A Phase 2 interventional study of vorinostat and conventional surgery in Adult Giant Cell Glioblastoma, Adult Glioblastoma and Adult Gliosarcoma, sponsored by National Cancer Institute (NCI). Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-05-23.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
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.
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.
1,920 studies on the registry are indexed under Glioblastoma; 450 are open to participants now.
This study's enrollment of 103 is above the median of 36 across 1,618 interventional studies indexed under Glioblastoma.
Browse Glioblastoma studies →National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.
Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria:
Histologically confirmed grade 4 astrocytoma (glioblastoma multiforme), including gliosarcoma, at primary diagnosis or recurrence
At least 8 weeks since prior radiotherapy
More than 6 weeks since prior stereotactic radiosurgery or interstitial brachytherapy, unless 1 of the following criteria is met:
Patients receive oral vorinostat (SAHA) twice daily for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Drug: vorinostat · Procedure: conventional surgery
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. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Drug: vorinostat · Procedure: conventional surgery
Given orally
Also known as: L-001079038, SAHA, suberoylanilide hydroxamic acid, Zolinza
Patients undergo surgery to remove tumor
Also known as: surgery, conventional
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
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)
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
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)
Participants were recruited from 24 medical clinics in the United States between September 2005 to May 2008.
| Milestone | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) |
|---|---|---|---|
| Started | 68 | 15 | 20 |
| Completed | 53 | 13 | 11 |
| Not completed | 15 | 2 | 9 |
| Withdrew: Withdrawal by subject | 11 | 1 | 2 |
| Withdrew: Death | 1 | 0 | 1 |
| Withdrew: Other medical problems | 2 | 0 | 2 |
| Withdrew: Poor tolerance of study treatment | 1 | 0 | 1 |
| Withdrew: Adverse event | 0 | 1 | 3 |
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.
| percentage of participants | Stratum 1 Patients That Started Treatment | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) |
|---|---|---|---|
| Proportion of Successes (Patients Alive and Progression-free) | 15.2 (7.5 to 26.1) | 26.7 (7.8 to 55.1) | 10 (1.2 to 31.7) |
Estimated using Kaplan-Meier survival curve.
| months | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) |
|---|---|---|---|
| Survival | 5.7 (0.7 to 28) | 10.2 (2.8 to 41.6) | 2.2 (0.26 to 42.3) |
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.
| percentage of participants | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) |
|---|---|---|---|
| Confirmed Tumor Response | 3.0 (0.4 to 10.5) | — | 0 (0 to 16.8) |
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.
| months | Stratum 1 Patients That Started Treatment | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) |
|---|---|---|---|
| Time to Progression | 1.9 (0.3 to 28) | 3.7 (1.4 to 41.6) | 1.4 (0.20 to 42.3) |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Stratum 1 (Not Undergoing Surgery) | — | 13/66 (19.7%) | 65/66 (98.5%) |
| Stratum 2 (Undergoing Surgery) | — | 3/15 (20%) | 14/15 (93.3%) |
| Stratum 3 (Not Undergoing Surgery) | — | 4/20 (20%) | 19/20 (95%) |
| Event | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) |
|---|---|---|---|
| HeadacheNervous system disorders | 0/66 | 2/15 | 0/20 |
| Platelet count decreasedInvestigations | 7/66 | 0/15 | 1/20 |
| Central nervous system necrosisNervous system disorders | 0/66 | 1/15 | 0/20 |
| HydrocephalusNervous system disorders | 1/66 | 1/15 | 0/20 |
| Disease progressionGeneral disorders | 1/66 | 0/15 | 1/20 |
| Muscle weakness left-sidedMusculoskeletal and connective tissue disorders | 0/66 | 0/15 | 1/20 |
| DizzinessNervous system disorders | 1/66 | 0/15 | 1/20 |
| Peripheral motor neuropathyNervous system disorders | 2/66 | 0/15 | 1/20 |
| SeizureNervous system disorders | 2/66 | 0/15 | 1/20 |
| Speech disorderNervous system disorders | 1/66 | 0/15 | 1/20 |
| Event | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) |
|---|---|---|---|
| FatigueGeneral disorders | 57/66 | 11/15 | 16/20 |
| Platelet count decreasedInvestigations | 45/66 | 12/15 | 17/20 |
| Hemoglobin decreasedBlood and lymphatic system disorders | 34/66 | 10/15 | 9/20 |
| Leukocyte count decreasedInvestigations | 26/66 | 9/15 | 5/20 |
| NauseaGastrointestinal disorders | 17/66 | 8/15 | 7/20 |
| AnorexiaMetabolism and nutrition disorders | 18/66 | 5/15 | 10/20 |
| DiarrheaGastrointestinal disorders | 21/66 | 7/15 | 8/20 |
| Neutrophil count decreasedInvestigations | 20/66 | 6/15 | 5/20 |
| Blood glucose increasedMetabolism and nutrition disorders | 22/66 | 1/15 | 3/20 |
| VomitingGastrointestinal disorders | 8/66 | 4/15 | 3/20 |
| Age, Continuous(years) | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) | Total |
|---|---|---|---|---|
| Median | 58 (26 to 78) | 49 (23 to 61) | 55.5 (25 to 78) | 56 (23 to 78) |
| Sex: Female, Male(Participants) | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) | Total |
|---|---|---|---|---|
| Female | 30 | 4 | 10 | 44 |
| Male | 38 | 11 | 10 | 59 |
| Region of Enrollment(participants) | Stratum 1 (Not Undergoing Surgery) | Stratum 2 (Undergoing Surgery) | Stratum 3 (Not Undergoing Surgery) | Total |
|---|---|---|---|---|
| United States | 68 | 15 | 20 | 103 |
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