Brain and Central Nervous System Tumors
Conditions
Keywords
brain tumor
Brief summary
Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving bortezomib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bortezomib together with temozolomide after surgery may kill any tumor cells that remain after surgery. This phase II trial is studying how well giving bortezomib before surgery followed by giving bortezomib together with temozolomide after surgery works in treating patients with recurrent malignant glioma.
Detailed description
Patients receive bortezomib IV on days 1, 4, and 8. Patients then undergo surgical resection of the tumor on day 8 or 9. Beginning approximately 14 days after surgery, patients receive oral temozolomide on days 1-7 and 14-21 and bortezomib IV on days 7 and 21. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Tumor tissue and blood samples are collected periodically for biomarker analysis, gene methylation studies, and pharmacokinetic studies. After completion of study therapy, patients are followed up every 3 months for 2 years.
Interventions
DRUGBortezomib
Before surgery, an injection of bortezomib is given on days 1, 4, and 8. After surgery, bortezomib is given on days 7 and 21 of each cycle (1 cycle = 28 days).
DRUGTemozolomide
After surgery, temozolomide is taken by mouth on days 1-7 and 14-21 of each cycle (1 cycle = 28 days).
Sponsors
Millennium Pharmaceuticals, Inc.
Northwestern 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
* Histologically confirmed malignant glioma, including any of the following subtypes: * Glioblastoma multiforme * Gliosarcoma * Anaplastic astrocytoma * Anaplastic oligodendroglioma * Anaplastic mixed oligoastrocytoma * Malignant astrocytoma not otherwise specified * Must show unequivocal evidence of tumor recurrence or progression by MRI or CT scan with contrast * Candidate for surgery AND requires surgery * Evaluable or measurable disease following resection of recurrent tumor is not required * Failed prior standard radiotherapy and temozolomide * Patients who have undergone stereotactic radiosurgery must have confirmation of true progressive disease (rather than radiation necrosis) by PET scan, magnetic resonance spectroscopy (MRS), or magnetic resonance perfusion (MRP) prior to surgery * Patients with lower-grade gliomas that have undergone radiographic malignant transformation allowed provided they failed radiotherapy (with or without temozolomide) and require surgery * Life expectancy \> 12 weeks
Exclusion criteria
* Not pregnant or nursing * Negative pregnancy test * No other medical issues (e.g., bleeding, infection, HIV, or serious medical or psychiatric illness) that would preclude study therapy * Myocardial infarction within the past 6 months * No other active cancer(s) except non-melanoma skin cancer or carcinoma in situ of the cervix, unless in complete remission and off of all therapy for that cancer for ≥ 3 years * No hypersensitivity to bortezomib, boron, or mannitol * More than 4 weeks since prior radiotherapy * At least 4 weeks since prior cytotoxic therapy (6 weeks for nitrosoureas) * At least 3 weeks since prior investigational drugs * At least 2 weeks since prior enzyme-inducing anticonvulsants * Concurrent non-enzyme-inducing anticonvulsants allowed * No other concurrent standard or investigational anticancer treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Surviving Without Disease Progression After 6 Months | From date of first treatment until disease progression, death, or early discontinuation of treatment (up to 24 months) | Patients will be monitored from date of first treatment to the date of first observation of progressive disease, non-reversible neurologic progression or increasing steroid requirements, death due to any cause, or early discontinuation of treatment. Progression-free survival will be defined as the absence of any of the above after 6 months. Progression (defined by MacDonald Criteria) is a 25% increase in the sum of products of all measurable lesions over smallest sum observed compared to baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to the cancer). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0) | Days 1, 4, 8 pre-surgery, and then at the start of every cycle (approximately every 4 weeks) post-surgery while on treatment | Adverse events (AEs) were graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. In general, AEs are graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE |
| Number of Participants Achieving a Response to Treatment (Either Complete or Partial Response) as Defined by MacDonald Criteria | Day of treatment post-surgery and then approximately every 8 weeks thereafter until off treatment | This measure was assessed only in patients who had residual tumor post-operatively. Per MacDonald Criteria: Complete Response requires complete disappearance of all measurable & evaluable disease, no new lesions, no evidence of non-evaluable disease, and only minimal or no use of steroids. Partial Response is defined as \>= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions, no progression of evaluable disease, and no new lesions. Responders must be on the same or decreasing doses of steroid. Response was assessed by imaging (MRI or CT with contrast). |
| Overall Survival (in Days) | Days 1, 4, 8 pre-surgery, once per cycle (every 4 weeks) while on treatment post-surgery, and then every 3 months up to 2 years during follow-up | — |
| Overall Survival Rate at 6 Months | After 6 months on study | The rate of overall survival at 6 months (regardless of disease progression) was calculated. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Bortezomib in Tumor Tissue Taken at the Time of Surgery. | Tissue sample taken at the time of surgery for all patients. | — |
| Change in MGMT Methylation Status as Well as Other Methylation Patterns in Plasma | Blood samples drawn on days 1, 4, and 8 pre-surgery, and then prior to cycle 1 and every 2 cycles thereafter | To determine MGMT methylation status as well as other methylation patterns in plasma |
| Correlation of Expression of NFKBIA Gene With Response to Therapy and Survival. | Tissue samples for analysis were obtained on the day of surgery for all patients | The effects of bortezomib on the endogenous modulators of NF-Kappa B pathways, especially the NFKBIA gene (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) were assessed using novel assay technology; expression of NFKBIA was then correlated with response to therapy and patient survival. |
Countries
United States
Participant flow
Recruitment details
The study opened on May 21, 2009 with an accrual goal of 29 patients; the study was designed to enroll 10 patients initially and do an interim efficacy assessment. Accrual was suspended on February 11, 2011 for this analysis. The interim results did not support further accrual, and so the study was permanently closed to accrual on March 29, 2011.
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib + Temozolomide Patients receive an injection of bortezomib 1.7mg/m\^2 on days 1, 4 and 8. Patients then undergo their standard of care surgery on day 8 or 9 to remove the tumor. Once recovered from surgery (approximately 14 days later), patients receive combination treatment with temozolomide and bortezomib in periods called cycles (1 cycle = 4 weeks or 28 days). Temozolomide (75 mg/m\^2) is taken by mouth on days 1-7 and 14-21 of each cycle, and bortezomib (1.3 mg/m\^2) is given intravenously (IV) on days 7 and 21 of each cycle. Patients continue to receive cycles of treatment until disease progression, development of unacceptable toxicity, or up to a maximum of 24 months. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Post-sugery Bortezomib + Temozolomide | Withdrawal by Subject | 1 |
| Pre-surgical Bortezomib | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Bortezomib + Temozolomide |
|---|---|
| Age, Customized 21-30 years | 0 participants |
| Age, Customized 31-40 years | 0 participants |
| Age, Customized 41-50 years | 6 participants |
| Age, Customized 51-60 years | 2 participants |
| Age, Customized 61-70 years | 2 participants |
| Age, Customized 71-80 years | 0 participants |
| Age, Customized 81-90 years | 0 participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 3 / 10 |
Outcome results
Primary
Number of Patients Surviving Without Disease Progression After 6 Months
Patients will be monitored from date of first treatment to the date of first observation of progressive disease, non-reversible neurologic progression or increasing steroid requirements, death due to any cause, or early discontinuation of treatment. Progression-free survival will be defined as the absence of any of the above after 6 months. Progression (defined by MacDonald Criteria) is a 25% increase in the sum of products of all measurable lesions over smallest sum observed compared to baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to the cancer).
Time frame: From date of first treatment until disease progression, death, or early discontinuation of treatment (up to 24 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib + Temozolomide | Number of Patients Surviving Without Disease Progression After 6 Months | 0 participants |
Secondary
Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0)
Adverse events (AEs) were graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. In general, AEs are graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Time frame: Days 1, 4, 8 pre-surgery, and then at the start of every cycle (approximately every 4 weeks) post-surgery while on treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bortezomib + Temozolomide | Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0) | Grade 1 | 80 adverse events |
| Bortezomib + Temozolomide | Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0) | Grade 2 | 30 adverse events |
| Bortezomib + Temozolomide | Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0) | Grade 3 | 11 adverse events |
| Bortezomib + Temozolomide | Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0) | Grade 4 | 1 adverse events |
| Bortezomib + Temozolomide | Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0) | Grade 5 | 0 adverse events |
Secondary
Number of Participants Achieving a Response to Treatment (Either Complete or Partial Response) as Defined by MacDonald Criteria
This measure was assessed only in patients who had residual tumor post-operatively. Per MacDonald Criteria: Complete Response requires complete disappearance of all measurable & evaluable disease, no new lesions, no evidence of non-evaluable disease, and only minimal or no use of steroids. Partial Response is defined as \>= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions, no progression of evaluable disease, and no new lesions. Responders must be on the same or decreasing doses of steroid. Response was assessed by imaging (MRI or CT with contrast).
Time frame: Day of treatment post-surgery and then approximately every 8 weeks thereafter until off treatment
Population: Only those participants who had residual tumor remaining after surgical resection were evaluated for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib + Temozolomide | Number of Participants Achieving a Response to Treatment (Either Complete or Partial Response) as Defined by MacDonald Criteria | 0 participants |
Secondary
Overall Survival (in Days)
Time frame: Days 1, 4, 8 pre-surgery, once per cycle (every 4 weeks) while on treatment post-surgery, and then every 3 months up to 2 years during follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib + Temozolomide | Overall Survival (in Days) | 248 days |
Secondary
Overall Survival Rate at 6 Months
The rate of overall survival at 6 months (regardless of disease progression) was calculated.
Time frame: After 6 months on study
Population: The 6-month overall survival rate was based on a median of 168 days of follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib + Temozolomide | Overall Survival Rate at 6 Months | 69 percentage of participants |
Other Pre-specified
Change in MGMT Methylation Status as Well as Other Methylation Patterns in Plasma
To determine MGMT methylation status as well as other methylation patterns in plasma
Time frame: Blood samples drawn on days 1, 4, and 8 pre-surgery, and then prior to cycle 1 and every 2 cycles thereafter
Other Pre-specified
Correlation of Expression of NFKBIA Gene With Response to Therapy and Survival.
The effects of bortezomib on the endogenous modulators of NF-Kappa B pathways, especially the NFKBIA gene (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) were assessed using novel assay technology; expression of NFKBIA was then correlated with response to therapy and patient survival.
Time frame: Tissue samples for analysis were obtained on the day of surgery for all patients
Other Pre-specified
Pharmacokinetics of Bortezomib in Tumor Tissue Taken at the Time of Surgery.
Time frame: Tissue sample taken at the time of surgery for all patients.