Brain and Central Nervous System Tumors
Conditions
Keywords
adult giant cell glioblastoma, adult gliosarcoma, adult glioblastoma
Brief summary
RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x-rays to kill tumor cells. Giving bevacizumab together with temozolomide and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and how well giving bevacizumab together with temozolomide and external beam radiation therapy works when given as first-line therapy in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma.
Detailed description
OBJECTIVES: Primary * To investigate the safety and tolerability of bevacizumab in combination with temozolomide and external beam fractionated regional radiotherapy as first-line treatment in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. (Pilot phase) * To estimate the overall survival of patients treated with this regimen. (Expansion phase) Secondary * To further investigate the safety and tolerability of this regimen in these patients. (Expansion phase) * To isolate DNA, RNA, and protein from frozen and paraffin-embedded archival tumor samples for evaluations, such as immunohistochemical pathway profiling of vascular endothelial growth factor (VEGF)-dependent angiogenic pathways, gene expression microarray, and O-6 methylguanine DNA methyltransferase (MGMT) promoter methylation status to define important molecular features of treatment response. OUTLINE: This is a multicenter study. Patients undergo external beam fractionated regional radiotherapy once daily 5 days a week for 6 weeks and receive concurrent oral temozolomide once daily for 6 weeks. Patients also receive bevacizumab IV over 30-90 minutes every 2 weeks beginning on the first day of radiotherapy and continuing in the absence of disease progression or unacceptable toxicity. Beginning 2-5 weeks after completion of radiotherapy, patients receive oral temozolomide on days 1-5. Treatment with temozolomide repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Blood and frozen and paraffin-embedded tumor tissue samples are collected for biomarker and genetic analysis. After completion of study treatment, patients are followed up periodically.
Interventions
BIOLOGICALbevacizumab
DRUGtemozolomide
RADIATIONexternal beam radiation therapy
Sponsors
Jonsson Comprehensive Cancer Center
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
* Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma. * Prior histologic diagnosis of low-grade glioma allowed provided it has been upgraded to GBM after repeat resection * Has undergone surgery to collect tumor tissue 3-6 weeks ago * Measurable or assessable disease is not required * Karnofsky performance status 60-100% * Life expectancy \> 8 weeks * White Blood Cell (WBC) ≥ 3,000/mm³ * Absolute Neutrophil Count (ANC) ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 10 g/dL (transfusion allowed) * Serum Glutamate Oxaloacetate Transaminase (SGOT) \< 2.5 times upper limit of normal (ULN) * Bilirubin \< 2.5 times ULN * INR (international normalized ratio) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy) * aPTT (activated partial thromboplastin time) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy) * Creatinine \< 1.5 mg/dL * Urine protein:creatinine ratio \< 1.0 * Negative pregnancy test * Fertile patients must use effective contraception * More than 28 days since prior major surgical procedures or open biopsy (other than craniotomy) * More than 7 days since prior minor surgical procedures (e.g., placement of PortoCath (port-a-cath - a port placed under the subjects skin), stereotactic biopsy, fine-needle aspirations, or core biopsies) * More than 4 weeks since prior and no concurrent participation in another experimental drug study. * Prior or concurrent corticosteroids, anti-epileptic drugs, analgesics, or other drugs to treat symptoms or prevent complications are allowed * Concurrent full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin) allowed
Exclusion criteria
* unstable angina * BP \> 150/100 mm Hg * New York Heart Association (NYHA) class II-IV congestive heart failure * myocardial infarction within the past 6 months * stroke within the past 6 months * clinically significant peripheral vascular disease * evidence of bleeding diathesis or coagulopathy * intracerebral abscess within past 6 months * abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months * serious, non-healing wound, ulcer, or bone fracture * Any wound requiring surgical intervention (including scalp wounds requiring cranioplasty) allowed provided the wound is clean and without further infection post-surgical intervention * significant traumatic injury within the past 28 days * concurrent serious uncontrolled medical illness including, but not limited to, the following: * Ongoing or active infection requiring IV antibiotics * Psychiatric illness/social situation that would limit compliance with study requirements * Disorders associated with significant immunocompromised state (e.g., HIV, systemic lupus erythematosus) * other cancer within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the cervix * disease that would obscure toxicity or dangerously alter drug metabolism * significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate study therapy * prior radiotherapy to the brain * prior cytotoxic or non-cytotoxic drug therapy or experimental drug therapy for the brain tumor * prior Gliadel wafers * concurrent participation in any other clinical trial * concurrent GM-CSF (granulocyte-macrophage colony-stimulating factor) * concurrent stereotactic radiosurgery or brachytherapy * concurrent major surgical procedure * other concurrent anticancer therapy, including chemotherapy, hormonal therapy, radiotherapy, or immunotherapy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Overall Survival | 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | 2 years | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Progression-free Survival at 6 Months | 6 months | participants who were alive and disease progression free at 6 months |
| Radiographic Response (When Evaluable) | 2 years | Radiation therapy (RT) median from diagnosis to RT. Patients will have brain MRI evaluation of response and progression every 8 weeks starting from the day 56 scan obtained 2 weeks after completion of radiation and daily temozolomide and assessment will be conducted on a 7-point scale. This scale is expected to be more useful in this study because many newly-diagnosed patients are likely not to have evaluable disease due to gross total resections. Determination of whether progression occurs based on the day 56 scan will take into account the untreated window between baseline MRI and day of 1 of study. 7 Point Likert Scale: 3 to -3, 3 means complete resolution of tumor, and -3 means new lesion. A -2 or -3 assessment will be taken as tumor progression. complete resolution of tumor: 3 tumor resolved 3 tumor definitely smaller: 2 tumor probably smaller: 1 tumor unchanged: 0 tumor probably worse: -1 tumor definitely worse: -2 New Lesion: -3 |
| Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status | 2 years | IDH1 and MGMT methylation are important independent prognostic biomarkers that have to be included in a Cox regression model. In addition, subgroup analysis could reveal differential sensitivities to the treatment arm. The MGMT promoter methylation status, IDH1 mutation status were not available for all of the control samples. Therefore, only the samples with both info available were included in the analysis. Baseline analysis results are included in the Baseline Characteristics module. |
Countries
United States
Participant flow
Recruitment details
Seventy patients with newly diagnosed Glioblastoma Multiforme were enrolled between August 2006 and November 2008 from two participating sites, comprised of University of California, Los Angeles (UCLA) and Kaiser Permanente Los Angeles.
Pre-assignment details
Control cohort was derived from University of California, Los Angeles/Kaiser Permanente Los Angeles patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm bevacizumab
temozolomide
external beam radiation therapy | 70 |
| Historical Control UCLA/Kaiser A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison. Data excluded where records not complete | 110 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 48 | 89 |
Baseline characteristics
| Characteristic | Treatment Arm | Total | Historical Control UCLA/Kaiser |
|---|---|---|---|
| Age, Continuous | 57.4 years | 59.305 years | 59.4 years |
| Age, Customized < 50 years | 15 participants | 45 participants | 30 participants |
| Age, Customized >= 50 years | 55 participants | 135 participants | 80 participants |
| Deaths | 48 participants | 137 participants | 89 participants |
| Enrollment by Site KPLA | 32 participants | 81 participants | 49 participants |
| Enrollment by Site UCLA | 38 participants | 99 participants | 61 participants |
| Extent of surgery Biopsy | 2 participants | 25 participants | 23 participants |
| Extent of surgery Gross total resection | 28 participants | 75 participants | 47 participants |
| Extent of surgery Subtotal resection | 40 participants | 80 participants | 40 participants |
| Follow-up | 24.2 years | 36.616 years | 41.8 years |
| IDH1 (Isocitrate dehydrogenase 1 ) mutational status IDH1-R132H mutation | 5 participants | 8 participants | 3 participants |
| IDH1 (Isocitrate dehydrogenase 1 ) mutational status Wild type | 65 participants | 133 participants | 68 participants |
| Karnofsky performance status 100 | 8 participants | 21 participants | 13 participants |
| Karnofsky performance status 60 | 3 participants | 7 participants | 4 participants |
| Karnofsky performance status 70 | 5 participants | 13 participants | 8 participants |
| Karnofsky performance status 80 | 27 participants | 50 participants | 23 participants |
| Karnofsky performance status 90 | 27 participants | 89 participants | 62 participants |
| MGMT (O-6-Methylguanine-DNA Methyltransferase) promoter methylation Methylated | 29 participants | 57 participants | 28 participants |
| MGMT (O-6-Methylguanine-DNA Methyltransferase) promoter methylation Unmethylated | 41 participants | 84 participants | 43 participants |
| Recurrent treatment Progressed | 56 participants | 152 participants | 96 participants |
| Recurrent treatment Progressed with bevacizumab | 29 participants | 86 participants | 57 participants |
| Recurrent treatment Progressed with chemotherapy | 39 participants | 103 participants | 64 participants |
| Recursive partitioning analysis by class III: MST 17.1 | 9 participants | 36 participants | 27 participants |
| Recursive partitioning analysis by class IV: MST 11.2 | 32 participants | 77 participants | 45 participants |
| Recursive partitioning analysis by class VI: MST 7.5 | 0 participants | 1 participants | 1 participants |
| Recursive partitioning analysis by class V: MST 7.5 | 29 participants | 66 participants | 37 participants |
| Sex: Female, Male Female | 31 Participants | 71 Participants | 40 Participants |
| Sex: Female, Male Male | 39 Participants | 109 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 70 |
| serious Total, serious adverse events | 54 / 70 |
Outcome results
Primary
Overall Survival
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Overall Survival | 19.6 Months |
| Historical Control UCLA/KPLA | Overall Survival | 21.1 Months |
Secondary
Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status
IDH1 and MGMT methylation are important independent prognostic biomarkers that have to be included in a Cox regression model. In addition, subgroup analysis could reveal differential sensitivities to the treatment arm. The MGMT promoter methylation status, IDH1 mutation status were not available for all of the control samples. Therefore, only the samples with both info available were included in the analysis. Baseline analysis results are included in the Baseline Characteristics module.
Time frame: 2 years
Population: Description: Kaplan-Meier analysis of overall survival was performed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment Arm | Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status | Median Overall survival of MGMT Unmethylated | 15.9 months |
| Treatment Arm | Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status | Median Overall survival of MGMT Methylated | 24.7 months |
| Historical Control UCLA/KPLA | Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status | Median Overall survival of MGMT Methylated | 26.7 months |
| Historical Control UCLA/KPLA | Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status | Median Overall survival of MGMT Unmethylated | 18.2 months |
Secondary
Progression-free Survival at 6 Months
participants who were alive and disease progression free at 6 months
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm | Progression-free Survival at 6 Months | 88.4 percentage of participants |
| Historical Control UCLA/KPLA | Progression-free Survival at 6 Months | 58.3 percentage of participants |
Secondary
Radiographic Response (When Evaluable)
Radiation therapy (RT) median from diagnosis to RT. Patients will have brain MRI evaluation of response and progression every 8 weeks starting from the day 56 scan obtained 2 weeks after completion of radiation and daily temozolomide and assessment will be conducted on a 7-point scale. This scale is expected to be more useful in this study because many newly-diagnosed patients are likely not to have evaluable disease due to gross total resections. Determination of whether progression occurs based on the day 56 scan will take into account the untreated window between baseline MRI and day of 1 of study. 7 Point Likert Scale: 3 to -3, 3 means complete resolution of tumor, and -3 means new lesion. A -2 or -3 assessment will be taken as tumor progression. complete resolution of tumor: 3 tumor resolved 3 tumor definitely smaller: 2 tumor probably smaller: 1 tumor unchanged: 0 tumor probably worse: -1 tumor definitely worse: -2 New Lesion: -3
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Radiographic Response (When Evaluable) | 4.14 Weeks |
| Historical Control UCLA/KPLA | Radiographic Response (When Evaluable) | 5 Weeks |
Secondary
Time to Disease Progression
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Time to Disease Progression | 13.6 Months |
| Historical Control UCLA/KPLA | Time to Disease Progression | 7.6 Months |