Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma

Brain Stem Glioma Clinical Trial

Official title:

A Randomized Phase II/III Study of Vorinostat and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01236560
• Other study ID #: NCI-2011-02616
• Secondary ID: NCI-2011-02616CD
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: January 26, 2011
• Est. completion date: December 31, 2023

Study information

• Verified date: January 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II/III trial is studying vorinostat, temozolomide, or bevacizumab to see how well they work compared with each other when given together with radiation therapy followed by bevacizumab and temozolomide in treating young patients with newly diagnosed high-grade glioma. Vorinostat 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. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether giving vorinostat is more effective then temozolomide or bevacizumab when given together with radiation therapy in treating glioma.

Description:

PRIMARY OBJECTIVES:

I. To identify the dose of vorinostat that is feasible when given in combination with radiotherapy (RT) in patients with newly diagnosed high-grade gliomas (HGG). II. To compare 1-year event-free survival of patients with newly diagnosed HGG treated with vorinostat (using MTD) versus bevacizumab versus temozolomide when given in combination with RT followed by maintenance therapy with bevacizumab and temozolomide. (Phase II) III. To compare the event-free survival of patients with newly diagnosed HGG treated with the superior chemoradiotherapy (from phase II portion) versus temozolomide given in combination with RT followed by maintenance chemotherapy with bevacizumab and temozolomide. (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate the anti-tumor activity, as measured by event-free survival (EFS), progression-free survival (PFS), and overall survival (OS), of patients with newly diagnosed HGG treated with vorinostat, bevacizumab, or temozolomide when given in combination with RT followed by maintenance chemotherapy with bevacizumab and temozolomide. II. To define and evaluate the toxicities of each of the treatment arms of the study.

III. To conduct gene expression profiling and SNP arrays in patients with newly diagnosed HGG.

IV. To assess telomerase activity, hTert expression, and telomere length in patients with newly diagnosed HGG. V. To document changes in perfusion and diffusion using MR imaging at baseline, prior to, during (prior to course 3), and after maintenance therapy with bevacizumab and temozolomide.

VI. To correlate functional changes in tumor with responses to bevacizumab treatment using MR diffusion/perfusion imaging. VII. To correlate the results of the bevacizumab biology studies in serum or tumor with EFS.

VIII. To explore the prognostic significance of MGMT status for patients newly diagnosed with HGG treated with combined surgery, radiation, chemotherapy, and anti-angiogenic therapy.

OUTLINE: This is a multicenter, feasibility, dose-escalation study of vorinostat, followed by a phase II study, followed by a phase III study.

FEASIBILITY STUDY: Patients undergo 3-D conformal radiotherapy (RT) or intensity-modulated RT 5 days a week for 6 weeks. Patients also receive vorinostat orally (PO) once daily on days 1-5. Courses repeat every week for 6 weeks in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Beginning 4 weeks after completion of chemoradiotherapy, patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and temozolomide PO on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

PHASE II STUDY: Patients are stratified according to extent of resection (near total resection or gross total resection vs other) and histology (glioblastoma multiforme vs other). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study.

ARM II: Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT.

ARM III: Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36.

Maintenance therapy in arms I, II, III: Patients in all arms receive maintenance therapy as in the feasibility study.

PHASE III study: Patients are randomized to 1 of 2 treatment arms.

ARM IV: Patients receive RT and temozolomide as in phase II, arm II.

ARM V: Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as the superior chemoradiotherapy arm in phase II.

Maintenance Therapy: Beginning 4 weeks after completion of chemoradiotherapy, patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and temozolomide PO on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Some patients undergo blood and tumor tissue sample (from surgery) collection for telomerase activity, hTert expression, telomere length, and gene expression profiling and SNP arrays analysis.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually for 5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: December 31, 2023
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 21 Years

Eligibility

Inclusion Criteria:

• Newly diagnosed high-grade glioma

• Anaplastic astrocytoma

• Glioblastomamultiforme

• Gliosarcoma

• Primary spinal cord malignant glioma allowed

• No oligodendroglioma oroligoastrocytoma

• Patient must have histological verification of diagnosis

• No M+ disease (defined as evidence of neuraxis dissemination)

• No positive CSF cytology

• ECOG performance status (PS) 0-2

• Karnofsky PS 50-100% (patients > 16 years of age)

• Lansky PS 50-100% (patients = 16 years of age)

• ANC = 1,000/µL

• Platelet count = 100,000/µL

• Hemoglobin = 8.0 mg/dL (transfusion independent)

• Creatinine clearance or radioisotope GFR = 70 mL/min OR serum creatinine based on age and/or gender as follows:

• 0.4 mg/dL (1 month to < 6 months of age)

• 0.5 mg/dL (6 months to < 1 year of age)

• 0.6 mg/dL (1 to < 2 years of age)

• 0.8 mg/dL (2 to < 6 years of age)

• 1.0 mg/dL (6 to < 10 years of age)

• 1.2 mg/dL (10 to < 13 years of age)

• 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

• 1.7 mg/dL (male) or 1.4 mg/dL (female) (= 16 years of age)

• Proteinuria < 2+ OR urine; protein ratio (UPC) = 0.5

• If UPC > 0.5, a 24-hour urine protein should be obtained and level should be < 1,000 mg of protein

• Total bilirubin = 1.5 times upper limit of normal (ULN)

• ALT < 2.5 times ULN

• Serum albumin = 2 g/dL

• PT INR = 1.5 times ULN

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during all study therapy and for = 6 months after completion of bevacizumab

• Hypertension well controlled (= 95^th percentile for age and height if patient is = 17years) by stable doses of medication allowed

• For patients > 17 years, systolic blood pressure (BP) = 150 mm Hg or diastolic BP = 100 mm Hg)

• Seizure disorder allowed provided patient is well-controlled and on nonenzyme-inducing anticonvulsants

• No history of myocardial infarction, severe or unstable angina, clinically significant peripheral vascular disease, = grade 2 heart failure, or serious and inadequately controlled cardiac arrhythmia

• No known bleeding diathesis or coagulopathy

• No prior arterial thromboembolic events, including transient ischemic attacks orcerebrovascular accidents

• No prior diagnosis of a deep venous thrombosis, including pulmonary embolism, and no known thrombophilic condition (e.g., protein S, protein C, antithrombin III deficiency, Factor V Leiden or Factor II G202'0A mutation, homocysteinemia, or antiphospholipid antibody syndrome)

• No history of an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• No serious or non-healing wound, ulcer, or bone fracture

• No evidence of significant postoperative intracranial hemorrhage, defined as > 1 cm of blood on postoperative MRI scan (potentially in addition to the postoperative scan) obtained within the past 14days

• No history of allergic reaction to Chinese hamster ovary cell products or other recombinanthuman antibodies

• No more than 31 days since definitive surgery

• Must not have received any prior chemotherapy, radiotherapy, immunotherapy, or bone marrow transplant

• More than 7 days since major surgical procedure and recovered

• For patients scheduled to receive bevacizumab:

• More than 28 days since major procedure

• More than 14 days since intermediate procedure

• More than 7 days since minor procedure (lumbar picture or placement of PICC lines are not considered minor procedures)

• No other current anti-cancer agents

• No concurrent nonsteroidal anti-inflammatory medications known to inhibit platelet function or known to selectively inhibit cyclooxygenase activity

• No concurrent enzyme inducing anticonvulsants

• No concurrent HDAC inhibitors (e.g., valproic acid)

• No concurrent anticoagulants including systemic thrombolytic agents, heparin, low molecular weight heparins, or warfarin except as required to maintain patency of pre-existing permanent vascular catheters or for prevention of thrombosis in the post-operative period

Related Conditions & MeSH terms

• Astrocytoma
• Brain Stem Glioma
• Cerebral Astrocytoma
• Childhood Cerebellar Anaplastic Astrocytoma
• Childhood Cerebral Anaplastic Astrocytoma
• Childhood Spinal Cord Neoplasm
• Glioma
• Spinal Cord Neoplasms

Intervention

Biological:
• Bevacizumab
Given IV

Drug:
• Temozolomide
Given PO
• Vorinostat
Given PO

Locations

Country	Name	City	State
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)	Quebec
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Tufts Children's Hospital	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Greenville Cancer Treatment Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Oncology Group	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD) of Vorinostat	The dose of vorinostat in mg/sq m/day to be administered with combination chemotherapy and radiation therapy.	10 weeks
Primary	Event-free Survival	Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first. Disease progression is evaluated according to the COG criteria for measurement of brain tumors and is defined to be a = 25% increase in the product of perpendicular diameters of ANY target lesion, taking as reference the smallest product observed since the start of treatment; OR the appearance of one or more new lesions, OR worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) PLUS any increase in tumor cross-sectional area (or tumor volume).	1 year after enrollment
Secondary	Overall Survival	Time from enrollment to death or last follow-up, whichever occurs first.	1 year after enrollment
Secondary	Cumulative Incidence of Disease Progression in Each Treatment Arm	Cumulative incidence of progression where death from any cause prior to progression and diagnosis of a second malignant neoplasm prior to progression are considered competing events. Disease progression is evaluated according to the COG criteria for measurement of brain tumors and is defined to be a = 25% increase in the product of perpendicular diameters of ANY target lesion, taking as reference the smallest product observed since the start of treatment; OR the appearance of one or more new lesions, OR worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) PLUS any increase in tumor cross-sectional area (or tumor volume).	1 year after enrollment