Glioblastoma, Gliosarcoma
Conditions
Keywords
Glioblastoma, Gliosarcoma, GBM, Bevacizumab, Avastin, Etoposide, Brain tumor, Irinotecan, Glioblastoma multiforme, Temodar, Temozolomide, Etopophos, Toposar, VePesid, VP-16, Camptosar
Brief summary
Primary objective To estimate 6-month progression free survival probability of pts w recurrent GBM treated w bev + either daily temozolomide/etoposide following progression on bev + irinotecan Secondary Objectives To evaluate safety & tolerability of bev + either daily temozolomide/etoposide among pts w recurrent GBM who have progressed on bev + irinotecan To evaluate radiographic response, progression free survival & overall survival of pts w recurrent GBM treated w bev + either daily temozolomide/etoposide following progression on bev + irinotecan
Detailed description
This is exploratory, two-arm, phase II study designed to assess anti-tumor activity of bev + either daily temozolomide/etoposide among GBM pts w progressive disease following bev + irinotecan. About 48 participants w recurrent GBM will take part in this study. Approximately 24 participants will receive bev plus temozolomide & approximately 24 will receive bev + etoposide. Pts must have confirmed diagnosis of GBM & radiographic evidence of recurrence following prior therapy bev + irinotecan. 24 pts will be enrolled onto each arm of this single-stage study. If 4 or more of these 24 pts live 6/more months without disease progression, treatment regimen will be considered worthy of further investigation. Otherwise, treatment regimen will be determined not worthy of further investigation within pt population. Type I & II error rates associated w testing are 0.030 & 0.115 respectively. Management guidelines dose reduction/interruption for temo, etoposide, & bev.
Interventions
DRUGTemo + Avastin
Patients have progressed/had gr3/\> toxicity related to etoposide, with no had progression/gr 3/\> toxicity related to temozolomide, will only be considered for bevacizumab and temozolomide. Bevacizumab intravenously at dose 10mg/kg every other wk. For patients on bevacizumab and temozolomide, temozolomide administered on continuous dosing schedule at 50mg/m2/day.
DRUGVP-16 + Avastin
Patients have progressed/had gr3/\> toxicity related to temozolomide, but have not progressed/gr3/\> toxicity related to etoposide,considered only for bevacizumab and etoposide. Bevacizumab intravenously at dose 10mg/kg every other wk. Patients on bevacizumab and etoposide, etoposide once daily at 50mg/m2/day first 21 days of each 28-day cycle.
Sponsors
Genentech, Inc.
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pts have confirmed diagnosis of GBM & radiographic evidence of recurrence following prior therapy w bev + irinotecan * Age \>18 yrs * Interval of \>4 wks between prior surgical resection/1 week from stereotactic biopsy * Interval of \>12 wks from end of prior external beam radiation therapy (XRT) unless there is new area of enhancement consistent w recurrent tumor outside of XRT field,/there are progressive changes on MRI on \>2 consecutive MRI scans \>4wks apart, /there is biopsy-proven tumor progression * Interval of \>4 wks from prior chemo / investigational agent unless pt has recovered from all anticipated toxicities associated w that therapy. * Eastern Cooperative Oncology Group (ECOG) 0-1 * Hematocrit \>29percent, absolute neutrophil count (ANC)\>1,000 cells/ml l, platelets \> 100,000 cells/ml l * Serum creatinine\<1.5 mg/dl, serum glutamate oxaloacetate transaminase (SGOT) & bilirubin\<1.5 times upper limit of normal (ULN) * Signed informed consent approved by Institutional Review Board (IRB) prior to pt entry * No evidence of hemorrhage on baseline MRI/CT scan other than those that are stable gr1 * If sexually active, pts will take contraceptive measures for duration of treatments
Exclusion criteria
* Co-medication that may interfere w study results * Active infection requiring intravenous antibiotics * Progression to daily etoposide/progression to daily temo * Gr3/greater toxicity related to prior bev therapy,/prior temozolomide/etoposide * Requires therapeutic anti-coagulation with warfarin. * Inability to comply w study and/or follow-up procedures * Current, recent,/planned participation in experimental drug study other than Genentech-sponsored bev cancer study * Inadequately controlled hypertension * Any prior history of hypertensive crisis/hypertensive encephalopathy * New York Heart Association (NYHA) Gr II/greater congestive heart failure * History of myocardial infarction (MI)/unstable angina within 6 mths prior to study enrollment * History of stroke/transient ischemic attack within 6 mths prior to study enrollment * Significant vascular disease * Symptomatic peripheral vascular disease * Evidence of bleeding diathesis or coagulopathy * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment * Serious, non-healing wound, ulcer, or bone fracture * Proteinuria at screening as demonstrated by either: * urine protein:creatinine (UPC) ratio \>1.0 at screening / * Urine dipstick for proteinuria ≥ 2+ * Known hypersensitivity to any component of bevacizumab * Pregnant or lactating. Use of effective means of contraception in subjects of child-bearing potential
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Outcome Measure is 6 Month Progression-free Survival. | 6 months | Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Response | 41 months | Percentage of participants with an objective response (complete response or partial response) based on modified Macdonald criteria. |
| Median Progression-free Survival (PFS) | 41 months | Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. |
| Median Overall Survival (OS) | 41 months | Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve. |
| Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities. | 41 months | Incidence of ≥Grade 3 treatment related, non-hematologic toxicity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide Arm Pts treated w Bev + Temozolomide | 10 |
| Etoposide Arm Pts treated w Bev + Etoposide | 13 |
| Total | 23 |
Baseline characteristics
| Characteristic | Temozolomide Arm | Etoposide Arm | Total |
|---|---|---|---|
| Age Continuous | 52.1 years STANDARD_DEVIATION 9.1 | 51.7 years STANDARD_DEVIATION 13.8 | 51.9 years STANDARD_DEVIATION 11.8 |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 11 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 11 / 13 |
| serious Total, serious adverse events | 4 / 10 | 2 / 13 |
Outcome results
Primary
The Primary Outcome Measure is 6 Month Progression-free Survival.
Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide Arm | The Primary Outcome Measure is 6 Month Progression-free Survival. | 0 percentage of participants |
| Etoposide Arm | The Primary Outcome Measure is 6 Month Progression-free Survival. | 7.7 percentage of participants |
Secondary
Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities.
Incidence of ≥Grade 3 treatment related, non-hematologic toxicity
Time frame: 41 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide Arm | Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities. | 1 participants |
| Etoposide Arm | Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities. | 2 participants |
Secondary
Median Overall Survival (OS)
Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time frame: 41 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide Arm | Median Overall Survival (OS) | 12.6 weeks |
| Etoposide Arm | Median Overall Survival (OS) | 19 weeks |
Secondary
Median Progression-free Survival (PFS)
Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time frame: 41 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide Arm | Median Progression-free Survival (PFS) | 4.1 weeks |
| Etoposide Arm | Median Progression-free Survival (PFS) | 8.1 weeks |
Secondary
Radiographic Response
Percentage of participants with an objective response (complete response or partial response) based on modified Macdonald criteria.
Time frame: 41 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide Arm | Radiographic Response | 0 percentage of participants |
| Etoposide Arm | Radiographic Response | 0 percentage of participants |