Isotretinoin With or Without Dinutuximab, Aldesleukin, and Sargramostim Following Stem Cell Transplant in Treating Patients With Neuroblastoma

Phase 3

Active, not recruiting

• Conditions: Recurrent Neuroblastoma; Regional Neuroblastoma; Stage 4S Neuroblastoma; Stage 4 Neuroblastoma; Localized Resectable Neuroblastoma; Localized Unresectable Neuroblastoma
• Interventions: Drug: Isotretinoin; Biological: Aldesleukin; Other: Laboratory Biomarker Analysis; Biological: Dinutuximab; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Biological: Sargramostim

• Registration Number: NCT00026312
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This partially randomized phase III trial studies isotretinoin with dinutuximab, aldesleukin, and sargramostim to see how well it works compared to isotretinoin alone following stem cell transplant in treating patients with neuroblastoma. Drugs used in chemotherapy, such as isotretinoin, 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. Monoclonal antibodies, such as dinutuximab, may block tumor growth in different ways by targeting certain cells. Aldesleukin and sargramostim may stimulate a person's white blood cells to kill cancer cells. It is not yet known if chemotherapy is more effective with or without dinutuximab, aldesleukin, and sargramostim following stem cell transplant in treating neuroblastoma.

Detailed Description

PRIMARY OBJECTIVES:

I. Determine if monoclonal antibody Ch14.18 (dinutuximab) + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves event free survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-autologous stem cell transplant (ASCT) response of complete response (CR), very good partial response (VGPR), or partial response (PR).

SECONDARY OBJECTIVES:

I. Determine if monoclonal antibody Ch14.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves overall survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

II. Determine if immunotherapy + RA improves event free survival and overall survival as compared to RA alone, in the subgroup of high risk International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

III. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines.

IV. To compare the outcome data of the patients with persistent disease documented by biopsy (Stratum 07) to the historical data for the analogous patients from Children's Cancer Group (CCG)-3981.

V. To further describe and refine the event free survival (EFS) and overall survival (OS) estimates and baseline characteristics for subjects receiving Ch14.18 + cytokines + RA, following cessation of the randomized portion of the study.

VI. To further describe the safety and toxicity of Ch14.18 + cytokines + RA under the new administration guidelines implemented following cessation of the randomized portion of the study with focus on: a) number of courses delivered per subject; b) number of dose reductions or stoppage (ch14.18 and/or interleukin \[IL\]-2); and c) number of toxic deaths.

TERTIARY OBJECTIVES:

I. In the subgroup of neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR, determine if there is a difference between the two randomized regimens in reducing the minimal residual disease (MRD) burden as detected by the following parameters: meta-iodobenylguanidine (MIBG) scan, immunocytology (IC) of blood and bone marrow samples, reverse transcriptase-polymerase chain reaction (RT-PCR) for tyrosine hydroxylase, phosphoglycolate phosphatase (PGP) 9.5, and melanoma antigen family A, 1 (MAGE-1) in blood and bone marrow.

II. Determine if change from baseline of MRD is associated with event free and overall survival.

III. Determine whether tumor biology at diagnosis correlates with event-free and overall survival, for either of the randomized regimens.

IV. To explore the relationship between antibody-dependent cellular cytoxicity (ADCC) and EFS.

V. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy.

VI. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if these levels and/or genetic variations correlate with EFS or systemic toxicity.

VII. To determine the potential effect of ch14.18 on cardiac repolarization and to evaluate ch14.18 plasma levels.

VIII. To determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions and blood levels of ch14.18.

IX. To determine if the genotype of Fc receptor (FcR) and killer cell immunoglobulin-like receptor (Kir)/Kir-ligand correlate with EFS.

X. To determine if natural killer cell p30-related protein (NKp30) isoform expression and single nucleotide polymorphism (SNP), and circulating ligand B7-H6 are prognostic of EFS or OS.

OUTLINE: Patients stratified with biopsy-confirmed post-ASCT persistent disease who are also enrolled on Children's Oncology Group (COG)-A3973 or COG-ANBL0532 are assigned to treatment Arm II. Patients in the first set of strata are randomized to 1 of 2 treatment arms.

ARM I: Beginning on day 56-85 post-ASCT, patients receive isotretinoin orally (PO) twice daily (BID) for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy. (closed to accrual as of 4/16/2009)

ARM II: Beginning on day 56-85 post-ASCT, patients receive immunotherapy comprising sargramostim (GM-CSF) subcutaneously (SC) or intravenously (IV) over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.

After completion of study treatment, patients are followed up periodically for 10 years.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study Start: 2001-10-18
• Study First Submitted: 2001-11-09
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2012-01-12
• Results First Submitted: 2017-02-09
• Results First Submitted QC: 2017-02-09
• Results First Posted: 2017-03-29
• Status Verified: 2024-12
• Last Update Submitted: 2025-01-01
• Last Update Posted: 2025-01-03
• Study Completion: 2025-03-07

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 1449

Inclusion Criteria

• All patients must be diagnosed with neuroblastoma, and categorized as high risk at the time of diagnosis; exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible

• All patients must have completed therapy including intensive induction followed by ASCT and radiotherapy to be eligible for ANBL0032; radiotherapy may be waived for patients who either have small adrenal masses which are completely resected up front, or who never have an identifiable primary tumor; examples of such therapies include:

  • Following treatment per A3973 protocol

  • Following treatment per Pediatric Oncology Group (POG)-9341/9342 protocol

  • Following treatment per CCG3891

  • Following treatment on New Approaches to Neuroblastoma Therapy (NANT) 2001-02

  • Enrollment on or following treatment per ANBL02P1

  • Enrollment on or following treatment per ANBL07P1

  • Tandem transplant patients are eligible:

    • Following treatment on or per ANBL0532
    • Following treatment per POG 9640
    • Following treatment per COG ANBL00P1
    • Following treatment per CHP 594/Dana-Farber Cancer Institute (DFCI) 34-DAT

• No more than 12 months from the date of starting the first induction chemotherapy after diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem ASCT patients, this will be the date of the FIRST stem cell infusion; exception: for those who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma, the 12 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT

• At pre-ASCT evaluation patients must meet the International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases and bone metastases; patients who meet those criteria must also meet the protocol specified criteria for bone marrow response as outlined below:

  • =< 10% tumor (of total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy
  • Patient who have no tumor seen on the prior bone marrow, and then have =< 10% tumor on any of the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment evaluation will also be eligible (note that per INRC this would have been defined as "overall" response of progressive disease [PD])

• Prior to enrollment on ANBL0032, a determination of mandatory disease staging must be performed (tumor imaging studies including computed tomography [CT] or magnetic resonance imaging [MRI], MIBG scan, and vanillylmandelic acid [VMA]/homovanillic acid [HVA]; bone marrow aspirates are required but biopsy may be omitted if negative prior to ASCT); this disease assessment is required for eligibility and should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before enrollment

  • For those with residual disease before radiotherapy, re-evaluation of irradiated residual tumors is preferably performed at the earliest 5 days after completing radiotherapy; patients with residual disease are eligible; biopsy is not required; patients who have biopsy proven residual disease after ASCT will be enrolled on Stratum 07
  • Patients must not have progressive disease at the time of study enrollment except for protocol specified bone marrow response and except for elevations of catecholamines as the only sign of disease in a patient who had normal catecholamines at pre-ASCT evaluation

• Patients must be enrolled before treatment begins; the date protocol therapy is projected to start must be no later than ten (10) calendar days after the date of study enrollment; patients should be enrolled preferably between day 56 and day 85 after peripheral blood stem cell (PBSC) infusion (day from 2nd stem cell infusion for tandem transplant); patients must be enrolled no later than day 200 after PBSC infusion; enrollment must occur after completion of radiotherapy, and after completion of tumor assessment post-ASCT and radiotherapy; informed consent should be obtained within 3 weeks pre-ASCT up to the time of registration

• Patients must not have received prior anti-disialoganglioside (GD2) antibody therapy

• Patients must have a Lansky or Karnofsky performance scale score of >= 50% and patients must have a life expectancy of >= 2 months

• Total absolute phagocyte count (APC = %neutrophils + %monocytes) X white blood cell (WBC) is at least 1000/uL

• 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:

  • No greater than 0.4 mg/dL (1 month to < 6 months)
  • No greater than 0.5 mg/dL (6 months to < 1 year)
  • No greater than 0.6 mg/dL (1 to < 2 years)
  • No greater than 0.8 mg/dL (2 to < 6 years)
  • No greater than 1.0 mg/dL (6 to < 10 years)
  • No greater than 1.2 mg/dL (10 to < 13 years)
  • No greater than 1.4 mg/dL (>= 13 years [female])
  • No greater than 1.5 mg/dL (13 to < 16 years [male])
  • No greater than 1.7 mg/dL (>= 16 years [male])

• Total bilirubin =< 1.5 x normal

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x normal

• Veno-occlusive disease, if present, should be stable or improving

• Shortening fraction of >= 27% by echocardiogram, or if shortening fraction abnormal, ejection fraction of >= 55% by gated radionuclide study or echocardiogram; note: the echocardiogram or gated radionuclide study must be performed within 4 weeks prior to enrollment

• Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) > 60% predicted by pulmonary function test; for children who are unable to do pulmonary function tests (PFTs), no evidence of dyspnea at rest and no exercise intolerance should be documented; note: the pulmonary function test must be performed within 4 weeks prior to enrollment

• Patients with seizure disorder may be enrolled if on anticonvulsants and well-controlled; central nervous system (CNS) toxicity < grade 2

• Written informed consent in accordance with institutional and Food and Drug Administration (FDA) guidelines must be obtained from parent or legal guardian

• Females of childbearing potential must have a negative pregnancy test; patients of childbearing potential must agree to use an effective birth control method; female patients who are lactating must agree to stop breast-feeding

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (isotretinoin) (closed to accrual as of 4/16/2009)	Laboratory Biomarker Analysis	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive isotretinoin PO BID for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy.
Arm I (isotretinoin) (closed to accrual as of 4/16/2009)	Pharmacological Study	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive isotretinoin PO BID for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy.
Arm I (isotretinoin) (closed to accrual as of 4/16/2009)	Quality-of-Life Assessment	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive isotretinoin PO BID for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy.
Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin)	Laboratory Biomarker Analysis	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.
Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin)	Pharmacological Study	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.
Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin)	Quality-of-Life Assessment	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.
Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin)	Dinutuximab	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.
Arm I (isotretinoin) (closed to accrual as of 4/16/2009)	Isotretinoin	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive isotretinoin PO BID for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy.
Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin)	Isotretinoin	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.
Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin)	Sargramostim	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.
Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin)	Aldesleukin	Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.

Primary Outcome Measures

Name	Time	Method
Event-Free Survival (EFS)	Three years	Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only

Secondary Outcome Measures

Name	Time	Method
Number of Courses of Therapy Delivered	Courses 1-6	Number of courses of therapy delivered for patients randomized to RA + Immunotherapy vs. patients non-randomly assigned to RA + Immunotherapy, excluding patients with persistent disease.
Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0	From enrollment to follow-up	Proportion of patients experiencing at least one Grade 3 or higher toxicity.
Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial	Three years	OS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
Event-Free Survival (EFS)	Three years	Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only for the subgroup of randomized patients with INSS Stage 4 disease. Descriptive comparison of outcome data for patients with persistent disease documented by biopsy to historical data for the analogous patients from CCG-3981.
Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial	Three years	EFS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
Overall Survival (OS)	Three years	Comparison to determine if RA + Immunotherapy improves OS as compared to RA Only. Comparison to determine if RA + Immunotherapy improves OS as compared to RA only and for the subgroup of randomized patients with INSS Stage 4 disease.

Trial Locations

Locations (197)

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

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

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

University of Hawaii Cancer Center; 🇺🇸 Honolulu, Hawaii, United States

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

Tripler Army Medical Center; 🇺🇸 Honolulu, Hawaii, United States

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

Laura and Isaac Perlmutter Cancer Center at NYU Langone; 🇺🇸 New York, New York, United States

Mount Sinai Hospital; 🇺🇸 New York, New York, 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

Greenville Cancer Treatment 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

Saint Jude Children's Research Hospital; 🇺🇸 Memphis, 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

Cook Children's Medical Center; 🇺🇸 Fort Worth, Texas, United States

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

Methodist Children's Hospital of South Texas; 🇺🇸 San Antonio, Texas, United States

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

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

University of Alabama at Birmingham Cancer Center; 🇺🇸 Birmingham, Alabama, United States

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

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

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

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

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

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

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, 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

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

Yale University; 🇺🇸 New Haven, Connecticut, United States

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

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

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Broward Health Medical Center; 🇺🇸 Fort Lauderdale, Florida, United States

Lee Memorial Health System; 🇺🇸 Fort Myers, Florida, 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

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

AdventHealth Orlando; 🇺🇸 Orlando, Florida, United States

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

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

Orlando Health Cancer Institute; 🇺🇸 Orlando, Florida, United States

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

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

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

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

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

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

Augusta University Medical Center; 🇺🇸 Augusta, Georgia, 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

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

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

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

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Sinai Hospital of Baltimore; 🇺🇸 Baltimore, Maryland, United States

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

Walter Reed National Military Medical Center; 🇺🇸 Bethesda, 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

Baystate Medical Center; 🇺🇸 Springfield, Massachusetts, United States

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

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

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

Hurley Medical Center; 🇺🇸 Flint, 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

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

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

Nevada Cancer Research Foundation NCORP; 🇺🇸 Las Vegas, 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

Overlook Hospital; 🇺🇸 Summit, New Jersey, United States

University of New Mexico Cancer Center; 🇺🇸 Albuquerque, New Mexico, United States

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

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

University of Rochester; 🇺🇸 Rochester, 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

Duke University Medical Center; 🇺🇸 Durham, 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

Mercy 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

Legacy Emanuel Hospital and Health Center; 🇺🇸 Portland, Oregon, United States

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

University of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, 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

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

Sydney Children's Hospital; 🇦🇺 Randwick, New South Wales, Australia

The Children's Hospital at Westmead; 🇦🇺 Westmead, New South Wales, Australia

Royal Brisbane and Women's Hospital; 🇦🇺 Herston, Queensland, Australia

Royal Children's Hospital-Brisbane; 🇦🇺 Herston, Queensland, Australia

Queensland Children's Hospital; 🇦🇺 South Brisbane, Queensland, Australia

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

Royal Children's Hospital; 🇦🇺 Parkville, Victoria, Australia

Princess Margaret Hospital for Children; 🇦🇺 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

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

CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL); 🇨🇦 Quebec, Canada

Starship Children's Hospital; 🇳🇿 Grafton, Auckland, New Zealand

Christchurch Hospital; 🇳🇿 Christchurch, New Zealand

San Jorge Children's Hospital; 🇵🇷 San Juan, Puerto Rico