Vorinostat and Bortezomib in Treating Patients With Progressive, Recurrent Glioblastoma Multiforme

Adult Glioblastoma Clinical Trial

Official title:

Phase II Study of Vorinostat (SAHA) in Combination With Bortezomib (PS-341) in Patients With Recurrent Glioblastoma Multiforme

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00641706
• Other study ID #: NCI-2009-00668
• Secondary ID: NCI-2009-00668CD
• Status: Completed
• Phase: Phase 2
• First received: March 21, 2008
• Last updated: April 28, 2014
• Start date: July 2008
• Est. completion date: November 2010

Study information

• Verified date: October 2011
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: November 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Glioblastoma
• Gliosarcoma
• Recurrent Adult Brain Tumor

Intervention

Drug:
• vorinostat
Given orally

Procedure:
• therapeutic conventional surgery
Patient undergoes surgery

Drug:
• bortezomib
Given IV

Locations

Country	Name	City	State
United States	Bixby Medical Center	Adrian	Michigan
United States	Hickman Cancer Center	Adrian	Michigan
United States	AnMed Health Hospital	Anderson	South Carolina
United States	Hospital District Sixth of Harper County	Anthony	Kansas
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	The Medical Center of Aurora	Aurora	Colorado
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Saint Francis Hospital and Health Centers	Beech Grove	Indiana
United States	Mary Rutan Hospital	Bellefontaine	Ohio
United States	Sanford Clinic North-Bemidgi	Bemidji	Minnesota
United States	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa
United States	Spectrum Health Big Rapids Hospital	Big Rapids	Michigan
United States	Billings Clinic	Billings	Montana
United States	Hematology-Oncology Centers of the Northern Rockies PC	Billings	Montana
United States	Montana Cancer Consortium CCOP	Billings	Montana
United States	Northern Rockies Radiation Oncology Center	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	Bismarck Cancer Center	Bismarck	North Dakota
United States	Mid Dakota Clinic	Bismarck	North Dakota
United States	Saint Alexius Medical Center	Bismarck	North Dakota
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Joseph Medical Center	Bloomington	Illinois
United States	Boulder Community Hospital	Boulder	Colorado
United States	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio
United States	Bozeman Deaconess Cancer Center	Bozeman	Montana
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Graham Hospital Association	Canton	Illinois
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Memorial Hospital	Carthage	Illinois
United States	Rocky Mountain Oncology	Casper	Wyoming
United States	Cedar Rapids Oncology Association	Cedar Rapids	Iowa
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	North Coast Cancer Care-Clyde	Clyde	Ohio
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton CCOP	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Samaritan North Health Center	Dayton	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Colorado Cancer Research Program CCOP	Denver	Colorado
United States	Exempla Saint Joseph Hospital	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Iowa Oncology Research Association CCOP	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Mercy Capitol	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Essentia Health Duluth Clinic CCOP	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Mayo Clinic Health System Eau Claire Hospital - Luther Campus	Eau Claire	Wisconsin
United States	Midelfort Clinic-Clairemont Campus	Eau Claire	Wisconsin
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	Elkhart General Hospital	Elkhart	Indiana
United States	Hematology Oncology Center Incorporated	Elyria	Ohio
United States	Swedish Medical Center	Englewood	Colorado
United States	Eureka Hospital	Eureka	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Sanford Clinic North-Fargo	Fargo	North Dakota
United States	Sanford Medical Center-Fargo	Fargo	North Dakota
United States	Lake Region Healthcare Corporation-Cancer Care	Fergus Falls	Minnesota
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Agnesian Cancer Center	Fond Du Lac	Wisconsin
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Fredericksburg Oncology Inc	Fredericksburg	Virginia
United States	Unity Hospital	Fridley	Minnesota
United States	Galesburg Cottage Hospital	Galesburg	Illinois
United States	Illinois CancerCare Galesburg	Galesburg	Illinois
United States	Illinois CancerCare-Cottage	Galesburg	Illinois
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado
United States	Grand Rapids Clinical Oncology Program	Grand Rapids	Michigan
United States	Mercy Health Saint Mary's	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Berdeaux, Donald MD (UIA Investigator)	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	North Colorado Medical Center	Greeley	Colorado
United States	Wayne Hospital	Greenville	Ohio
United States	Illinois CancerCare-Havana	Havana	Illinois
United States	Mason District Hospital	Havana	Illinois
United States	Northern Montana Hospital	Havre	Montana
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Hopedale Medical Complex - Hospital	Hopedale	Illinois
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois
United States	Glacier Oncology PLLC	Kalispell	Montana
United States	Kalispell Medical Oncology	Kalispell	Montana
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Community Howard Regional Health	Kokomo	Indiana
United States	IU Health La Porte Hospital	La Porte	Indiana
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Lima Memorial Hospital	Lima	Ohio
United States	Meeker County Memorial Hospital	Litchfield	Minnesota
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	McKee Medical Center	Loveland	Colorado
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Mcdonough District Hospital	Macomb	Illinois
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	Saint Luke's Hospital	Maumee	Ohio
United States	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio
United States	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio
United States	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Virginia Piper Cancer Institute	Minneapolis	Minnesota
United States	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana
United States	Community Medical Hospital	Missoula	Montana
United States	Guardian Oncology and Center for Wellness	Missoula	Montana
United States	Montana Cancer Specialists	Missoula	Montana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois
United States	Porubcin, Michael MD (UIA Investigator)	Moline	Illinois
United States	Sharis, Christine M MD (UIA Investigator)	Moline	Illinois
United States	Stoffel, Thomas J MD (UIA Investigator)	Moline	Illinois
United States	Holy Family Medical Center	Monmouth	Illinois
United States	Illinois CancerCare-Monmouth	Monmouth	Illinois
United States	Community Cancer Center of Monroe	Monroe	Michigan
United States	Mercy Memorial Hospital	Monroe	Michigan
United States	Mercy Health Mercy Campus	Muskegon	Michigan
United States	Mercy Health Partners-Hackley Campus	Muskegon	Michigan
United States	Licking Memorial Hospital	Newark	Ohio
United States	Bromenn Regional Medical Center	Normal	Illinois
United States	Community Cancer Center Foundation	Normal	Illinois
United States	Illinois CancerCare-Community Cancer Center	Normal	Illinois
United States	Saint Charles Hospital	Oregon	Ohio
United States	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Pekin Cancer Treatment Center	Pekin	Illinois
United States	Pekin Hospital	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois Oncology Research Association CCOP	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Proctor Hospital	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Illinois Valley Hospital	Peru	Illinois
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Perry Memorial Hospital	Princeton	Illinois
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Reid Hospital and Health Care Services	Richmond	Indiana
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic	Rochester	Minnesota
United States	Rutherford Hospital	Rutherfordton	North Carolina
United States	Metro-Minnesota CCOP	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	North Coast Cancer Care	Sandusky	Ohio
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Hematology Oncology Associates	Sioux City	Iowa
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	South Bend Clinic	South Bend	Indiana
United States	Spartanburg Regional Medical Center	Spartanburg	South Carolina
United States	Upstate Carolina CCOP	Spartanburg	South Carolina
United States	Illinois CancerCare-Spring Valley	Spring Valley	Illinois
United States	Saint Margaret's Hospital	Spring Valley	Illinois
United States	Lakeland Hospital	St. Joseph	Michigan
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Flower Hospital	Sylvania	Ohio
United States	North Suburban Medical Center	Thornton	Colorado
United States	Mercy Hospital of Tiffin	Tiffin	Ohio
United States	Mercy Saint Anne Hospital	Toledo	Ohio
United States	Saint Vincent Mercy Medical Center	Toledo	Ohio
United States	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio
United States	University of Toledo	Toledo	Ohio
United States	Munson Medical Center	Traverse City	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	Carle Cancer Center	Urbana	Illinois
United States	Carle Clinic-Urbana Main	Urbana	Illinois
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Fulton County Health Center	Wauseon	Ohio
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Exempla Lutheran Medical Center	Wheat Ridge	Colorado
United States	Geisinger Wyoming Valley	Wilkes-Barre	Pennsylvania
United States	Clinton Memorial Hospital	Wilmington	Ohio
United States	Minnesota Oncology and Hematology PA-Woodbury	Woodbury	Minnesota
United States	Metro Health Hospital	Wyoming	Michigan
United States	Greene Memorial Hospital	Xenia	Ohio
United States	Genesis HealthCare System	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	At 6 months	No
Secondary	Overall Survival	Estimated using Kaplan-Meier survival curve.	From study registration to date of death due to any cause or last follow-up (up to 5 years)	No
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.	From study registration to date of progression (up to 5 years)	No
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.	Assessed up to 5 years	No