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

Phase 2

Completed

Conditions: Brain Stem Glioma
Childhood Spinal Cord Neoplasm
Cerebral Astrocytoma
Childhood Cerebellar Anaplastic Astrocytoma
Childhood Cerebral Anaplastic Astrocytoma

Interventions: Biological: Bevacizumab
Drug: Temozolomide
Drug: Vorinostat

Registration Number: NCT01236560

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 101

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm IV (temozolomide, Phase 3 Arm B)	Bevacizumab	Patients undergo RT as in the Arm II and receive temozolomide PO once daily for 42 days beginning on day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm I (vorinostat, Phase II Arm A)	Bevacizumab	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm II (temozolomide, Phase II Arm B)	Bevacizumab	Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm III (Bevacizumab, Phase II Arm)	Bevacizumab	Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy)	Bevacizumab	Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Feasibility (vorinostat)	Bevacizumab	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm I (vorinostat, Phase II Arm A)	Temozolomide	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm I (vorinostat, Phase II Arm A)	Vorinostat	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm II (temozolomide, Phase II Arm B)	Temozolomide	Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm III (Bevacizumab, Phase II Arm)	Temozolomide	Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm IV (temozolomide, Phase 3 Arm B)	Temozolomide	Patients undergo RT as in the Arm II and receive temozolomide PO once daily for 42 days beginning on day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy)	Temozolomide	Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy)	Vorinostat	Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Feasibility (vorinostat)	Vorinostat	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
Feasibility (vorinostat)	Temozolomide	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Vorinostat	10 weeks	The dose of vorinostat in mg/sq m/day to be administered with combination chemotherapy and radiation therapy.
Event-free Survival	1 year after enrollment	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).

Secondary Outcome Measures

Name	Time	Method
Overall Survival	1 year after enrollment	Time from enrollment to death or last follow-up, whichever occurs first.
Cumulative Incidence of Disease Progression in Each Treatment Arm	1 year after enrollment	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).

Trial Locations

Locations (132): Mattel Children's Hospital UCLA
🇺🇸
Los Angeles, California, United States
Naval Medical Center - Portsmouth
🇺🇸
Portsmouth, Virginia, United States
Children's Oncology Group
🇺🇸
Philadelphia, Pennsylvania, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Nevada Cancer Research Foundation NCORP
🇺🇸
Las Vegas, Nevada, United States
Nicklaus Children's Hospital
🇺🇸
Miami, Florida, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸
Indianapolis, Indiana, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸
Las Vegas, Nevada, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, 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
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸
Oakland, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
University of Hawaii Cancer Center
🇺🇸
Honolulu, Hawaii, United States
Tufts Children's Hospital
🇺🇸
Boston, Massachusetts, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Albany Medical Center
🇺🇸
Albany, New York, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Penn State Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸
Bethlehem, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸
Philadelphia, Pennsylvania, United States
Saint Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
University of Wisconsin Carbone Cancer Center
🇺🇸
Madison, Wisconsin, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
Saskatoon Cancer Centre
🇨🇦
Saskatoon, Saskatchewan, Canada
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
West Virginia University Charleston Division
🇺🇸
Charleston, West Virginia, United States
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦
Quebec, Canada
Mayo Clinic in Rochester
🇺🇸
Rochester, Minnesota, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸
New Hyde Park, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Arnold Palmer Hospital for Children
🇺🇸
Orlando, Florida, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Marshfield Medical Center-Marshfield
🇺🇸
Marshfield, Wisconsin, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Michigan State University Clinical Center
🇺🇸
East Lansing, Michigan, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸
Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Cardinal Glennon Children's Medical Center
🇺🇸
Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, 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
University of Rochester
🇺🇸
Rochester, New York, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Sanford Broadway Medical Center
🇺🇸
Fargo, North Dakota, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸
Toledo, Ohio, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
Brooke Army Medical Center
🇺🇸
Fort Sam Houston, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Scott and White Memorial Hospital
🇺🇸
Temple, Texas, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
Prisma Health Richland Hospital
🇺🇸
Columbia, South Carolina, United States
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Greenville Cancer Treatment Center
🇺🇸
Greenville, South Carolina, United States