Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma
- Conditions
- GanglioneuroblastomaRecurrent Neuroblastoma
- Interventions
- Biological: DinutuximabOther: Laboratory Biomarker AnalysisBiological: Sargramostim
- Registration Number
- NCT01767194
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This randomized phase II trial studies how well irinotecan hydrochloride and temozolomide with temsirolimus or dinutuximab work in treating younger patients with neuroblastoma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, 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. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as dinutuximab, may find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving irinotecan hydrochloride and temozolomide together with temsirolimus or dinutuximab is more effective in treating neuroblastoma.
- Detailed Description
PRIMARY OBJECTIVES:
I. To identify whether temsirolimus or ch14.18 (dinutuximab) is the optimal therapeutic agent to consider for further testing in a future Phase III randomized trial for treatment of newly diagnosed high-risk neuroblastoma.
II. To determine the response rate of patients with relapsed, refractory or progressive neuroblastoma following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab) and to compare this with the known response rate of patients treated with irinotecan and temozolomide alone.
EXPLORATORY OBJECTIVES:
I. To compare the response rates (RR) for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan (irinotecan hydrochloride) and temozolomide.
II. To compare the progression free survival (PFS) and overall survival (OS) rates for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan and temozolomide.
III. To compare the toxicities associated with temsirolimus or ch14.18 (dinutuximab) when combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma.
IV. To compare the ability to maintain intended dose intensity of all agents when temsirolimus or ch14.18 (dinutuximab) is combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma.
V. To determine the concordance between tumor responses as defined by standard International Neuroblastoma Response Criteria (INRC) versus response per the revised INRC.
VI. To study the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving ch14.18 (dinutuximab) antibody.
VII. To study the clinical relevance of natural killer (NK) receptor natural cytotoxicity triggering receptor 3 (NKp30) isoforms in patients receiving ch14.18 (dinutuximab) antibody or temsirolimus.
VIII. To study the association between host factors and response to irinotecan, temozolomide and ch14.18 (dinutuximab).
IX. To characterize the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab).
X. To study the association between changes in the tumor immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) with response following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab).
XI. To study the association between tumor genomic and transcriptomic aberrations as well as levels of circulating ganglioside (GD2) with response to irinotecan, temozolomide and ch14.18 (dinutuximab).
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I (CLOSED TO ACCRUAL 06/17/2016): Patients receive temozolomide orally (PO) on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8.
ARM II: Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours on days 6-12.
In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 73
-
Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e., > 2 x upper limit of normal [ULN]), at the time of initial diagnosis
-
For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 or more agents that must include an alkylating agent and a platinum-containing compound; patients must have ONE of the following:
- First episode of recurrent disease following completion of aggressive multi-drug frontline therapy
- First episode of progressive disease during aggressive multi-drug frontline therapy
- Primary resistant/refractory disease (less than partial response by INRC) detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1, etc.)
-
Patients must have at least ONE of the following:
- Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT) scan obtained within 3 weeks prior to study entry; measurable is defined as >= 10 mm in at least one dimension on spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates increased fludeoxyglucose (FDG) uptake on positron emission tomography (PET) scan
- MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a minimum of one site; this site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction
- Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan must undergo biopsy to document the presence of viable neuroblastoma; biopsy is not required for patients who have new site of soft tissue disease (radiographic evidence of disease progression) regardless of whether progression occurs while receiving therapy or after completion of therapy
- Note: Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study
-
Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
-
Patients must have received frontline therapy (including surgery, chemotherapy, autologous stem cell transplant [SCT] +/- MIBG, immunotherapy, radiotherapy, and retinoids) but may NOT have received second line chemotherapy for resistant/refractory, relapsed disease or progressive disease
-
At least 14 days must have elapsed since completion of myelosuppressive therapy
-
At least 7 days must have elapsed since the completion of therapy with a non-myelosuppressive biologic agent or retinoid
-
No interim time prior to study entry is required following prior radiation therapy (RT) for non-target lesions; however, patients must not have received radiation for a minimum of 4 weeks prior to study entry at the site of any lesion that will be identified as a target lesion to measure tumor response; lesions that have been previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at the site following radiation or a biopsy done following radiation shows viable neuroblastoma; palliative radiation is allowed to sites that will not be used to measure response during this study
-
Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell infusions as long as hematologic and other eligibility criteria have been met
-
Patients are eligible >= 6 weeks after therapeutic 131I-MIBG provided that all other eligibility criteria are met
-
Subjects who have previously received anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging are eligible unless they have had progressive disease while receiving prior anti-GD2 therapy; subjects who have received autologous marrow infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads, but no other form of anti-GD2 monoclonal antibody, are eligible
-
Patients must not have received long-acting myeloid growth factors (e.g., Neulasta) within 14 days of entry on this study; seven days must have elapsed since administration of a short acting myeloid growth factor
-
Peripheral absolute neutrophil count (ANC) >= 750/uL
-
Platelet count >= 75,000/uL (transfusion independent)
-
Patients known to have bone marrow involvement with neuroblastoma are eligible provided that minimum ANC and platelet count criteria are met but are not evaluable for hematological toxicity
-
Creatinine clearance or estimated radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
-
A serum creatinine =< upper limit of normal (ULN) based on age/gender as follows:
- Age 1 month to < 6 months: 0.4 for males, 0.4 for females
- Age 6 months to < 1 year: 0.5 for males, 0.5 for females
- Age 1 to < 2 years: 0.6 for males, 0.6 for females
- Age 2 to < 6 years: 0.8 for males, 0.8 for females
- Age 6 to < 10 years: 1 for males, 1 for females
- Age 10 to < 13 years: 1.2 for males, 1.2 for females
- Age 13 to < 16 years: 1.5 for males, 1.4 for females
- Age >= 16 years: 1.7 for males, 1.4 for females
-
Total bilirubin =< 1.5 x ULN for age AND
-
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x ULN for age (=< 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L
-
Adequate central nervous system function defined as:
- Patients with a history of central nervous system (CNS) disease must have no clinical or radiological evidence of CNS disease at the time of study enrollment
- Patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsants
- CNS toxicity =< grade 2
-
Shortening fraction of >= 27% by echocardiogram (ECHO) OR
-
Ejection fraction >= 50% by ECHO or gated radionuclide study
-
Adequate coagulation defined as:
- Prothrombin time (PT) =< 1.2 x upper limit of normal
-
Adequate pulmonary function defined as:
- No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry > 94% if there is a clinical indication for pulse oximetry; normal pulmonary function tests in patients who are capable of cooperating with testing (including diffusion capacity of the lung of carbon monoxide [DLCO]) are required if there is a clinical indication for determination; for patients who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT required
- Men and women of childbearing potential and their partners must agree to use adequate contraception while enrolled on this study; based on the established teratogenic potential of alkylating agents, pregnant women will be excluded from this study; female patients who are lactating must agree to stop breastfeeding or will otherwise be excluded from this study; females of childbearing potential must have a negative pregnancy test to be eligible for this study
- Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study
- Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment; patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study are ineligible; the only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions; the use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency
- Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study enrollment; patients receiving non-enzyme inducing anticonvulsants such as gabapentin or levetiracetam will be eligible
- Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma
- Patients with symptoms of congestive heart failure are not eligible
- Patients must not have >= grade 2 diarrhea
- Patients must not have uncontrolled infection
- Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or reactions that required discontinuation of the anti-GD2 therapy are not eligible
- Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of study agents or to significantly increase the severity of the toxicities experienced from study treatment are not eligible
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm I (temozolomide, irinotecan hydrochloride, temsirolimus) Irinotecan Hydrochloride CLOSED TO ACCRUAL 06/17/2016 Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Arm I (temozolomide, irinotecan hydrochloride, temsirolimus) Laboratory Biomarker Analysis CLOSED TO ACCRUAL 06/17/2016 Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Arm I (temozolomide, irinotecan hydrochloride, temsirolimus) Temozolomide CLOSED TO ACCRUAL 06/17/2016 Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Arm II (temozolomide, irinotecan hydrochloride, dinutuximab) Dinutuximab Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Arm II (temozolomide, irinotecan hydrochloride, dinutuximab) Laboratory Biomarker Analysis Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Arm II (temozolomide, irinotecan hydrochloride, dinutuximab) Sargramostim Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Arm I (temozolomide, irinotecan hydrochloride, temsirolimus) Temsirolimus CLOSED TO ACCRUAL 06/17/2016 Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Arm II (temozolomide, irinotecan hydrochloride, dinutuximab) Irinotecan Hydrochloride Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Arm II (temozolomide, irinotecan hydrochloride, dinutuximab) Temozolomide Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12.
- Primary Outcome Measures
Name Time Method Percentage of Randomized Patients Who Are Responders Up to the first 6 cycles of treatment The percentage of patients who are responders will be tabulated, including a 95% confidence interval on the response rate. Responders are defined as patients who achieve a best overall response of complete response (CR), very good partial response (VGPR), or partial response (PR) per the International Neuroblastoma Response Criteria (INRC). Per INRC: CR= Disappearance of all target lesions. No evidence of tumor at any site; VGPR= \>90% decrease of the disease measurement for CT/MRI target lesions. All pre-existing bone lesions with CR by MIBG; MIBG scan can be stable disease (SD) or CR in soft tissue lesions corresponding to lesions on CT/MRI. CR in bone marrow. No new sites of tumor; PR= \>=30% decrease in the disease measurement for CT/MRI target lesions. Bone marrow with CR. MIBG with either PR/CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Homovanillic acid (HVA)/Vanillylmandelic acid (VMA) may still be elevated.
Percentage of Patients in the Dinutuximab Arm Who Are Responders Up to the first 6 cycles of treatment Percentage of patients who are responders to therapy with dinutuximab will be tabulated, including a 95% confidence interval on the response rate. Responders are defined as patients who achieve a best overall response of complete response (CR), very good partial response (VGPR), or partial response (PR) per the International Neuroblastoma Response Criteria (INRC). Per INRC: CR= Disappearance of all target lesions. No evidence of tumor at any site; VGPR= \>90% decrease of disease measurement for CT/MRI target lesions. All pre-existing bone lesions with CR by MIBG; MIBG scan can be stable disease (SD) or CR in soft tissue lesions corresponding to lesions on CT/MRI. CR in bone marrow. No new sites of tumor; PR= ≥30% decrease in disease measurement for CT/MRI target lesions. Bone marrow with CR. MIBG with either PR/CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Homovanillic acid (HVA)/ Vanillylmandelic acid (VMA) may still be elevated.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (157)
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, 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
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸Las Vegas, Nevada, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸Indianapolis, Indiana, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Children's Hospital of San Antonio
🇺🇸San Antonio, Texas, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
UCSF Medical Center-Parnassus
🇺🇸San Francisco, California, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Kaiser Permanente Downey Medical Center
🇺🇸Downey, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Lee Memorial Health System
🇺🇸Fort Myers, Florida, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸Pensacola, Florida, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸Oak Lawn, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Johns Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸Atlanta, Georgia, United States
Saint Mary's Hospital
🇺🇸West Palm Beach, Florida, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, 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
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Nevada Cancer Research Foundation NCORP
🇺🇸Las Vegas, Nevada, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Dartmouth Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
University Medical Center of Southern Nevada
🇺🇸Las Vegas, Nevada, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
Sunrise Hospital and Medical Center
🇺🇸Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸Las Vegas, Nevada, United States
University of Rochester
🇺🇸Rochester, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸New Hyde Park, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
The Children's Hospital at TriStar Centennial
🇺🇸Nashville, Tennessee, United States
BI-LO Charities Children's Cancer Center
🇺🇸Greenville, South Carolina, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
Medical City Dallas Hospital
🇺🇸Dallas, Texas, United States
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
East Tennessee Childrens Hospital
🇺🇸Knoxville, Tennessee, United States
Penn State Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸San Antonio, Texas, United States
University of Virginia Cancer Center
🇺🇸Charlottesville, Virginia, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
The Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Starship Children's Hospital
🇳🇿Grafton, Auckland, New Zealand
Janeway Child Health Centre
🇨🇦Saint John's, Newfoundland and Labrador, Canada
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Children's Hospital
🇨🇦London, Ontario, Canada
Queensland Children's Hospital
🇦🇺South Brisbane, Queensland, Australia
Princess Margaret Hospital for Children
🇦🇺Perth, Western Australia, Australia
West Virginia University Healthcare
🇺🇸Morgantown, West Virginia, United States
Royal Children's Hospital-Brisbane
🇦🇺Herston, Queensland, Australia
San Jorge Children's Hospital
🇵🇷San Juan, Puerto Rico
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Quebec
🇨🇦Quebec, Canada
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸Denver, Colorado, United States
Children's Hospital and Medical Center of Omaha
🇺🇸Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Legacy Emanuel Children's Hospital
🇺🇸Portland, Oregon, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, 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
Christchurch Hospital
🇳🇿Christchurch, New Zealand
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Mission Hospital
🇺🇸Asheville, North Carolina, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
MedStar Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Saint Luke's Cancer Institute - Boise
🇺🇸Boise, Idaho, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, 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
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
University of Illinois
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Eastern Maine Medical Center
🇺🇸Bangor, Maine, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
Ascension Saint John Hospital
🇺🇸Detroit, Michigan, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Michigan State University Clinical Center
🇺🇸East Lansing, Michigan, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
NYU Winthrop Hospital
🇺🇸Mineola, New York, United States
Albany Medical Center
🇺🇸Albany, 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
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸Toledo, Ohio, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Sutter Medical Center Sacramento
🇺🇸Sacramento, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸Orlando, Florida, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Children's Hospital Medical Center of Akron
🇺🇸Akron, Ohio, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
Children's Hospital New Orleans
🇺🇸New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
🇺🇸New Orleans, Louisiana, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
Blank Children's Hospital
🇺🇸Des Moines, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
University of Wisconsin Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States