A Randomized Phase II/III Study of Vorinostat (IND# 71976) and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab (IND# 7921) and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas
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 arm I and receive temozolomide PO once daily for 42 days
beginning on day 5 of RT.
ARM III: Patients undergo RT as in arm I and receive bevacizumab IV over 30-90 minutes on
days 22 and 36. 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. Patients in all arms receive
maintenance therapy as in the feasibility study. 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.
Interventional
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of vorinostat when given concurrently with radiation therapy determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (feasability study)
10 weeks
Yes
Maryam Fouladi
Principal Investigator
Children's Oncology Group
United States: Food and Drug Administration
NCI-2011-02616
NCT01236560
November 2010
Name | Location |
---|---|
Baylor College of Medicine | Houston, Texas 77030 |
Johns Hopkins University | Baltimore, Maryland 21205 |
Memorial Sloan Kettering Cancer Center | New York, New York 10021 |
Cleveland Clinic Foundation | Cleveland, Ohio 44195 |
Roswell Park Cancer Institute | Buffalo, New York 14263 |
Mayo Clinic | Rochester, Minnesota 55905 |
Children's Hospital of Philadelphia | Philadelphia, Pennsylvania 19104 |
University of Mississippi Medical Center | Jackson, Mississippi 39216-4505 |
Washington University School of Medicine | Saint Louis, Missouri 63110 |
Medical University of South Carolina | Charleston, South Carolina 29425-0721 |
University of Texas Health Science Center at San Antonio | San Antonio, Texas 78284-7811 |
Midwest Children's Cancer Center | Milwaukee, Wisconsin 53226 |
Bronson Methodist Hospital | Kalamazoo, Michigan 49007 |
Morristown Memorial Hospital | Morristown, New Jersey 07962-1956 |
Marshfield Clinic | Marshfield, Wisconsin 54449 |
Loma Linda University Medical Center | Loma Linda, California 92354 |
New York Medical College | Valhalla, New York 10595 |
Dana-Farber Cancer Institute | Boston, Massachusetts 02115 |
Cedars-Sinai Medical Center | Los Angeles, California 90048 |
University of Arkansas for Medical Sciences | Little Rock, Arkansas 72205 |
Brooke Army Medical Center | Fort Sam Houston, Texas 78234-6200 |
University of Nebraska Medical Center | Omaha, Nebraska 68198-3330 |
Hackensack University Medical Center | Hackensack, New Jersey 07601 |
Children's Hospital Los Angeles | Los Angeles, California 90027-0700 |
Children's National Medical Center | Washington, District of Columbia 20010-2970 |
Miami Children's Hospital | Miami, Florida 33155-4069 |
All Children's Hospital | St. Petersburg, Florida 33701 |
Saint Jude Midwest Affiliate | Peoria, Illinois 61637 |
Carolinas Medical Center | Charlotte, North Carolina 28232-2861 |
University of Oklahoma Health Sciences Center | Oklahoma City, Oklahoma 73104 |
St. Jude Children's Research Hospital | Memphis, Tennessee 38105-2794 |
Driscoll Children's Hospital | Corpus Christi, Texas 78466 |
Scott and White Memorial Hospital | Temple, Texas 76508 |
Southern California Permanente Medical Group | Downey, California 90242 |
Children's Hospital Central California | Madera, California 93638-8762 |
Kosair Children's Hospital | Louisville, Kentucky 40202-3830 |
Children's Hospital Medical Center of Akron | Akron, Ohio 44308 |
University of Wisconsin Hospital and Clinics | Madison, Wisconsin 53792-0001 |
Overlook Hospital | Summit, New Jersey 07902-0220 |
Cincinnati Children's Hospital Medical Center | Cincinnati, Ohio 45229-3039 |
Methodist Children's Hospital of South Texas | San Antonio, Texas 78229-3993 |
Primary Children's Medical Center | Salt Lake City, Utah 84113-1100 |
Naval Medical Center - Portsmouth | Portsmouth, Virginia 23708-2197 |
Montefiore Medical Center | Bronx, New York 10467-2490 |
Rady Children's Hospital - San Diego | San Diego, California 92123-4282 |
Children's Hospitals and Clinics of Minnesota - Minneapolis | Minneapolis, Minnesota 55404 |
University of New Mexico Cancer Center | Albuquerque, New Mexico 87131-5636 |
Nationwide Children's Hospital | Columbus, Ohio 43205-2696 |
Children's Hospital of Pittsburgh of UPMC | Pittsburgh, Pennsylvania 15213 |
Dell Children's Medical Center of Central Texas | Austin, Texas 78723 |
Children's Hospital and Research Center at Oakland | Oakland, California 94609-1809 |
Mary Bridge Children's Hospital and Health Center | Tacoma, Washington 98415-0299 |
Lehigh Valley Hospital - Muhlenberg | Bethlehem, Pennsylvania 18017 |
Lee Memorial Health System | Fort Myers, Florida 33902 |
University of Alabama at Birmingham | Birmingham, Alabama 35294-3300 |
Children's Hospital of Alabama | Birmingham, Alabama 35233 |
Connecticut Children's Medical Center | Hartford, Connecticut 06106 |
Vanderbilt University | Nashville, Tennessee 37232-6305 |
University of North Carolina | Chapel Hill, North Carolina 27599 |
University of Rochester | Rochester, New York 14642 |
Nemours Children's Clinic - Pensacola | Pensacola, Florida 32504 |
Helen DeVos Children's Hospital at Spectrum Health | Grand Rapids, Michigan 49503 |
Yale University | New Haven, Connecticut 06520 |
Wayne State University | Detroit, Michigan 48202 |
BI-LO Charities Children's Cancer Center | Greenville, South Carolina 29605 |
Albany Medical Center | Albany, New York 12208 |
University of Kentucky | Lexington, Kentucky 40536-0098 |
Oregon Health and Science University | Portland, Oregon 97201 |
Virginia Commonwealth University | Richmond, Virginia |
Florida Hospital | Orlando, Florida 32803 |
Memorial Health University Medical Center | Savannah, Georgia 31404 |
University of Chicago Comprehensive Cancer Center | Chicago, Illinois 60637-1470 |
Seattle Children's Hospital | Seattle, Washington 98105 |
Wake Forest University Health Sciences | Winston-Salem, North Carolina 27157 |
Childrens Memorial Hospital | Chicago, Illinois 60614 |
M D Anderson Cancer Center- Orlando | Orlando, Florida 32806 |
University of Hawaii | Honolulu, Hawaii 96813 |
Saint Vincent Hospital and Health Services | Indianapolis, Indiana 46260 |
Michigan State University - Breslin Cancer Center | East Lansing, Michigan 48824-1313 |
Saint John's Mercy Medical Center | Saint Louis, Missouri 63141 |
Nevada Cancer Research Foundation CCOP | Las Vegas, Nevada 89106 |
New York University Langone Medical Center | New York, New York 10016 |
Columbia University Medical Center | New York, New York 10032 |
State University of New York Upstate Medical University | Syracuse, New York 13210 |
University of Illinois | Chicago, Illinois 60612 |
Cook Children's Medical Center | Fort Worth, Texas 76104 |
West Virginia University Charleston | Charleston, West Virginia 25304 |
The Children's Medical Center of Dayton | Dayton, Ohio 45404 |
University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami, Florida 33136 |
Children's Oncology Group | Arcadia, California 91006-3776 |
C S Mott Children's Hospital | Ann Arbor, Michigan 48109 |
Southern Illinois University | Springfield, Illinois 62702 |
Riley Hospital for Children | Indianapolis, Indiana 46202 |
Cardinal Glennon Children's Medical Center | St. Louis, Missouri 63104 |
UMDNJ - Robert Wood Johnson University Hospital | New Brunswick, New Jersey 08903 |
Miller Children's Hospital | Long Beach, California 90806 |
Childrens Hospital of Orange County | Orange, California 92868-3874 |
Alfred I duPont Hospital for Children | Wilmington, Delaware 19803 |
Nemours Children's Clinic - Jacksonville | Jacksonville, Florida 32207-8426 |
Nemours Childrens Clinic - Orlando | Orlando, Florida 32806 |
Saint Joseph Children's Hospital of Tampa | Tampa, Florida 33607 |
Children's Healthcare of Atlanta - Egleston | Atlanta, Georgia 30322 |
The Childrens Mercy Hospital | Kansas City, Missouri 64108 |
Rainbow Babies and Childrens Hospital | Cleveland, Ohio 44106 |
Penn State Hershey Children's Hospital | Hershey, Pennsylvania 17033 |
Palmetto Health Richland | Columbia, South Carolina 29203 |
East Tennessee Childrens Hospital | Knoxville, Tennessee 37916 |
Children's Hospital and Medical Center of Omaha | Omaha, Nebraska 68114 |
Saint Joseph's Regional Medical Center | Paterson, New Jersey 07503 |
Sanford Medical Center-Fargo | Fargo, North Dakota 58122 |
Floating Hospital for Children at Tufts Medical Center | Boston, Massachusetts 02111 |
Lucile Packard Children's Hospital Stanford University | Palo Alto, California 94304 |
University of California San Francisco Medical Center-Parnassus | San Francisco, California 94143 |
Raymond Blank Children's Hospital | Des Moines, Iowa 50309 |
The Toledo Hospital/Toledo Children's Hospital | Toledo, Ohio 43606 |
Greenville Cancer Treatment Center | Greenville, South Carolina 29605 |
Sanford USD Medical Center - Sioux Falls | Sioux Falls, South Dakota 57117-5134 |
Providence Sacred Heart Medical Center and Children's Hospital | Spokane, Washington 99204 |
The Steven and Alexandra Cohen Children's Medical Center of New York | New Hyde Park, New York 11040 |
Mattel Children's Hospital UCLA | Los Angeles, California 90095 |