Glioblastoma, Gliosarcoma, Grade 4 Malignant Glioma, Malignant Glioma
Conditions
Keywords
malignant glioma, Grade 4 malignant glioma, glioblastoma, gliosarcoma, adult brain tumor
Brief summary
Studies which have separately studied bevacizumab for recurrent gliomas and bevacizumab for newly-diagnosed glioma have shown good results and the regimens have been well-tolerated by patients. This study seeks to investigate the use of bevacizumab with the standard therapy (radiation therapy and temozolomide) in newly diagnosed patients, followed by bevacizumab and temozolomide with the continuation of bevacizumab following progression. Two critical questions remain- the role of bevacizumab maintenance and bevacizumab at the time of progression in a patient previously treated with bevacizumab at the time of initial diagnosis.
Detailed description
Given the possible synergism with irinotecan and bevacizumab for colorectal carcinomas, the combination has been studied in gliomas. In a study of 21 patients, the combination of irinotecan and bevacizumab produced a 43% response rate, with acceptable toxicity. The response rate is significantly higher than irinotecan alone and any other therapy for recurrent glioma. There were two serious adverse events, one intracranial hemorrhage and one bowel perforation. At the Duke Brain Tumor Center, the investigators have treated over 1000 glioblastoma patients with a bevacizumab-containing regimen, and there is marked clinical benefit and acceptable toxicity. Our initial study looking at the combination of bevacizumab and irinotecan for patients with recurrent glioblastoma published in 2007 found impressive response rates and survival and corroborated the earlier experience of Starks-Vance. The investigators completed a study for newly diagnosed glioblastoma that utilized bevacizumab, radiation therapy and temozolomide followed by 6 months of bevacizumab, irinotecan and temozolomide. In addition, the group at University of California at Los Angeles published a study with bevacizumab, radiation therapy and temozolomide followed by 12 months of bevacizumab and temozolomide for newly diagnosed glioblastoma. These two phase II studies reported acceptable toxicity and a suggestion of improved survival compared to historical controls, and led to two large phase III randomized, placebo controlled studies of the addition of bevacizumab for newly diagnosed glioblastoma patients. The current proposal builds on the encouraging results of the addition of bevacizumab to the standard therapy for newly diagnosed glioblastoma patients. Two critical questions remain- the role of bevacizumab maintenance and bevacizumab at the time of progression in a patient previously treated with bevacizumab at the time of initial diagnosis. In addition, a retrospective analysis of data collected at our center from patients with recurrent disease suggests that continuation of bevacizumab at the time of progression may improve overall survival in comparison with cessation of bevacizumab.
Interventions
RADIATIONRadiation Therapy
DRUGTemozolomide
DRUGBevacizumab
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
* Patients with histologically confirmed WHO Grade IV primary malignant glioma (glioblastoma or gliosarcoma); * Patients ≥ 18 years of age; * An interval of at least 2 weeks, but not ≥ 8 weeks between prior surgical procedure and initiation of treatment; * Karnofsky Performance Status (KPS) ≥ 60% * Laboratory Values: * Platelet Count ≥ 125,000 cells/µL * Absolute neutrophil count (ANC) ≥ 1,500 cells/µL * Adequate renal function indicated by all of the following: * Serum creatinine ≤ 1.25 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 ml/min * Urine dipstick for proteinuria \< 2+ unless a 24-hour urine protein \< 1 g of protein is demonstrated * internationalized normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 x upper limit of normal (ULN) within 7 days prior to first study treatment for patients not receiving anti-coagulation. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment. * Patients will sign an Institutional Review Board-approved informed consent form. * Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, \[i.e. with a failure rate of \< 1% per year\] are implants, injectables, combined oral contraceptives, intra-uterine device \[Intrauterine Device (IUD); only hormonal\], sexual abstinence or vasectomized partner) during the trial and for a period of \> 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 7 days prior to first study treatment. * Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control \[i.e. with a failure rate of \< 1% per year\] include a female partner using implants, injectables, combined oral contraceptives, Intrauterine Device (IUDs) \[only hormonal\], sexual abstinence or prior vasectomy) during the trial and for a period of \> 6 months following the last administration of trial drugs.
Exclusion criteria
* Any prior treatment for any grade glioma, including, but not limited to gliadel wafers, immunotherapy (including vaccine therapy), radiation therapy or chemotherapy, irrespective of grade of the tumor (NOTE: 5-aminolevulinic acid (ALA)-mediated photodynamic therapy administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent.); * Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids; * Active infection requiring intravenous antibiotics; * Prior or current treatment with bevacizumab or other anti-angiogenic treatment (i.e. anti-vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) therapies or tyrosine kinase inhibitors) for any condition; * Treatment with any other investigational agent within 28 days or 2 investigational agent half-lives (whichever is longer) prior to first study treatment; * Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin; * Evidence of \> Grade 1 central nervous system (CNS) hemorrhage on post-operative MRI scan, unless repeat MRI or CT performed prior to initiating bevacizumab shows stable grade 1 or resolving (\< grade 1) CNS hemorrhage. Bevacizumab-Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 5 Years | To assess the effect on overall survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of first diagnosis of grade IV malignant glioma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity: Percentage of Subjects With Unacceptable Toxicities | 5 Years | The occurrence of ≥ grade 2 CNS (central nervous system) hemorrhage or grade 4 or 5 non-hematologic toxicity is defined as being unacceptable. Unacceptable toxicity rates of 5% or less are considered desirable, while rates of 20% or greater are considered as undesirable. |
| Progression-free Survival (PFS) | 5 Years | To assess the effect on progression-free survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of initiation of treatment to the first occurrence of progression, or death |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevaczimab, Radiation Therapy, Temozolomide In Part A, newly-diagnosed patients with Grade 4 malignant gliomas will receive standard radiation therapy, daily Temodar 75mg/M for 6-8 weeks. Bevacizumab will be given concurrently with radiation therapy and Temodar, 10 mg/kg every two weeks.
If they are stable at the end of Part A, they will continue to Part B. In Part B patients will receive up to 12 cycles of bevacizumab and Temodar. Bevacizumab will be given on Days 1 and 15 of a 28-day cycle. Temodar will be 200 mg/meter squared daily for 5 days (days 1-5) of each cycle.
If they have not progressed, patients will start Part C. In Part C, patients will receive bevacizumab 10mg/kg approximately every 2 weeks or 15 mg/kg approximately every 3 weeks.
If patients progress during Part B or C, they will start Part D. In Part D, patients will receive bevacizumab-based therapy containing bevacizumab in combination with a chemotherapy and/or biologic agent, as determined by the Duke treating physician.
Radiation Therapy
Temozolomide
Bevacizumab | 68 |
| Total | 68 |
Baseline characteristics
| Characteristic | Bevaczimab, Radiation Therapy, Temozolomide |
|---|---|
| Age, Continuous | 55.43 years STANDARD_DEVIATION 10.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 64 Participants |
| Region of Enrollment United States | 68 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 68 / 68 |
| other Total, other adverse events | 68 / 68 |
| serious Total, serious adverse events | 41 / 68 |
Outcome results
Primary
Overall Survival
To assess the effect on overall survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of first diagnosis of grade IV malignant glioma.
Time frame: 5 Years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevaczimab, Radiation Therapy, Temozolomide | Overall Survival | 17.8 months |
Secondary
Progression-free Survival (PFS)
To assess the effect on progression-free survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of initiation of treatment to the first occurrence of progression, or death
Time frame: 5 Years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevaczimab, Radiation Therapy, Temozolomide | Progression-free Survival (PFS) | 9.9 months |
Secondary
Toxicity: Percentage of Subjects With Unacceptable Toxicities
The occurrence of ≥ grade 2 CNS (central nervous system) hemorrhage or grade 4 or 5 non-hematologic toxicity is defined as being unacceptable. Unacceptable toxicity rates of 5% or less are considered desirable, while rates of 20% or greater are considered as undesirable.
Time frame: 5 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevaczimab, Radiation Therapy, Temozolomide | Toxicity: Percentage of Subjects With Unacceptable Toxicities | 11.8 percentage of participants |