Biological Therapy, Sargramostim, and Isotretinoin in Treating Patients With Relapsed or Refractory Neuroblastoma

Phase 2

Completed

Conditions: Recurrent Neuroblastoma

Interventions: Biological: hu14.18-IL2 fusion protein
Drug: isotretinoin
Biological: sargramostim
Other: laboratory biomarker analysis

Registration Number: NCT01334515

Lead Sponsor: Children's Oncology Group

Brief Summary: This phase II trial is studying how well hu14.18-interleukin-2 (IL2) fusion protein works when given together with sargramostim and isotretinoin in treating patients with relapsed or refractory neuroblastoma. Biological therapy, such as hu14.18-IL2 fusion protein, and sargramostim work in different ways to stimulate the immune system and stop tumor cells from growing. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving hu14.18-IL2 fusion protein together with sargramostim and isotretinoin may kill more tumor cells.

Detailed Description: PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of sargramostim (GM-CSF) and isotretinoin given in combination with hu14.18-IL-2 (hu14.18-IL2 fusion protein), as a test of feasibility for a future Phase III study.

II. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma with disease measurable by standard radiographic criteria (stratum-1).

III. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma evaluable only by meta iodo benzyl guanidine I 123 (MIBG) scintigraphy and/or bone marrow histology (stratum-2).

SECONDARY OBJECTIVES:

I. To describe the disease burden of stratum-2 patients by semi-quantitative assessment of bone marrow and MIBG scintigraphy and determine whether there is an association between lower disease burden and response to hu14.18-IL2.

II. To assess molecular parameters of response (reverse-transcriptase (RT) polymerase chain reaction (PCR)) for patients meeting complete response (CR) criteria.

III. To evaluate the immunologic activation induced in vivo by hu14.18-IL2. IV. To determine the induction of anti-hu14.18-IL2 antibody by treatment with hu14.18-IL2.

V. To test for associations between tumor response versus immune activation and anti-hu14.18-IL2 activity, and between measurements of toxicity versus immune activation and anti-hu14.18-IL2 activity.

OUTLINE: This is a multicenter study. Patients are stratified according to measurable disease (disease measurable by standard radiographic criteria \[stratum-1\] vs disease evaluable only by meta iodo benzyl guanidine I 123 (MIBG) and/or bone marrow histology \[stratum-2\]).

Patients receive sargramostim subcutaneously (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin orally (PO) twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then yearly for 2 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

The target tumor is limited to neuroblastoma; patients must have had histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines at the time of initial diagnosis
Patients must have resistant/refractory or recurrent neuroblastoma
Tumor imaging and bone marrow evaluation for histologic analysis of marrow tumor cell quantity must be obtained within 3 weeks (21 days) prior to enrollment onto study and patients must have one of the following:
- Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT) scan, or x-ray defined as minimum of 20 mm in at least one dimension; measurable is defined as minimum of 20 mm in at least one dimension; for patients who are in first response (i.e., those patients with persistent sites of tumor after frontline therapy, but who have never relapsed), a biopsy of a lesion or bone marrow must demonstrate viable neuroblastoma following completion of therapy; if the lesion was irradiated, the biopsy must be done at least 4 weeks after radiation is completed
- Meta iodo benzyl guanidine I 123 (MIBG) scan with positive uptake at minimum of one site; for patients in first response, a biopsy of site must demonstrate viable tumor; if lesion was radiated, biopsy must be done at least 4 weeks after radiation completed
- Bone marrow with tumor cells seen on routine morphology (not by neuron specific enolase (NSE) staining only) of bilateral aspirate and/or biopsy on one bone marrow sample
Patients must have a performance status of 0, 1 or 2; use Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age
Patients must have a life expectancy of ≥ 8 weeks
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto this study (4 weeks if prior nitrosourea).
Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a non-myelosuppressive biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; for information on half-lives of these agents, refer to the table provided in the following link: https://members.childrensoncologygroup.org/_files/disc/dvl/Half-lifetableforeligibility.pdf
External beam radiation therapy (XRT): >= 2 wks for local palliative XRT (small port); >= 6 months must have elapsed if prior craniospinal XRT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation
Autologous stem cell transplant (ASCT): Patients are eligible > 56 days after autologous stem cell infusion following myeloablative therapy; patients receiving an autologous stem cell infusion to support non-myeloablative therapy (including 131I-MIBG given as a single agent) are eligible at any time as long as they meet the hematologic and other organ function criteria for eligibility; patients who have received an allogenic stem cell transplant are excluded
radioactive iodine (131 I) MIBG therapy: Patients are eligible > 6 weeks after therapeutic 131I-MIBG
Study specific limitations on prior therapy: Subjects who have previously received in vivo anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging, are eligible unless they have had progressive disease or a severe allergic reaction while receiving prior anti-disialoganglioside (GD2) therapy; subjects who have received autologous marrow infusions or autologous stem cell infusions using monoclonal antibody linked to beads to purge specimens, but no other form of anti-GD2 monoclonal antibody, are eligible
Growth factor(s): Must not have received within 1 week of entry onto this study
Steroids: Patients who require or are likely to require corticosteroid or other immunosuppressive drugs for intercurrent disease (any other significant medical problem related to or independent from the neuroblastoma or its treatment) while tentatively scheduled to be 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 transfusion in order to avoid allergic transfusion reactions
Peripheral absolute phagocyte count (APC=neutrophils + monocytes) >= 1000/uL
Platelet count ≥ 20,000/μL*
Hemoglobin ≥ 8 g/dL*
Transfusions are permitted to meet these platelet and hemoglobin criteria, if the patient is known to have a history of bone marrow involvement with tumor; patients with platelet counts < 20,000/uL who are refractory to platelet transfusions are not eligible for this study; patients requiring transfusions of platelets or red blood cells (RBC) to meet eligibility criteria will not be evaluable for hematologic toxicity
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR serum creatinine based on age/gender as follows:
- 0.4 mg/dL (1 month to < 6 months of age)
- 0.5 mg/dL (6 months to < 1 years of age)
- 0.6 mg/dL (1 to < 2 years of age)
- 0.8 mg/dL (2 to < 6 years of age)
- 1.0 mg/dL (6 to < 10 years of age)
- 1.2 mg/dL (10 to < 13 years of age)
- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
Total bilirubin =< 1.5 times upper limit of normal (ULN)
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x upper limit of normal (ULN) for age
Shortening fraction of >= 27% by echocardiogram
Ejection fraction of >= 55% by gated radionuclide study (interleukin 2 [IL2] is associated with capillary leak and, at high doses, pulmonary edema)
Corrected QT (QTC) interval < 450 msec
Due to risk of IL2 associated vascular leak and pulmonary edema, patients must have normal respiratory function; this is defined as no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% on room air; if pulmonary function tests (PFTs) are performed, the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) must be greater than 60%
Patients with a history of central nervous system (CNS) disease must have no clinical or radiological evidence of CNS disease at the time of protocol enrollment; (it is currently unknown whether hu14.18-IL2 penetrates the blood brain barrier to provide effective CNS treatment)
Patients with seizure disorders may be enrolled if on anti-convulsants and well-controlled
CNS toxicity =< grade 2

Exclusion Criteria

Females of childbearing potential must have a negative pregnancy test
Patients of childbearing potential must agree to use an effective birth control method (as isotretinoin is known to be teratogenic)
Female patients who are lactating must agree to stop breast-feeding
Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance are not eligible
Patients with symptomatic pleural effusions or ascites (requiring constant or intermittent drainage) because IL2 is associated with capillary leak are not eligible
Patients who have had major surgery (i.e., laparotomy or thoracotomy) within the past 2 weeks are not eligible, due to the capillary leak associated with IL2
Patients with organ allografts (including bone marrow or stem cell) due to the immune activating effects of IL2 are not eligible; patients receiving prior autologous bone marrow or stem cell re-infusions are eligible
Patients with prior history of ventilator support related to lung injury (lung injury such as pneumonia, hemorrhagic pneumonitis, capillary leakage) are excluded
Patients with significant serious intercurrent illnesses (any other ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and which is expected to interfere with the action of hu14.18-IL2 or to significantly increase the severity of the toxicities experienced from hu14.18-IL2 treatment are not eligible

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Disease evaluable only by I-MIBG or BM histology	hu14.18-IL2 fusion protein	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
Disease measured by standard radiographic criteria	sargramostim	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
Disease measured by standard radiographic criteria	laboratory biomarker analysis	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
Disease measured by standard radiographic criteria	hu14.18-IL2 fusion protein	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
Disease evaluable only by I-MIBG or BM histology	sargramostim	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
Disease evaluable only by I-MIBG or BM histology	laboratory biomarker analysis	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
Disease measured by standard radiographic criteria	isotretinoin	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.
Disease evaluable only by I-MIBG or BM histology	isotretinoin	Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs)	Up to 10 courses	Test for tolerability and monitor for the occurrence of too many unacceptable DLTs using a two-stage stopping rule: (Stage 1) Accrue 10 patients. If more than 1 experience at least one unacceptable DLT during the first treatment cycle, the regimen will be considered to have unacceptable toxicity, and accrual will be temporarily closed, to review all relevant data and consider modifying the regimen to improve safety. If 1 or no patients have an unacceptable DLT in the first treatment cycle, then continue. (Stage 2) Accrue 20 more patients. If 7 or more experience at least one unacceptable DLT in the first treatment cycle, temporarily close the study for possible dosing-safety modifications. If 6 or fewer have an unacceptable DLT in the first treatment cycle, it is reasonable to assume that the combination therapy is safe.

Secondary Outcome Measures

Name	Time	Method
Overall Response Evaluated in This Study Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors (RECIST)	Every two cycles (each cycle lasts 28 days)	Number of patients where best overall response is a complete response (CR)-\[disappearance of all target lesions and disappearance of any other measureable disease\], a very Good Partial Response (VGPR)- \[\>90% decrease of the disease measurement for CT/MRI lesions, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size\], or partial Response (PR)- \[\>= 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size\], and maintains the response. It is possible that a subject's response to therapy may not occur until after several months of treatment. In order to prevent bias, the maximum duration of time/treatment over which a subject's response is to be assessed for determination of the best overall response is after the completion of up to 10 courses.

Trial Locations

Locations (76): Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Lehigh Valley Hospital - Muhlenberg
🇺🇸
Bethlehem, Pennsylvania, United States
Natalie W Bryant Cancer Center
🇺🇸
Tulsa, Oklahoma, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
Childrens Hospital-King's Daughters
🇺🇸
Norfolk, Virginia, United States
The Toledo Hospital/Toledo Children's Hospital
🇺🇸
Toledo, Ohio, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
The Children's Medical Center of Dayton
🇺🇸
Dayton, Ohio, United States
Penn State Hershey Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Children's Oncology Group
🇺🇸
Arcadia, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
Children's Hospital Central California
🇺🇸
Madera, California, United States
Childrens Hospital of Orange County
🇺🇸
Orange, California, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Nemours Children's Clinic - Jacksonville
🇺🇸
Jacksonville, Florida, United States
Florida Hospital
🇺🇸
Orlando, Florida, United States
All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
University of Hawaii
🇺🇸
Honolulu, Hawaii, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
Southern Illinois University
🇺🇸
Springfield, Illinois, United States
Raymond Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
University of Kentucky
🇺🇸
Lexington, Kentucky, United States
Kosair Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Children's Hospital-Main Campus
🇺🇸
New Orleans, Louisiana, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Cardinal Glennon Children's Medical Center
🇺🇸
Saint Louis, Missouri, United States
Morristown Memorial Hospital
🇺🇸
Morristown, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Carolinas Medical Center
🇺🇸
Charlotte, North Carolina, United States
Presbyterian Hospital
🇺🇸
Charlotte, North Carolina, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
University of California San Francisco Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Vanderbilt-Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Primary Children's Medical Center
🇺🇸
Salt Lake City, Utah, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Kalamazoo Center for Medical Studies
🇺🇸
Kalamazoo, Michigan, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Hospital Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Saint Vincent Hospital
🇺🇸
Green Bay, Wisconsin, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
Alberta Children's Hospital
🇨🇦
Calgary, Alberta, Canada
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
Miami Children's Hospital
🇺🇸
Miami, Florida, United States