Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
Brief summary
This phase II trial is studying how well giving vorinostat together with bortezomib works in treating patients with progressive, recurrent glioblastoma multiforme. Vorinostat and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with bortezomib may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. To determine the clinical efficacy of vorinostat (SAHA) and bortezomib, in terms of progression-free survival (PFS) at 6 months, in patients with progressive, recurrent glioblastoma multiforme. SECONDARY OBJECTIVES: I. To determine the clinical efficacy of this regimen, in terms of overall survival, PFS at 12 months, time to progression, and objective response rate, in these patients. II. To identify molecular predictors of response in baseline tumor specimens from these patients. III. To determine molecular changes in response to this regimen in tumor specimens from patients undergoing surgery. OUTLINE: This is a multicenter study. Patients are stratified according to planned surgery (no \[stratum 1\] vs yes \[stratum 2\]). STRATUM 1 (NOT UNDERGOING SURGERY): Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib intravenously (IV) on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. STRATUM 2 (UNDERGOING SURGERY): Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1. Tumor tissue samples are collected at baseline and during surgery (stratum 2) for correlative laboratory studies. Tissue samples are analyzed for baseline total and phosphorylated AKT and p27\^KIp1 expression by IHC. Tissue samples from patients in stratum 2 are also analyzed for histone acetylation status; markers of proteasome inhibition; total and phosphorylated Bax expression by IHC; and gene expression profiles. After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months thereafter.
Interventions
DRUGvorinostat
Given orally
PROCEDUREtherapeutic conventional surgery
Patient undergoes surgery
DRUGbortezomib
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed glioblastoma multiforme * Gliosarcoma or other grade 4 astrocytoma variant (e.g., giant cell glioblastoma) allowed * Recurrent disease * Must have evidence of tumor progression by MRI or CT scan after radiotherapy or after the most recent antitumor therapy * Bidimensionally measurable or evaluable disease by MRI or CT scan * Patients receiving corticosteroids must be on a fixed dose for at least 1 week prior to baseline scan * ECOG performance status 0-2 * WBC ≥ 3,000/mm³ * ANC ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 9 g/dL * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * AST ≤ 3 times ULN * Creatinine normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 6 months after the last dose of vorinostat * Willing to provide mandatory correlative laboratory tissue samples * Able to take oral medications * No uncontrolled infection * No known hypersensitivity to any of the components of vorinostat or bortezomib * No myocardial infarction or unstable angina within the past 6 months * No congestive heart failure requiring use of ongoing maintenance therapy or history of life-threatening ventricular arrhythmias * No concurrent uncontrolled illness including, but not limited to, any of the following: * Ongoing or active infection * Psychiatric illness or social situation that would limit compliance with study requirements * No other active malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the cervix * No comorbid systemic illness or other severe concurrent disease that, in the judgment of the investigator, would preclude study entry or significantly interfere with proper assessment of safety and toxicity of the prescribed study regimens * Not immunocompromised * Patients known to be HIV positive are eligible provided there is no clinical evidence of an immunocompromised state * No peripheral neuropathy ≥ grade 2 * No peripheral neuropathy with pain ≥ grade 1 * No congenital long QT syndrome * No prolonged OTC interval (\> 450 msec) * No other concurrent anticancer therapy (other than hormonal therapy) * At least 8 weeks since prior radiotherapy * More than 6 weeks since prior stereotactic radiosurgery or interstitial brachytherapy, unless there is a separate lesion on MRI that is not part of the prior treatment field * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) * No more than 1 prior chemotherapy regimen\* for progressive/recurrent disease (stratum 1) * Patients in stratum 2 may have received any number of prior chemotherapy regimens\* for progressive/recurrent disease * More than 2 weeks since prior small molecule cell cycle inhibitors * More than 7 days since prior valproic acid * More than 7 days since prior category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: * Quinidine, procainamide, disopyramide * Amiodarone, sotalol, ibutilide, dofetilide * Erythromycin, clarithromycin * Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide * Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin,lidoflazine * More than 4 weeks since prior bevacizumab * No prior treatment with vorinostat or bortezomib * No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin,fosphenytoin, carbamazepine, phenobarbital, or primidone) * No other concurrent potent CYP3A4 inducer (e.g., rifampin or St. John's wort) * No other concurrent investigational therapy for the primary neoplasm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival at 6 Months | At 6 months | Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. For patients with bidimensionally measurable disease (measurable disease), progression is defined as \> 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients without bidimensionally measurable disease (evaluable disease), progression is defined as unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From study registration to date of death due to any cause or last follow-up (up to 5 years) | Estimated using Kaplan-Meier survival curve. |
| Time to Progression | From study registration to date of progression (up to 5 years) | Estimated using Kaplan-Meier survival curve. Patients who died were considered to have disease progression at the time of death unless there was documented evidence that no progression occurred before death. For patients with bidimensionally measurable disease (measurable disease), progression is defined as \> 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients without bidimensionally measurable disease (evaluable disease), progression is defined as unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions. |
| Proportion of Confirmed Tumor Response Defined as an Objective Status of Confirmed Response (CR), Partial Response (PR), or Regression (REGR) on Two Consecutive Evaluations | Assessed up to 5 years | Confidence intervals for the true proportion will be calculated using the exact binomial method. Measurable patients must achieve at least a 50% reduction in the product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. Evaluable patients must achieve unequivocal reduction in size of contrast-enhancement or decrease in mass effect as agreed upon independently by primary physician and quality control physicians; no new lesions. Patient should be on stable or decreased steroid dose. |
Countries
United States
Participant flow
Recruitment details
45 patients were enrolled from 28 medical clinics between July 4, 2008 and February 16, 2010.
Pre-assignment details
One patient cancelled prior to treatment initiation and is excluded in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Not Undergoing Surgery) Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
bortezomib : Given IV
vorinostat : Given orally | 37 |
| Arm B (Undergoing Surgery) Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.
surgery : Patient undergoes therapeutic conventional surgery
bortezomib : Given IV
vorinostat : Given orally | 7 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Clinical Decline | 1 | 0 |
| Overall Study | Lead Investigator Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | Arm A (Not Undergoing Surgery) | Arm B (Undergoing Surgery) | Total |
|---|---|---|---|
| Age, Continuous | 52 years | 51 years | 52 years |
| Region of Enrollment United States | 37 participants | 7 participants | 44 participants |
| Sex: Female, Male Female | 10 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Male | 27 Participants | 6 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 37 | 7 / 7 |
| serious Total, serious adverse events | 18 / 37 | 0 / 7 |
Outcome results
Primary
Progression-free Survival at 6 Months
Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. For patients with bidimensionally measurable disease (measurable disease), progression is defined as \> 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients without bidimensionally measurable disease (evaluable disease), progression is defined as unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.
Time frame: At 6 months
Population: Patients that started treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Not Undergoing Surgery) | Progression-free Survival at 6 Months | 0 percentage of patients |
| Arm B (Undergoing Surgery) | Progression-free Survival at 6 Months | 29 percentage of patients |
Secondary
Overall Survival
Estimated using Kaplan-Meier survival curve.
Time frame: From study registration to date of death due to any cause or last follow-up (up to 5 years)
Population: Patients that started treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Not Undergoing Surgery) | Overall Survival | 3.2 months |
| Arm B (Undergoing Surgery) | Overall Survival | 8.7 months |
Secondary
Proportion of Confirmed Tumor Response Defined as an Objective Status of Confirmed Response (CR), Partial Response (PR), or Regression (REGR) on Two Consecutive Evaluations
Confidence intervals for the true proportion will be calculated using the exact binomial method. Measurable patients must achieve at least a 50% reduction in the product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. Evaluable patients must achieve unequivocal reduction in size of contrast-enhancement or decrease in mass effect as agreed upon independently by primary physician and quality control physicians; no new lesions. Patient should be on stable or decreased steroid dose.
Time frame: Assessed up to 5 years
Population: Arm A patients that started treatment. Arm B patients were not analyzed for this outcome because they received surgery and hence response was not measured.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Not Undergoing Surgery) | Proportion of Confirmed Tumor Response Defined as an Objective Status of Confirmed Response (CR), Partial Response (PR), or Regression (REGR) on Two Consecutive Evaluations | 0.027 proportion of patients |
Secondary
Time to Progression
Estimated using Kaplan-Meier survival curve. Patients who died were considered to have disease progression at the time of death unless there was documented evidence that no progression occurred before death. For patients with bidimensionally measurable disease (measurable disease), progression is defined as \> 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients without bidimensionally measurable disease (evaluable disease), progression is defined as unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.
Time frame: From study registration to date of progression (up to 5 years)
Population: Patients that started treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Not Undergoing Surgery) | Time to Progression | 1.5 months |
| Arm B (Undergoing Surgery) | Time to Progression | 4.2 months |