Glioblastoma Multiforme, Gliosarcoma
Conditions
Keywords
malignant glioma, glioblastoma multiforme, gliosarcoma, Avastin, bevacizumab, Temodar, temozolomide, Irinotecan, CPT-11, Pro00019065, Vredenburgh, Duke
Brief summary
The primary objective of the study is to determine the efficacy of Avastin in combination with temozolomide and irinotecan in terms of response rate. The secondary objectives are to describe the overall and progression-free survivals of unresectable patients treated with upfront Avastin, temozolomide and irinotecan and to assess the safety of Avastin, temozolomide and irinotecan in unresectable glioblastoma patients. This is a phase II study with the combination of Avastin, temozolomide and irinotecan for unresectable or multifocal World Health Organization (WHO) grade IV malignant glioma patients. Patients will receive up to four cycles of Avastin, temozolomide and irinotecan. Approximately 41 subjects will take part in this study at Duke.
Interventions
DRUGAvastin
Avastin, by intravenous infusion, 10 mg/kg every 14 days
DRUGTemozolomide
Oral temozolomide at 200 mg/m2 daily for 5 days
DRUGIrinotecan
Irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Sponsors
Genentech, Inc.
Katy Peters
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 will be unresectable or have multifocal disease. * Age \> or = to 18 years and a life expectancy of \>12 weeks. * Evidence of measurable primary Central Nervous System (CNS) neoplasm on contrast enhanced MRI. * An interval of at least one week between prior biopsy or four weeks from surgical resection and enrollment on this protocol. * Karnofsky \> or = to 60%. * Hemoglobin \> or = to 9g/dl, absolute neutrophil count (ANC) \> or = to 1,500 cells/microliter, platelets \> or = to 125,000 cells/microliter. * Serum creatinine ≤ 1.5 mg/dl, serum serum glutamic oxaloacetic transaminase (SGOT) and direct bilirubin ≤ 1.5 times upper limit of normal (if the total bilirubin is greater than or equal to 1.5 x the upper limit of normal, then the direct bilirubin must be ≤ 1.5 x the upper limit of normal). * Signed informed consent approved by the Institutional Review Board prior to patient entry. * If sexually active, patients will take contraceptive measures for the duration of the treatments.
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. * Treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor. * Evidence of \> grade 1 CNS hemorrhage on baseline MRI or CT scan. Avastin-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | 4 months | The percentage of participants with a complete or partial response as determined by a modification of the Response Assessment in Neuro-Oncology (RANO) criteria. Complete Response (CR) was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Per the criteria, confirmation of response was required. Response rate = CR+PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Central Nervous System (CNS) Hemorrhage and Systemic Hemorrhage | 4 months | Incidence and severity of CNS hemorrhage and systemic hemorrhage- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov. |
| Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities | 4 months | Incidence of treatment-related, grade ≥ 4 hematologic and ≥ grade 3 non-hematologic toxicities- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov. |
| Median Progression-free Survival (PFS) | 36 months | Time in months from the start of study treatment to the date of first progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, worsening T2/FLAIR, any new lesion, or clinical deterioration. 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) | 36 months | Time in months from the start of study treatment to the 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Avastin in Combination With Temozolomide and Irinotecan Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2.
Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism) | 41 |
| Total | 41 |
Baseline characteristics
| Characteristic | Avastin in Combination With Temozolomide and Irinotecan |
|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 41 |
| serious Total, serious adverse events | 18 / 41 |
Outcome results
Primary
Response Rate
The percentage of participants with a complete or partial response as determined by a modification of the Response Assessment in Neuro-Oncology (RANO) criteria. Complete Response (CR) was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Per the criteria, confirmation of response was required. Response rate = CR+PR.
Time frame: 4 months
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avastin in Combination With Temozolomide and Irinotecan | Response Rate | 22 percentage of participants |
Secondary
Incidence and Severity of Central Nervous System (CNS) Hemorrhage and Systemic Hemorrhage
Incidence and severity of CNS hemorrhage and systemic hemorrhage- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.
Time frame: 4 months
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Avastin in Combination With Temozolomide and Irinotecan | Incidence and Severity of Central Nervous System (CNS) Hemorrhage and Systemic Hemorrhage | Systemic hemorrhage (all grade 3) | 3 participants |
| Avastin in Combination With Temozolomide and Irinotecan | Incidence and Severity of Central Nervous System (CNS) Hemorrhage and Systemic Hemorrhage | CNS hemorrhage (grade 3) | 1 participants |
Secondary
Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities
Incidence of treatment-related, grade ≥ 4 hematologic and ≥ grade 3 non-hematologic toxicities- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.
Time frame: 4 months
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Avastin in Combination With Temozolomide and Irinotecan | Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities | Grade > or = to 4 hematologic toxicity | 7 participants |
| Avastin in Combination With Temozolomide and Irinotecan | Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities | Grade > or = to 3 non-hematologic toxicity | 17 participants |
Secondary
Median Overall Survival (OS)
Time in months from the start of study treatment to the 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: 36 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avastin in Combination With Temozolomide and Irinotecan | Median Overall Survival (OS) | 12 months |
Secondary
Median Progression-free Survival (PFS)
Time in months from the start of study treatment to the date of first progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, worsening T2/FLAIR, any new lesion, or clinical deterioration. 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: 36 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avastin in Combination With Temozolomide and Irinotecan | Median Progression-free Survival (PFS) | 8.6 months |