Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
Brief summary
This phase II trial is studying how well vorinostat works in treating patients with progressive or recurrent glioblastoma multiforme. Drugs used in chemotherapy, such as vorinostat, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vorinostat before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving it after surgery may kill any remaining tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. Determine the efficacy of vorinostat (SAHA), in terms of 6-month progression-free survival, in patients with progressive or recurrent glioblastoma multiforme. II. Determine the safety and toxicity of this drug in these patients. SECONDARY OBJECTIVES: I. Determine the pharmacokinetics of this drug in these patients. II. Determine the biologic effect of this drug in target tissues, including primary tumor tissue, in these patients. III. Correlate genetic alteration of tumors with response in patients treated with this drug. OUTLINE: This is an open-label, multicenter study. Patients are stratified according to planned surgery (yes \[stratum 1\] vs no \[stratum 2\]) and number of prior chemotherapy regimens for progressive/recurrent disease (≤ 1 \[stratum 1A\] vs ≥ 2 \[stratum 1B\]). STRATUM 1: Patients receive oral vorinostat (SAHA) twice daily for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. (not undergoing surgery) STRATUM 2: Beginning 3 days prior to surgery, patients receive oral SAHA once or twice daily for a total of 6 doses. Patients then undergo surgery to remove the tumor. Beginning within 1-4 weeks after surgery, patients receive oral SAHA twice daily for 2 weeks. (undergoing surgery) Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 5 years.
Interventions
DRUGvorinostat
Given orally
PROCEDUREconventional surgery
Patients undergo surgery to remove tumor
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
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 grade 4 astrocytoma (glioblastoma multiforme), including gliosarcoma, at primary diagnosis or recurrence * Progressive or recurrent disease * Measurable or evaluable disease by MRI or CT scan * Performance status - ECOG 0-2 * WBC ≥ 3,000/mm\^3 * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 8 g/dL * AST ≤ 3 times upper limit of normal (ULN) * Bilirubin normal * Creatinine ≤ 1.5 times ULN * No myocardial infarction within the past 6 months * No congestive heart failure * No life-threatening ventricular arrhythmia requiring ongoing maintenance therapy * No known HIV positivity * Not immunocompromised except if related to the use of corticosteroids * No known hypersensitivity to any of the components of the study drug * No uncontrolled infection * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 6 months after completion of study treatment * No other malignancy * No other severe disease that would preclude study participation * Prior adjuvant chemotherapy allowed * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) * More than 2 weeks since prior small molecule cell cycle inhibitor * Concurrent corticosteroids allowed as long as dose has been stable for ≥ 1 week * At least 8 weeks since prior radiotherapy * Must have evidence of tumor progression by MRI or CT scan after radiotherapy * More than 6 weeks since prior stereotactic radiosurgery or interstitial brachytherapy, unless 1 of the following criteria is met: * There is a separate lesion by MRI outside of the prior treatment field * There is evidence of recurrent disease by biopsy, MRI spectroscopy, or positron-emission tomography scan * More than 2 weeks since prior valproic acid
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Successes (Patients Alive and Progression-free) | At 6 months | Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients) and the Binomial 95% confidence interval estimated by the exact method. Definition of progression: Bidimensionally measurable disease: \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Confirmed Tumor Response | Assessed up to 5 years | A confirmed tumor response will be defined as an objective status of complete response (CR), partial response (PR), or regression (REGR) on two consecutive evaluations, which include neuroimaging, lasting during a period of at least 6 weeks. Confidence intervals for the true proportion will be calculated using the exact binomial method. Bidimensionally measurable disease:≥50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): 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 to Progression | From registration to disease progression (up to 5 years) | Estimated using Kaplan-Meier survival curve. Definition of progression: Bidimensionally measurable disease: \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from 24 medical clinics in the United States between September 2005 to May 2008.
Participants by arm
| Arm | Count |
|---|---|
| Stratum 1 (Not Undergoing Surgery) Patients not receiving pre-surgery SAHA with ≤1 prior chemotherapy regimens for progressive/recurrent disease. Patients receive oral vorinostat (SAHA) twice daily for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
vorinostat : Given orally, 200 milligrams two times a day for 14 days followed by 7 days rest. | 68 |
| Stratum 2 (Undergoing Surgery) Beginning 3 days prior to surgery, patients receive oral vorinostat (SAHA) once or twice daily for a total of 6 doses. Patients then undergo surgery to remove the tumor. Beginning within 1-4 weeks after surgery, patients receive oral SAHA twice daily for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
vorinostat : Given orally, 200 milligrams two times a day for 14 days followed by 7 days rest.
surgery : Patients undergo surgery to remove tumor | 15 |
| Stratum 3 (Not Undergoing Surgery) Patients not receiving pre-surgery SAHA with ≥2 prior chemotherapy regimens for progressive/recurrent disease. Patients receive oral vorinostat (SAHA) twice daily for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
vorinostat : Given orally, 200 milligrams two times a day for 14 days followed by 7 days rest. | 20 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 3 |
| Overall Study | Death | 1 | 0 | 1 |
| Overall Study | Other Medical Problems | 2 | 0 | 2 |
| Overall Study | Poor tolerance of study treatment | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 1 | 2 |
Baseline characteristics
| Characteristic | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) | Total |
|---|---|---|---|---|
| Age, Continuous | 58 years | 49 years | 55.5 years | 56 years |
| Region of Enrollment United States | 68 participants | 15 participants | 20 participants | 103 participants |
| Sex: Female, Male Female | 30 Participants | 4 Participants | 10 Participants | 44 Participants |
| Sex: Female, Male Male | 38 Participants | 11 Participants | 10 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 65 / 66 | 14 / 15 | 19 / 20 |
| serious Total, serious adverse events | 13 / 66 | 3 / 15 | 4 / 20 |
Outcome results
Primary
Proportion of Successes (Patients Alive and Progression-free)
Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients) and the Binomial 95% confidence interval estimated by the exact method. Definition of progression: Bidimensionally measurable disease: \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions.
Time frame: At 6 months
Population: 68 Stratum 1 patients were enrolled. 2 stratum 1 patients did not receive treatment. Therefore, the remaining 66 patients were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1 Patients That Started Treatment | Proportion of Successes (Patients Alive and Progression-free) | 15.2 percentage of participants |
| Stratum 2 (Undergoing Surgery) | Proportion of Successes (Patients Alive and Progression-free) | 26.7 percentage of participants |
| Stratum 3 (Not Undergoing Surgery) | Proportion of Successes (Patients Alive and Progression-free) | 10 percentage of participants |
Secondary
Confirmed Tumor Response
A confirmed tumor response will be defined as an objective status of complete response (CR), partial response (PR), or regression (REGR) on two consecutive evaluations, which include neuroimaging, lasting during a period of at least 6 weeks. Confidence intervals for the true proportion will be calculated using the exact binomial method. Bidimensionally measurable disease:≥50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): 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: Stratum 1: 68 patients were enrolled. 2 patients did not receive treatment. Therefore, the remaining 66 patients were analyzed.~Stratum 2: Since the patients underwent surgery, response is not applicable and hence 0 patients analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1 Patients That Started Treatment | Confirmed Tumor Response | 3.0 percentage of participants |
| Stratum 3 (Not Undergoing Surgery) | Confirmed Tumor Response | 0 percentage of participants |
Secondary
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: Stratum 1: 68 patients were enrolled. 2 patients did not receive treatment. Therefore, the remaining 66 patients were analyzed. The patient that survived 28 months was alive at last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1 Patients That Started Treatment | Survival | 5.7 months |
| Stratum 2 (Undergoing Surgery) | Survival | 10.2 months |
| Stratum 3 (Not Undergoing Surgery) | Survival | 2.2 months |
Secondary
Time to Progression
Estimated using Kaplan-Meier survival curve. Definition of progression: Bidimensionally measurable disease: \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions.
Time frame: From registration to disease progression (up to 5 years)
Population: Stratum 1: 68 patients were enrolled. 2 stratum 1 patients did not receive treatment. Therefore, the remaining 66 patients were analyzed. The patient that survived 28 months was progression-free at last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1 Patients That Started Treatment | Time to Progression | 1.9 months |
| Stratum 2 (Undergoing Surgery) | Time to Progression | 3.7 months |
| Stratum 3 (Not Undergoing Surgery) | Time to Progression | 1.4 months |