO Grade IV WHO Grade IV Malignant Glioma | 25 |
| Total | 57 |
Baseline characteristics
| Characteristic | Who Grade III | WHO Grade IV | Total |
|---|---|---|---|
| Age Continuous | 48.8 years STANDARD_DEVIATION 12.8 | 51.5 years STANDARD_DEVIATION 13.4 | 49.98 years STANDARD_DEVIATION 13.05 |
| Sex: Female, Male Female | 8 Participants | 12 Participants | 20 Participants |
| Sex: Female, Male Male | 24 Participants | 13 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 52 / 57 |
| serious Total, serious adverse events | 20 / 57 |
Outcome results
Primary
6 Month Progression-free Survival
The proportion of patients alive and progression free at 6 months
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Who Grade III | 6 Month Progression-free Survival | .438 proportion of participants |
| WHO Grade IV | 6 Month Progression-free Survival | .292 proportion of participants |
Secondary
Association of Biomarkers and One-year Survival - EGFR vIII
Archival tumor samples from grade IV participants were examined by immunohistochemistry for biomarkers.
Time frame: 1 year
Population: Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Who Grade III | Association of Biomarkers and One-year Survival - EGFR vIII | 1 participants |
| WHO Grade IV | Association of Biomarkers and One-year Survival - EGFR vIII | 7 participants |
p-value: 0.613Fisher Exact
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.
Time frame: 1 year
Population: Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. One tumor had an insufficient measurement for analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Who Grade III | Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR) | 7 participants |
| WHO Grade IV | Association of Biomarkers and One-year Survival - Epidermal Growth Factor (EGFR) | 0 participants |
p-value: 1Fisher Exact
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.
Time frame: 1 year
Population: Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. One tumor had an insufficient measurement for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Who Grade III | Association of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN) | 1 participants |
| WHO Grade IV | Association of Biomarkers and One-year Survival - Phosphatase and Tensin Homologue (PTEN) | 7 participants |
p-value: 1Fisher Exact
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.
Time frame: 1 year
Population: Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. Six tumors had an insufficient measurement for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Who Grade III | Association of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK) | 5 participants |
| WHO Grade IV | Association of Biomarkers and One-year Survival - Phosphorylated Mitogen-activated Protein Kinase (pMAPK) | 1 participants |
p-value: 1Fisher Exact
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.
Time frame: 1 year
Population: Tumors from 22 GBM participants were available to undergo immunohistochemical staining to identify potential biomarkers of response or survival benefit. Four tumors had an insufficient measurement for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Who Grade III | Association of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT) | 6 participants |
| WHO Grade IV | Association of Biomarkers and One-year Survival - Phosphorylated Protein Kinase B (pAKT) | 1 participants |
p-value: 1Fisher Exact
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.
Time frame: 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Who Grade III | Association of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF) | 40 IHC Expression Score |
| WHO Grade IV | Association of Biomarkers and One-year Survival - Vascular Endothelial Growth Factor (VEGF) | 60 IHC Expression Score |
p-value: 0.179Wilcoxon (Mann-Whitney)
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.
Time frame: 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Who Grade III | Association of Biomarkers and One-year Survival - VEGFR-2 | 50 IHC Expression Score |
| WHO Grade IV | Association of Biomarkers and One-year Survival - VEGFR-2 | 120 IHC Expression Score |
p-value: 0.008Wilcoxon (Mann-Whitney)
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
Time frame: Day 1 and 42 of Dosing Erlotinib
Population: 22 WHO Grade IV participants were available for pharmacokinetics studies of erlotinib
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Who Grade III | Pharmacokinetics of Erlotinib: AUC | Day1 AUC 0-24{ng/ml.h} 200mg n=12 | 11072 ng/ml.h |
| Who Grade III | Pharmacokinetics of Erlotinib: AUC | Day1 AUC 0-24{ng/ml.h} 500mg n=10 | 15611 ng/ml.h |
| Who Grade III | Pharmacokinetics of Erlotinib: AUC | Day42 AUC 0-24{ng/ml.h}200mg n=9 | 26072 ng/ml.h |
| Who Grade III | Pharmacokinetics of Erlotinib: AUC | Day42 AUC 0-24{ng/ml.h}500mg n=9 | 21421 ng/ml.h |
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
Time frame: Day 1 and 42 of Dosing Erlotinib
Population: 22 WHO Grade IV participants were available for pharmacokinetics studies of erlotinib
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Who Grade III | Pharmacokinetics of Erlotinib: Cmax | Day1 Cmax{ng/ml}500mg n=10 | 1323 ng/ml |
| Who Grade III | Pharmacokinetics of Erlotinib: Cmax | Day42 Cmax{ng/ml}200mg n=9 | 1320 ng/ml |
| Who Grade III | Pharmacokinetics of Erlotinib: Cmax | Day42 Cmax{ng/ml}500mg n=9 | 1400 ng/ml |
| Who Grade III | Pharmacokinetics of Erlotinib: Cmax | Day1 Cmax{ng/ml}200mg n=12 | 794 ng/ml |
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.
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Who Grade III | Radiographic Response | Complete | 1 participants |
| Who Grade III | Radiographic Response | Partial | 9 participants |
| WHO Grade IV | Radiographic Response | Partial | 11 participants |
| WHO Grade IV | Radiographic Response | Complete | 1 participants |