Glioblastoma, Gliosarcoma, Malignant Glioma
Conditions
Keywords
malignant glioma, glioblastoma, gliosarcoma, Avastin, bevacizumab, Topotecan, Hycamtin, Temozolomide, Temodar, Pro00019960, Vredenburgh, Duke, Desjardins
Brief summary
This is a phase II study of the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan in grade IV malignant glioma patients.
Detailed description
The primary objective of this study is to use 6-month progression-free survival to assess the efficacy of the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan in the treatment of grade IV malignant glioma patients following surgical resection. Secondary objectives are to determine the overall survival following the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan and to describe the toxicity of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan. The study will have survival and toxicity endpoints. Patients will be treated with standard radiation therapy and daily temozolomide for 6 and a half weeks of radiation. Avastin will be administered every other week beginning a minimum of 28 days after the last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of radiation therapy, patients will have a MRI and if there is no evidence of disease progression, patients will receive 12 cycles of Avastin, temozolomide, and topotecan (beginning a minimum of 14 days after the last radiation treatment). Subjects will be identified by the investigator as those patients who have newly diagnosed grade 4 malignant glioma (glioblastoma multiforme or gliosarcoma), and be within 6 weeks of the last major surgical procedure, craniotomy, open biopsy, or stereotactic biopsy. Fifty (50) patients will initially be accrued to the study and the overall efficacy of the treatment regimen assessed. Analyses will be conducted within subgroups defined by methylation status. Early side effects of radiation that may start during radiation include hair loss, scalp redness, inflammation of the ear canals, and fatigue. There is a small chance of long-term effects from radiation, occurring after months or years after completion. These may include worsening of mental function, hearing, vision, strength and coordination. In initial Phase I and II clinical trials, four potential Avastin-associated safety signals were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage. Temozolomide has been well tolerated by both adults and children with the most common toxicity being mild myelosuppression. Other, less likely, potential toxicities include nausea and vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, and hepatotoxicity. With topotecan, reversible myelosuppression with leukopenia and thrombocytopenia is dose limiting. Nausea and vomiting, as well as diarrhea and alopecia, are frequent. Moderate fatigue, transient elevation of hepatic transaminase levels, stomatitis, anemia, fever, mucositis, flu-like symptoms, and rash have been reported.
Interventions
DRUGBevacizumab
Bevacizumab (Avastin) at 10 mg/kg every other week during standard radiation therapy (XRT). Following XRT, bevacizumab will remain at 10 mg/kg every other week.
DRUGTemozolomide
Daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation therapy (XRT). Following XRT, temozolomide will be dosed at 150 mg/m2 daily the first 5 days of each 28-day cycle.
RADIATIONRadiation Therapy (XRT)
Standard radiation therapy for approximately 6.5 weeks
DRUGTopotecan
Following standard radiation therapy, patients will receive topotecan on days 2 through 6 of each 28-day cycle at a dose of 1.5 mg/m2 for patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs) and 2.0 mg/m2 for patients taking EIAEDs.
Sponsors
Genentech, Inc.
GlaxoSmithKline
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 must have histologically confirmed diagnosis of WHO grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within 6 weeks of the last major surgical procedure. * Age \> or = to 18 years. * An interval of at least 2 weeks and not \> 6 weeks between prior major surgical procedure and study enrollment. * No prior radiotherapy or chemotherapy for a brain tumor * Karnofsky \> or = to 60%. * Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,500 cells/microliter, platelets ≥ 125,000 cells/microliter. * Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal. * Signed informed consent approved by the Institutional Review Board * If sexually active, patients must agree to use appropriate contraceptive measures for the duration of the study and for 6 months afterwards as stated in the informed consent.
Exclusion criteria
* Pregnancy or breast feeding. * Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids. * Active infection requiring IV antibiotics. * Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor. * Evidence of \> grade 1 central nervous system (CNS) hemorrhage on baseline MRI on CT scan. Avastin-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
|---|---|---|
| One and Two Year Overall Survival | One year and two years | 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 Overall Survival | 27 months | OS was defined as 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. |
| Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage | 27 months | Number of times a CNS hemorrhage or systemic hemorrhage was experienced |
| Number of Patients Experiencing a Greater Than or Equal to Grade 4 Hematologic or a Greater Than or Equal to Grade 3 Non-hematologic Toxicity | 27 months | Number of times a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity was experienced |
| Median Progression-free Survival | 27 months | PFS was defined as 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Avastin, XRT, Temodar Followed by Avastin, Temodar, Topotecan Avastin, XRT, Temodar followed by Avastin, Temodar, Topotecan : Standard radiation therapy and daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation in combination with Avastin at 10 mg/kg every other week.
This will be followed by Avastin at 10 mg/kg every other week, temozolomide at 150 mg/m2 daily the first 5 days in combination with topotecan at 1.5 mg/m2 (patients not taking enzyme-inducing anti-epileptic drugs) or 2.0 mg/m2 (patients taking enzyme-inducing anti-epileptic drugs) on Days 2-6 of each 28-day cycle. | 80 |
| Total | 80 |
Baseline characteristics
| Characteristic | Avastin, XRT, Temodar Followed by Avastin, Temodar, Topotecan |
|---|---|
| Age, Continuous | 53.7 years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 80 |
| serious Total, serious adverse events | 17 / 80 |
Outcome results
Primary
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
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab, XRT, Temozolomide, Topotecan | 6-month Progression-free Survival | 88.8 percentage of participants |
Secondary
Median Overall Survival
OS was defined as 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: 27 months
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab, XRT, Temozolomide, Topotecan | Median Overall Survival | 17.2 months |
Secondary
Median Progression-free Survival
PFS was defined as 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: 27 months
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab, XRT, Temozolomide, Topotecan | Median Progression-free Survival | 11.1 months |
Secondary
Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage
Number of times a CNS hemorrhage or systemic hemorrhage was experienced
Time frame: 27 months
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab, XRT, Temozolomide, Topotecan | Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage | Grade 2 central nervous system (CNS) hemorrhage | 1 participants |
| Bevacizumab, XRT, Temozolomide, Topotecan | Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage | Grade 3 CNS hemorrhage | 0 participants |
| Bevacizumab, XRT, Temozolomide, Topotecan | Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage | Grade 4 CNS hemorrhage | 2 participants |
Secondary
Number of Patients Experiencing a Greater Than or Equal to Grade 4 Hematologic or a Greater Than or Equal to Grade 3 Non-hematologic Toxicity
Number of times a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity was experienced
Time frame: 27 months
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab, XRT, Temozolomide, Topotecan | Number of Patients Experiencing a Greater Than or Equal to Grade 4 Hematologic or a Greater Than or Equal to Grade 3 Non-hematologic Toxicity | Greater than equal Gr.4 hematologic toxicites | 23 participants |
| Bevacizumab, XRT, Temozolomide, Topotecan | Number of Patients Experiencing a Greater Than or Equal to Grade 4 Hematologic or a Greater Than or Equal to Grade 3 Non-hematologic Toxicity | Greater than equal Gr.3 non-hematologic toxicites | 17 participants |
Secondary
One and Two Year Overall Survival
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.
Time frame: One year and two years
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab, XRT, Temozolomide, Topotecan | One and Two Year Overall Survival | One year Overall Survival | 73.8 percentage of participants |
| Bevacizumab, XRT, Temozolomide, Topotecan | One and Two Year Overall Survival | Two year Overall Survival | 35.6 percentage of participants |