Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma

Phase 2

Active, not recruiting

• Conditions: Medulloblastoma
• Interventions: Drug: Cisplatin; Drug: Cyclophosphamide; Other: Laboratory Biomarker Analysis; Drug: Lomustine; Procedure: Magnetic Resonance Imaging; Radiation: Radiation Therapy; Drug: Vincristine; Drug: Vincristine Sulfate

• Registration Number: NCT02724579
• Lead Sponsor: Children's Oncology Group

Brief Summary

This phase II trial studies how well reduced doses of radiation therapy to the brain and spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using chemotherapy and radiation therapy have been shown to be effective in treating patients with WNT-driven medulloblastoma. However, there is a concern about the late side effects of treatment, such as learning difficulties, lower amounts of hormones, or other problems in performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine sulfate, cyclophosphamide and lomustine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving reduced craniospinal radiation therapy and chemotherapy may kill tumor cells and may also reduce the late side effects of treatment.

Detailed Description

PRIMARY OBJECTIVE:

I. To estimate the progression-free survival (PFS) of children \>= 3 years of age with wingless-type MMTV integration site family (WNT)-driven average-risk medulloblastoma using reduced craniospinal radiotherapy (CSI) (18 Gray \[Gy\]) with a limited target volume boost to the tumor bed of 36 Gy for a total of 54 Gy and reduced chemotherapy approach (no vincristine \[vincristine sulfate\] during radiotherapy and reduced-dose maintenance chemotherapy) and to monitor the PFS for early evidence that the outcome is unacceptable.

SECONDARY OBJECTIVES:

I. To prospectively test the hypothesis that deoxyribonucleic acid (DNA) methylation profiling will accurately classify WNT-driven medulloblastoma.

II. To prospectively evaluate and longitudinally model the cognitive, social, emotional, behavioral, and quality of life (QoL) functioning of children who are treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced chemotherapy (reduced cisplatin, vincristine, and lomustine \[CCNU\]).

EXPLORATORY OBJECTIVES:

I. To explore whether DNA methylation profiling of medulloblastoma samples will result in a predictive classification scheme for the Sonic Hedgehog (SHH), Group 3, and Group 4 medulloblastoma subgroups according to the Heidelberg classifier. This will be addressed in a separate biology protocol.

II. To describe the audiologic and endocrinologic toxicities, as well as peripheral neuropathy, in children treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced cisplatin and vincristine chemotherapy.

OUTLINE:

RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks.

MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine orally (PO) on day 1, vincristine sulfate intravenously (IV) via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients also undergo magnetic resonance imaging (MRI) throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

Study Timeline

• Study First Submitted: 2016-03-25
• Study First Submitted QC: 2016-03-25
• Study First Posted: 2016-03-31
• Study Start: 2017-11-17
• Status Verified: 2025-02
• Last Update Submitted: 2025-03-18
• Last Update Posted: 2025-03-19
• Primary Completion: 2027-06-30
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

• Patients must be greater than or equal to 3 years and less than 22 years of age at the time of enrollment

• Patients must be newly diagnosed and have:

  • Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1:

    • Classical histologic type (non LC/A) WNT medulloblastoma
    • Positive nuclear beta-catenin by immunohistochemistry (IHC)
    • Positive for CTNNB1 mutation by Sanger sequencing
    • Negative for MYC and MYCN by fluorescence in situ hybridization (FISH)

• Patient must have negative lumbar cerebrospinal fluid (CSF) cytology

  • Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF; ideally, CSF should be obtained between day 14 and day 21 to allow for final staging status before enrollment onto the study; patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status; patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated; patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively

• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1; patients must have =< 1.5 cm^2 maximal cross-sectional area of residual tumor; whole brain magnetic resonance imaging (MRI) with and without gadolinium and spine MRI with gadolinium must be performed

• Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (day 0)

• Peripheral absolute neutrophil count (ANC) >= 1000/uL

• Platelet count >= 100,000/uL (transfusion independent)

• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

  • 3 to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and females)

  • 6 to < 10 years of age: max serum creatinine 1 mg/dL (males and females)

  • 10 to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)

  • 13 to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL (females)

  • >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)

    • The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC)

• Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

• Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3x ULN); for the purpose of this study, the ULN for SGPT is 45 U/L

• Central nervous system function defined as:

  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
  • Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment

• Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and neurocognitive assessments; if a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted

• All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible; patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible

• Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids

• Pregnancy and Breast Feeding

  • Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies
  • Lactating females are not eligible unless they have agreed not to breastfeed their infants
  • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
  • Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

• Patients with a history of moderate to profound intellectual disability (i.e., intelligence quotient [Q)]=< 55) are not eligible for enrollment; PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study. Children with posterior fossa syndrome (also known as cerebellar mutism) are eligible for this study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (reduced radiation therapy and chemotherapy)	Laboratory Biomarker Analysis	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
Treatment (reduced radiation therapy and chemotherapy)	Lomustine	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
Treatment (reduced radiation therapy and chemotherapy)	Magnetic Resonance Imaging	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
Treatment (reduced radiation therapy and chemotherapy)	Vincristine Sulfate	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
Treatment (reduced radiation therapy and chemotherapy)	Radiation Therapy	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
Treatment (reduced radiation therapy and chemotherapy)	Cisplatin	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
Treatment (reduced radiation therapy and chemotherapy)	Cyclophosphamide	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
Treatment (reduced radiation therapy and chemotherapy)	Vincristine	RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS)	From the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to 10 years	PFS along with the confidence intervals will be estimated using the Kaplan-Meier method. PFS will also be reported based on central radiology review.

Secondary Outcome Measures

Name	Time	Method
Deoxyribonucleic acid (DNA) methylation profiling as real-time classification of WNT-driven medulloblastoma	Within 32 days of definitive surgery	Results will be compared to the results of the molecular screening tests. The sensitivity and specificity comparison between DNA methylation arrays and the standard methods (molecular screening tests for WNT using immunohistochemistry \[IHC\] and CTNNB1 sequencing) will be performed using McNemar's test.
Change in neurocognitive function (cognitive, social, emotional and behavioral) according to Children Oncology Group Standard Neuropsychological Battery	Baseline to up to 60 months post-diagnosis	Neurocognitive function will be measured at 9, 30 and 60 months post diagnosis and will be compared with the neurocognitive outcomes from an age and gender matched ACNS0331 cohort to the WNT patients treated on ACNS1422. Data for all assessments will be available as standardized t-scores. The change over time for each component of the neuropsychological testing will be estimated using the Generalized Estimating Equation (GEE) approach, with the standardized t-scores as the dependent variable and the assessment times as a covariate. Within the ACNS1422 cohort GEE models will also be used to explore associations of changes over time with factors such as gender, age at initiation of radiation therapy, tumor location, number of surgical interventions, etc.

Trial Locations

Locations (196)

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

USA Health Strada Patient Care Center; 🇺🇸 Mobile, Alabama, United States

Providence Alaska Medical Center; 🇺🇸 Anchorage, Alaska, United States

Banner Children's at Desert; 🇺🇸 Mesa, Arizona, United States

Phoenix Childrens Hospital; 🇺🇸 Phoenix, Arizona, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center; 🇺🇸 Downey, California, 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

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

Cedars Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Mattel Children's Hospital UCLA; 🇺🇸 Los Angeles, California, United States

Valley Children's Hospital; 🇺🇸 Madera, California, United States

UCSF Benioff Children's Hospital Oakland; 🇺🇸 Oakland, California, United States

Kaiser Permanente-Oakland; 🇺🇸 Oakland, California, United States

Children's Hospital of Orange County; 🇺🇸 Orange, California, United States

Lucile Packard Children's Hospital Stanford University; 🇺🇸 Palo Alto, California, United States

Sutter Medical Center Sacramento; 🇺🇸 Sacramento, California, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Rady Children's Hospital - San Diego; 🇺🇸 San Diego, California, United States

UCSF Medical Center-Mission Bay; 🇺🇸 San Francisco, California, United States

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center; 🇺🇸 Torrance, California, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center; 🇺🇸 Denver, Colorado, United States

Connecticut Children's Medical Center; 🇺🇸 Hartford, Connecticut, United States

Alfred I duPont Hospital for Children; 🇺🇸 Wilmington, Delaware, United States

MedStar Georgetown University Hospital; 🇺🇸 Washington, District of Columbia, United States

Golisano Children's Hospital of Southwest Florida; 🇺🇸 Fort Myers, Florida, United States

University of Florida Health Science Center - Gainesville; 🇺🇸 Gainesville, Florida, United States

Memorial Regional Hospital/Joe DiMaggio Children's Hospital; 🇺🇸 Hollywood, Florida, United States

Nemours Children's Clinic-Jacksonville; 🇺🇸 Jacksonville, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center; 🇺🇸 Miami, Florida, United States

Nicklaus Children's Hospital; 🇺🇸 Miami, Florida, United States

AdventHealth Orlando; 🇺🇸 Orlando, Florida, United States

Arnold Palmer Hospital for Children; 🇺🇸 Orlando, Florida, United States

Nemours Children's Hospital; 🇺🇸 Orlando, Florida, United States

Nemours Children's Clinic - Pensacola; 🇺🇸 Pensacola, Florida, United States

Sacred Heart Hospital; 🇺🇸 Pensacola, Florida, United States

Johns Hopkins All Children's Hospital; 🇺🇸 Saint Petersburg, Florida, United States

Tampa General Hospital; 🇺🇸 Tampa, Florida, United States

Saint Joseph's Hospital/Children's Hospital-Tampa; 🇺🇸 Tampa, Florida, United States

Saint Mary's Medical Center; 🇺🇸 West Palm Beach, Florida, United States

Children's Healthcare of Atlanta - Arthur M Blank Hospital; 🇺🇸 Atlanta, Georgia, United States

Memorial Health University Medical Center; 🇺🇸 Savannah, Georgia, United States

Kapiolani Medical Center for Women and Children; 🇺🇸 Honolulu, Hawaii, United States

Saint Luke's Cancer Institute - Boise; 🇺🇸 Boise, Idaho, United States

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

University of Illinois; 🇺🇸 Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

Advocate Children's Hospital-Oak Lawn; 🇺🇸 Oak Lawn, Illinois, United States

Advocate Children's Hospital-Park Ridge; 🇺🇸 Park Ridge, Illinois, United States

Saint Jude Midwest Affiliate; 🇺🇸 Peoria, Illinois, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Riley Hospital for Children; 🇺🇸 Indianapolis, Indiana, United States

Ascension Saint Vincent Indianapolis Hospital; 🇺🇸 Indianapolis, Indiana, United States

Blank Children's Hospital; 🇺🇸 Des Moines, Iowa, United States

University of Iowa/Holden Comprehensive Cancer Center; 🇺🇸 Iowa City, Iowa, United States

University of Kentucky/Markey Cancer Center; 🇺🇸 Lexington, Kentucky, United States

Norton Children's Hospital; 🇺🇸 Louisville, Kentucky, United States

Children's Hospital New Orleans; 🇺🇸 New Orleans, Louisiana, United States

Ochsner Medical Center Jefferson; 🇺🇸 New Orleans, Louisiana, United States

Eastern Maine Medical Center; 🇺🇸 Bangor, Maine, United States

Maine Children's Cancer Program; 🇺🇸 Scarborough, Maine, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Tufts Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

UMass Memorial Medical Center - University Campus; 🇺🇸 Worcester, Massachusetts, United States

C S Mott Children's Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Children's Hospital of Michigan; 🇺🇸 Detroit, Michigan, United States

Henry Ford Health Saint John Hospital; 🇺🇸 Detroit, Michigan, United States

Michigan State University Clinical Center; 🇺🇸 East Lansing, Michigan, United States

Corewell Health Grand Rapids Hospitals - Butterworth Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Bronson Methodist Hospital; 🇺🇸 Kalamazoo, Michigan, United States

West Michigan Cancer Center; 🇺🇸 Kalamazoo, Michigan, United States

Corewell Health Children's; 🇺🇸 Royal Oak, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis; 🇺🇸 Minneapolis, Minnesota, United States

University of Minnesota/Masonic Cancer Center; 🇺🇸 Minneapolis, Minnesota, United States

Mayo Clinic in Rochester; 🇺🇸 Rochester, Minnesota, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

University of Missouri Children's Hospital; 🇺🇸 Columbia, Missouri, United States

Children's Mercy Hospitals and Clinics; 🇺🇸 Kansas City, Missouri, United States

Cardinal Glennon Children's Medical Center; 🇺🇸 Saint Louis, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Mercy Hospital Saint Louis; 🇺🇸 Saint Louis, Missouri, United States

Children's Hospital and Medical Center of Omaha; 🇺🇸 Omaha, Nebraska, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

University Medical Center of Southern Nevada; 🇺🇸 Las Vegas, Nevada, United States

Sunrise Hospital and Medical Center; 🇺🇸 Las Vegas, Nevada, United States

Alliance for Childhood Diseases/Cure 4 the Kids Foundation; 🇺🇸 Las Vegas, Nevada, United States

Summerlin Hospital Medical Center; 🇺🇸 Las Vegas, Nevada, United States

Renown Regional Medical Center; 🇺🇸 Reno, Nevada, United States

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center; 🇺🇸 Lebanon, New Hampshire, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Saint Peter's University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Newark Beth Israel Medical Center; 🇺🇸 Newark, New Jersey, United States

Saint Joseph's Regional Medical Center; 🇺🇸 Paterson, New Jersey, United States

Albany Medical Center; 🇺🇸 Albany, New York, United States

Montefiore Medical Center - Moses Campus; 🇺🇸 Bronx, New York, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

NYU Langone Hospital - Long Island; 🇺🇸 Mineola, New York, United States

The Steven and Alexandra Cohen Children's Medical Center of New York; 🇺🇸 New Hyde Park, New York, United States

Mount Sinai Hospital; 🇺🇸 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

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

State University of New York Upstate Medical University; 🇺🇸 Syracuse, New York, United States

New York Medical College; 🇺🇸 Valhalla, New York, United States

Mission Hospital; 🇺🇸 Asheville, North Carolina, United States

UNC Lineberger Comprehensive Cancer Center; 🇺🇸 Chapel Hill, North Carolina, United States

Carolinas Medical Center/Levine Cancer Institute; 🇺🇸 Charlotte, North Carolina, United States

Novant Health Presbyterian Medical Center; 🇺🇸 Charlotte, North Carolina, United States

East Carolina University; 🇺🇸 Greenville, North Carolina, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

Sanford Broadway Medical Center; 🇺🇸 Fargo, North Dakota, United States

Children's Hospital Medical Center of Akron; 🇺🇸 Akron, Ohio, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital; 🇺🇸 Cleveland, Ohio, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, 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

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Legacy Emanuel Children's Hospital; 🇺🇸 Portland, Oregon, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Lehigh Valley Hospital-Cedar Crest; 🇺🇸 Allentown, Pennsylvania, United States

Lehigh Valley Hospital - Muhlenberg; 🇺🇸 Bethlehem, Pennsylvania, United States

Geisinger Medical Center; 🇺🇸 Danville, Pennsylvania, United States

Penn State Children's Hospital; 🇺🇸 Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia; 🇺🇸 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

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Prisma Health Richland Hospital; 🇺🇸 Columbia, South Carolina, United States

BI-LO Charities Children's Cancer Center; 🇺🇸 Greenville, South Carolina, United States

Sanford USD Medical Center - Sioux Falls; 🇺🇸 Sioux Falls, South Dakota, United States

T C Thompson Children's Hospital; 🇺🇸 Chattanooga, Tennessee, United States

East Tennessee Childrens Hospital; 🇺🇸 Knoxville, Tennessee, United States

The Children's Hospital at TriStar Centennial; 🇺🇸 Nashville, Tennessee, United States

Vanderbilt University/Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Dell Children's Medical Center of Central Texas; 🇺🇸 Austin, Texas, United States

Driscoll Children's Hospital; 🇺🇸 Corpus Christi, Texas, United States

Medical City Dallas Hospital; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

El Paso Children's Hospital; 🇺🇸 El Paso, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; 🇺🇸 Houston, Texas, United States

Covenant Children's Hospital; 🇺🇸 Lubbock, Texas, United States

UMC Cancer Center / UMC Health System; 🇺🇸 Lubbock, Texas, United States

Children's Hospital of San Antonio; 🇺🇸 San Antonio, Texas, 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

Scott and White Memorial Hospital; 🇺🇸 Temple, Texas, United States

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States

University of Vermont and State Agricultural College; 🇺🇸 Burlington, Vermont, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

Inova Fairfax Hospital; 🇺🇸 Falls Church, Virginia, United States

Children's Hospital of The King's Daughters; 🇺🇸 Norfolk, Virginia, United States

Naval Medical Center - Portsmouth; 🇺🇸 Portsmouth, Virginia, United States

Virginia Commonwealth University/Massey Cancer Center; 🇺🇸 Richmond, Virginia, United States

Carilion Children's; 🇺🇸 Roanoke, Virginia, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

Providence Sacred Heart Medical Center and Children's Hospital; 🇺🇸 Spokane, Washington, United States

Mary Bridge Children's Hospital and Health Center; 🇺🇸 Tacoma, Washington, United States

Madigan Army Medical Center; 🇺🇸 Tacoma, Washington, United States

West Virginia University Healthcare; 🇺🇸 Morgantown, West Virginia, United States

Saint Vincent Hospital Cancer Center Green Bay; 🇺🇸 Green Bay, Wisconsin, United States

University of Wisconsin Carbone Cancer Center - University Hospital; 🇺🇸 Madison, Wisconsin, United States

Marshfield Medical Center-Marshfield; 🇺🇸 Marshfield, Wisconsin, United States

Children's Hospital of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

John Hunter Children's Hospital; 🇦🇺 Hunter Regional Mail Centre, New South Wales, Australia

Women's and Children's Hospital-Adelaide; 🇦🇺 North Adelaide, South Australia, Australia

Princess Margaret Hospital for Children; 🇦🇺 Perth, Western Australia, Australia

Perth Children's Hospital; 🇦🇺 Perth, Western Australia, Australia

Alberta Children's Hospital; 🇨🇦 Calgary, Alberta, Canada

University of Alberta Hospital; 🇨🇦 Edmonton, Alberta, Canada

British Columbia Children's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

CancerCare Manitoba; 🇨🇦 Winnipeg, Manitoba, Canada

Janeway Child Health Centre; 🇨🇦 Saint John's, Newfoundland and Labrador, Canada

IWK Health Centre; 🇨🇦 Halifax, Nova Scotia, Canada

McMaster Children's Hospital at Hamilton Health Sciences; 🇨🇦 Hamilton, Ontario, Canada

Kingston Health Sciences Centre; 🇨🇦 Kingston, Ontario, Canada

Children's Hospital; 🇨🇦 London, Ontario, Canada

Children's Hospital of Eastern Ontario; 🇨🇦 Ottawa, Ontario, Canada

Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

The Montreal Children's Hospital of the MUHC; 🇨🇦 Montreal, Quebec, Canada

Centre Hospitalier Universitaire Sainte-Justine; 🇨🇦 Montreal, Quebec, Canada

Jim Pattison Children's Hospital; 🇨🇦 Saskatoon, Saskatchewan, Canada

Saskatoon Cancer Centre; 🇨🇦 Saskatoon, Saskatchewan, Canada

HIMA San Pablo Oncologic Hospital; 🇵🇷 Caguas, Puerto Rico

University Pediatric Hospital; 🇵🇷 San Juan, Puerto Rico

King Faisal Specialist Hospital and Research Centre; 🇸🇦 Riyadh, Saudi Arabia