Glioblastoma Multiforme
Conditions
Keywords
Glioblastoma Multiforme, Radiation Therapy, Temozolomide, Bevacizumab, Everolimus
Brief summary
In this phase II trial the investigators plan to incorporate two targeted agents, bevacizumab and everolimus, into the first-line multimodality therapy of glioblastoma. In the first portion of the treatment, bevacizumab will be added to standard concurrent radiation therapy plus temozolomide. After completing radiation therapy, patients will continue treatment with the combination of bevacizumab and everolimus.
Detailed description
Although this maintenance regimen departs from the standard treatment with single agent temozolomide, we feel this approach may add to the overall efficacy of treatment for the following reasons: 1) results with bevacizumab/everolimus in renal cell carcinoma suggest there is at least an additive efficacy when these drugs are used in combination; 2) the efficacy of single agent temozolomide following standard concurrent radiation therapy/temozolomide has not been proven, 3) the use of the three-drug maintenance program (i.e., bevacizumab/everolimus/temozolomide) would probably not be tolerated well on a chronic basis in this patient population; and 4) the bevacizumab/everolimus combination has potential advantages as a maintenance therapy, since it has been well tolerated for many months in patients with other malignancies.
Interventions
RADIATIONRadiation therapy
Radiation therapy, 2.0 Gy daily, 5 days per week by single daily dose, to a total of 60 Gy over 6 weeks
DRUGTemozolomide
Temozolomide 75mg/m2 by mouth daily, beginning day 1 of radiation therapy and continuing through the last day of radiation therapy
DRUGBevacizumab
Bevacizumab 10mg/kg IV, every 2 weeks, beginning day 1 of radiation therapy
DRUGEverolimus
Everolimus 10mg by mouth daily, beginning Week 11
Sponsors
Genentech, Inc.
Novartis
SCRI Development Innovations, LLC
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
* Age \>=18 years. * Histologically confirmed intracranial glioblastoma multiforme (WHO grade 4). * Patients who have had partial or complete surgical debulking are eligible, as are those with inoperable glioblastoma. * No previous treatment with radiotherapy or systemic therapy. Local therapy with a Gliadel wafer placed at the time of surgical debulking is permitted. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Adequate bone marrow function * Adequate liver function: * Serum creatinine \<=1.5 x institutional ULN. * Ability to swallow whole pills. * Women of child-bearing potential must have a negative serum pregnancy test performed within 7 days prior to start of treatment. Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control) while receiving study treatment and for 6 months after the last study treatment. Hormonal contraceptives are not acceptable as a sole method of contraception. Female patients must not breast feed. * INR \<1.3 or PT/PTT within normal limits in patients not receiving anticoagulation. However, patients receiving anticoagulation treatment with an agent such as warfarin or heparin are also eligible. For patients on warfarin, the INR should be measured prior to initiation of everolimus and monitored at least weekly, or as defined by the local standard of care, until INR is stable. * Fasting serum cholesterol \<=300 mg/dL OR \<=7.75 mmol/L AND fasting triglycerides \<= 2.5 x institutional ULN.
Exclusion criteria
* New York Heart Association (NYHA) grade II or greater congestive heart failure (see Appendix B) or symptomatic congestive heart failure. * Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg). * History of myocardial infarction or unstable angina within 6 months prior to beginning study treatment. * History of stroke or transient ischemic attack within 6 months prior to beginning study treatment. * Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to beginning study treatment. * Prior history of hypertensive crisis or hypertensive encephalopathy. * History of hemoptysis (\>=1/2 teaspoon of bright red blood per episode) within 1 month prior to beginning study treatment. * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). * History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1. * Serious, non-healing wound, active ulcer, or untreated bone fracture. * Proteinuria as demonstrated by urine dipstick for proteinuria \>=2+. For patients with \>=2+ proteinuria on dipstick urinalysis, a urine protein: creatinine (UPC) ratio will be determined or a 24-hour urine collection will be done. Patients with a UPC ratio \<1 or a 24-hour urine protein \<1 gram are eligible. * Minor surgical procedures (excluding placement of a vascular access device), fine-needle aspirations, or core biopsies within 7 days prior to starting treatment. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting protocol treatment or anticipation of need for major surgical procedure during the course of study treatment. Patients who have not recovered from the side effects of any major surgery are not eligible. * Treatment with any investigational agents within 4 weeks of study entry. * Chronic, systemic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled steroids are allowed. * Other malignancies within the past 3 years except for adequately treated carcinoma in situ of the cervix or basal cell or superficial squamous (skin cell) carcinomas.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 18 months | Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Toxicity After This Novel Multimodality Regimen | 18 months | The toxicity assessments were made according to the common terminology criteria for adverse events (CTCAE version 3.0) of the National Cancer Institute. Number of participants with Grade 1 to 5 adverse events are reported here. |
| Overall Survival of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen | 18 months | Overall survival was defined as the interval from the first day of study treatment until the date of death. |
| Objective Response Rate of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen | 18 months | Response to treatment was assessed by MRI using the MacDonald criteria based on the assessment of the MRI scan for measurable, evaluable, and new lesions. The objective response rate is defined as the proportion of patients with improvement and or decreased extent of lesions compared to baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Radiotherapy administered in 2.0 Gy single daily fractions, Monday through Friday, to a total of at least 60 Gy. Temozolomide 75 mg/m2 orally daily and bevacizumab 10 mg/kg IV every 2 weeks, both beginning on day 1 of radiation therapy | 68 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Maintenance Treatment | Adverse Event | 6 |
| Maintenance Treatment | Intercurrent Illness | 7 |
| Maintenance Treatment | Lack of Efficacy | 13 |
| Maintenance Treatment | Symptomatic Deterioration | 2 |
| Maintenance Treatment | Withdrawal by Subject | 5 |
| Maintenance Treatment | Withdrawn Consent | 1 |
| Modality Therapy | Adverse Event | 1 |
| Modality Therapy | Disease Progression | 2 |
| Modality Therapy | Withdrawal by Subject | 1 |
| Treatment-Free Interval | Adverse Event | 3 |
| Treatment-Free Interval | Intercurrent Illness | 2 |
| Treatment-Free Interval | Lack of Efficacy | 1 |
| Treatment-Free Interval | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 59 years |
| Region of Enrollment United States | 68 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 53 / 68 |
| serious Total, serious adverse events | 32 / 68 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever comes first.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study | Progression-free Survival (PFS) | 11.3 Months |
Secondary
Number of Participants Experiencing Toxicity After This Novel Multimodality Regimen
The toxicity assessments were made according to the common terminology criteria for adverse events (CTCAE version 3.0) of the National Cancer Institute. Number of participants with Grade 1 to 5 adverse events are reported here.
Time frame: 18 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study | Number of Participants Experiencing Toxicity After This Novel Multimodality Regimen | 53 Participants |
Secondary
Objective Response Rate of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen
Response to treatment was assessed by MRI using the MacDonald criteria based on the assessment of the MRI scan for measurable, evaluable, and new lesions. The objective response rate is defined as the proportion of patients with improvement and or decreased extent of lesions compared to baseline.
Time frame: 18 months
Population: Only 51 patients had measurable tumor and were evaluable for response assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study | Objective Response Rate of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen | 31 Participants |
Secondary
Overall Survival of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen
Overall survival was defined as the interval from the first day of study treatment until the date of death.
Time frame: 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Study | Overall Survival of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen | 13.9 Months |