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NCT03533582Active, not recruitingPhase 3

Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery

Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)

Source: ClinicalTrials.gov · Last updated 14 Sept 2026

Brief summary (registry, in English)

This partially randomized phase II/III trial studies how well, in combination with surgery, cisplatin and combination chemotherapy works in treating children and young adults with hepatoblastoma or hepatocellular carcinoma. Drugs used in chemotherapy, such as cisplatin, doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan, sorafenib, gemcitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving combination chemotherapy may kill more tumor cells than one type of chemotherapy alone.

Status (registry)
Active, not recruiting
Phase (registry)
Phase 3
Study type
Interventional
Enrollment
537 (estimated)
First submitted
11 May 2018
Start date
24 May 2018
Primary completion date
31 Mar 2027
Lead sponsor
Children's Oncology Group
NCT number
NCT03533582

What you commit to

  • Study type: Interventional · Phase 3
  • Planned participants: 537
  • From 24 May 2018 to the primary completion date, 31 Mar 2027
  • 205 sites in 6 countries
  • Visits and tests: ask the trial team, the registry does not list them

Built from the registry fields of ClinicalTrials.gov. It describes the study, not your situation.

Who cannot take part

Copied verbatim from ClinicalTrials.gov and grouped by topic. Only the trial team decides who can take part.

Prior treatment

  • Patients who are currently receiving another investigational drug
  • Patients who are currently receiving other anticancer agents
  • Patients who previously received a solid organ transplant, other than those who previously received an orthotopic liver transplantation (OLT) as primary treatment of their hepatocellular carcinoma
  • Group D:
    • Patients with chronic inflammatory bowel disease and/or bowel obstruction
    • Patients with concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment
  • These criteria apply ONLY to patients who may receive chemotherapy (all groups other than Group E1):
    • Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
    • Lactating females who plan to breastfeed their infants
    • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
    • Note for Group F: patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment

Other illness

  • Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible
  • Patients with uncontrolled infection
  • Patients with hypersensitivity to any drugs on their expected treatment arm

Lab values

  • Group F:
    • Patients with peripheral sensitive neuropathy with functional impairment
    • Patients with a personal or family history of congenital long QT syndrome

Other

  • Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)

Who the study is looking for

  • Patients in Group F must have a body surface area (BSA) \>= 0.6 m\^2
  • 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 who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified, should be classified and treated per hepatoblastoma treatment arms; note that rapid central pathology review is required in some cases; please note: all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by immunohistochemistry (IHC) according to the practices at the institution
  • Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining
  • For all Group A patients, WDF status as determined by rapid review will be used to further stratify patients to Group A1 or A2
    • For Groups B, C and D, rapid review is required if patients are either \>= 8 years of age or have an alphafetoprotein (AFP) =\< 100 at diagnosis
    • For all Groups E and F patients, rapid central pathology review is required
  • In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy
    • Clinical situations in which emergent treatment may be indicated include, but are not limited to, the following circumstances:
    • Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.)
    • Uncorrectable coagulopathy
    • For a patient to maintain eligibility for AHEP1531 when emergent treatment is given, the following must occur:
    • The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment
    • Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment
    • Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to undergoing a diagnostic biopsy, pathologic review of material obtained in the future during either biopsy or surgical resection must either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be included in the analysis of the study aims
  • Patients may have had surgical resection of the hepatic malignancy prior to enrollment; all other anti-cancer therapy for the current liver lesion is prohibited
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 or
    • A serum creatinine based on age/gender as follows:
    • Age: maximum serum creatinine (mg/dL)
    • 1 month to \< 6 months: 0.4 (male and female)
    • 6 months to \< 1 year: 0.5 (male and female)
    • 1 to \< 2 years: 06 (male and female)
    • 2 to \< 6 years: 0.8 (male and female)
    • 6 to \< 10 years: 1 (male and female)
    • 10 to \< 13 years: 1.2 (male and female)
    • 13 to \< 16 years: 1.5 (male), 1.4 (female)
    • \>= 16 years: 1.7 (male), 1.4 (female)
  • Total bilirubin =\< 5 x upper limit of normal (ULN) for age
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 10 x upper limit of normal (ULN) for age
  • Shortening fraction of \>= 28% by echocardiogram (for patients on doxorubicin-containing regimens \[Groups C, D, E2, and F\] assessed within 8 weeks prior to study enrollment) or
  • Ejection fraction of \>= 47% by echocardiogram or radionuclide angiogram (for patients on doxorubicin-containing regimens \[Groups C, D, E2, and F\] assessed within 8 weeks prior to study enrollment)
  • Group F patients only: QT/corrected QT (QTc) interval =\< 450 milliseconds for males and =\< 470 milliseconds for females (assessed within 8 weeks prior to study enrollment)
  • Normal pulmonary function tests (including diffusion capacity of the lung for carbon monoxide \[DLCO\]) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy \[Groups A, B, C, D, E2, F\]); for patients who do not have respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Age in the registry: - to 30 years · Sex: All · Does not accept healthy volunteers

Full criteria on ClinicalTrials.gov

Sites (205)

Sites in registry order. Pick your city on the disease page to sort them by distance.

SiteCityCountrySite status
John Hunter Children's Hospital
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Hunter Regional Mail CentreAustraliaUnknown status
Women's and Children's Hospital-Adelaide
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North AdelaideAustraliaUnknown status
Royal Children's Hospital
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ParkvilleAustraliaUnknown status
Perth Children's Hospital
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PerthAustraliaUnknown status
Sydney Children's Hospital
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RandwickAustraliaUnknown status
Queensland Children's Hospital
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South BrisbaneAustraliaUnknown status
The Children's Hospital at Westmead
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WestmeadAustraliaUnknown status
Alberta Children's Hospital
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CalgaryCanadaUnknown status
University of Alberta Hospital
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EdmontonCanadaUnknown status
IWK Health Centre
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HalifaxCanadaUnknown status
McMaster Children's Hospital at Hamilton Health Sciences
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HamiltonCanadaUnknown status
Kingston Health Sciences Centre
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KingstonCanadaUnknown status
Children's Hospital
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LondonCanadaUnknown status
The Montreal Children's Hospital of the MUHC
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MontrealCanadaUnknown status
Centre Hospitalier Universitaire Sainte-Justine
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MontrealCanadaUnknown status
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
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QuébecCanadaUnknown status
Saskatoon Cancer Centre
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SaskatoonCanadaUnknown status
Jim Pattison Children's Hospital
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SaskatoonCanadaUnknown status
Hospital for Sick Children
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TorontoCanadaUnknown status
CancerCare Manitoba
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WinnipegCanadaUnknown status
Christchurch Hospital
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ChristchurchNew ZealandUnknown status
Starship Children's Hospital
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GraftonNew ZealandUnknown status
San Jorge Children's Hospital
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San JuanPuerto RicoUnknown status
University Pediatric Hospital
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San JuanPuerto RicoUnknown status
King Faisal Specialist Hospital and Research Centre
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RiyadhSaudi ArabiaUnknown status
Children's Hospital Medical Center of Akron
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AkronUnited StatesUnknown status
Albany Medical Center
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AlbanyUnited StatesUnknown status
University of New Mexico Cancer Center
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AlbuquerqueUnited StatesUnknown status
Lehigh Valley Hospital-Cedar Crest
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AllentownUnited StatesUnknown status
Providence Alaska Medical Center
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AnchorageUnited StatesUnknown status
C S Mott Children's Hospital
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Ann ArborUnited StatesUnknown status
Mission Hospital
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AshevilleUnited StatesUnknown status
Children's Healthcare of Atlanta - Arthur M Blank Hospital
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AtlantaUnited StatesUnknown status
Augusta University Medical Center
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AugustaUnited StatesUnknown status
Children's Hospital Colorado
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AuroraUnited StatesUnknown status
Dell Children's Medical Center of Central Texas
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AustinUnited StatesUnknown status
University of Maryland/Greenebaum Cancer Center
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BaltimoreUnited StatesUnknown status
Sinai Hospital of Baltimore
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BaltimoreUnited StatesUnknown status
Johns Hopkins University/Sidney Kimmel Cancer Center
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BaltimoreUnited StatesUnknown status
Eastern Maine Medical Center
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BangorUnited StatesUnknown status
Walter Reed National Military Medical Center
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BethesdaUnited StatesUnknown status
Children's Hospital of Alabama
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BirminghamUnited StatesUnknown status
Saint Luke's Cancer Institute - Boise
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BoiseUnited StatesUnknown status
Massachusetts General Hospital Cancer Center
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BostonUnited StatesUnknown status
Dana-Farber Cancer Institute
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BostonUnited StatesUnknown status
Tufts Children's Hospital
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BostonUnited StatesUnknown status
Roswell Park Cancer Institute
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BuffaloUnited StatesUnknown status
University of Vermont and State Agricultural College
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BurlingtonUnited StatesUnknown status
UNC Lineberger Comprehensive Cancer Center
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Chapel HillUnited StatesUnknown status
West Virginia University Charleston Division
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CharlestonUnited StatesUnknown status
Medical University of South Carolina
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CharlestonUnited StatesUnknown status
Novant Health Presbyterian Medical Center
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CharlotteUnited StatesUnknown status
Carolinas Medical Center/Levine Cancer Institute
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CharlotteUnited StatesUnknown status
University of Virginia Cancer Center
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CharlottesvilleUnited StatesUnknown status
T C Thompson Children's Hospital
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ChattanoogaUnited StatesUnknown status
University of Chicago Comprehensive Cancer Center
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ChicagoUnited StatesUnknown status
University of Illinois
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ChicagoUnited StatesUnknown status
Lurie Children's Hospital-Chicago
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ChicagoUnited StatesUnknown status
Cincinnati Children's Hospital Medical Center
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CincinnatiUnited StatesUnknown status
Rainbow Babies and Childrens Hospital
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ClevelandUnited StatesUnknown status
Cleveland Clinic Foundation
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ClevelandUnited StatesUnknown status
Prisma Health Richland Hospital
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ColumbiaUnited StatesUnknown status
University of Missouri Children's Hospital
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ColumbiaUnited StatesUnknown status
Nationwide Children's Hospital
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ColumbusUnited StatesUnknown status
Driscoll Children's Hospital
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Corpus ChristiUnited StatesUnknown status
UT Southwestern/Simmons Cancer Center-Dallas
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DallasUnited StatesUnknown status
Medical City Dallas Hospital
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DallasUnited StatesUnknown status
Geisinger Medical Center
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DanvilleUnited StatesUnknown status
Dayton Children's Hospital
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DaytonUnited StatesUnknown status
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
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DenverUnited StatesUnknown status
Blank Children's Hospital
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Des MoinesUnited StatesUnknown status
Henry Ford Health Saint John Hospital
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DetroitUnited StatesUnknown status
Wayne State University/Karmanos Cancer Institute
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DetroitUnited StatesUnknown status
Children's Hospital of Michigan
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DetroitUnited StatesUnknown status
Kaiser Permanente Downey Medical Center
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DowneyUnited StatesUnknown status
Duke University Medical Center
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DurhamUnited StatesUnknown status
Michigan State University
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East LansingUnited StatesUnknown status
El Paso Children's Hospital
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El PasoUnited StatesUnknown status
Inova Fairfax Hospital
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Falls ChurchUnited StatesUnknown status
Golisano Children's Hospital of Southwest Florida
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Fort MyersUnited StatesUnknown status
Cook Children's Medical Center
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Fort WorthUnited StatesUnknown status
UF Health Cancer Institute - Gainesville
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GainesvilleUnited StatesUnknown status
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
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Grand RapidsUnited StatesUnknown status
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
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Grand RapidsUnited StatesUnknown status
BI-LO Charities Children's Cancer Center
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GreenvilleUnited StatesUnknown status
Hackensack University Medical Center
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HackensackUnited StatesUnknown status
Connecticut Children's Medical Center
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HartfordUnited StatesUnknown status
Penn State Children's Hospital
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HersheyUnited StatesUnknown status
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
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HollywoodUnited StatesUnknown status
Kapiolani Medical Center for Women and Children
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HonoluluUnited StatesUnknown status
UT MD Anderson Cancer Center
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HoustonUnited StatesUnknown status
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
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HoustonUnited StatesUnknown status
Riley Hospital for Children
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IndianapolisUnited StatesUnknown status
Ascension Saint Vincent Indianapolis Hospital
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IndianapolisUnited StatesUnknown status
University of Iowa/Holden Comprehensive Cancer Center
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Iowa CityUnited StatesUnknown status
University of Mississippi Medical Center
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JacksonUnited StatesUnknown status
Nemours Children's Clinic-Jacksonville
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JacksonvilleUnited StatesUnknown status
West Michigan Cancer Center
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KalamazooUnited StatesUnknown status
Bronson Methodist Hospital
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KalamazooUnited StatesUnknown status
Children's Mercy Hospitals and Clinics
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Kansas CityUnited StatesUnknown status
East Tennessee Childrens Hospital
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KnoxvilleUnited StatesUnknown status
University Medical Center of Southern Nevada
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Las VegasUnited StatesUnknown status
Sunrise Hospital and Medical Center
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Las VegasUnited StatesUnknown status
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
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Las VegasUnited StatesUnknown status
Summerlin Hospital Medical Center
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Las VegasUnited StatesUnknown status
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
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LebanonUnited StatesUnknown status
University of Kentucky/Markey Cancer Center
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LexingtonUnited StatesUnknown status
Arkansas Children's Hospital
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Little RockUnited StatesUnknown status
Loma Linda University Medical Center
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Loma LindaUnited StatesUnknown status
Miller Children's and Women's Hospital Long Beach
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Long BeachUnited StatesUnknown status
Children's Hospital Los Angeles
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Los AngelesUnited StatesUnknown status
Mattel Children's Hospital UCLA
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Los AngelesUnited StatesUnknown status
Norton Children's Hospital
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LouisvilleUnited StatesUnknown status
UMC Cancer Center / UMC Health System
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LubbockUnited StatesUnknown status
Covenant Children's Hospital
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LubbockUnited StatesUnknown status
Valley Children's Hospital
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MaderaUnited StatesUnknown status
University of Wisconsin Carbone Cancer Center - University Hospital
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MadisonUnited StatesUnknown status
Marshfield Medical Center-Marshfield
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MarshfieldUnited StatesUnknown status
Loyola University Medical Center
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MaywoodUnited StatesUnknown status
Saint Jude Children's Research Hospital
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MemphisUnited StatesUnknown status
Banner Children's at Desert
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MesaUnited StatesUnknown status
University of Miami Miller School of Medicine-Sylvester Cancer Center
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MiamiUnited StatesUnknown status
Nicklaus Children's Hospital
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MiamiUnited StatesUnknown status
Children's Hospital of Wisconsin
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MilwaukeeUnited StatesUnknown status
University of Minnesota/Masonic Cancer Center
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MinneapolisUnited StatesUnknown status
Children's Hospitals and Clinics of Minnesota - Minneapolis
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MinneapolisUnited StatesUnknown status
West Virginia University Healthcare
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MorgantownUnited StatesUnknown status
Morristown Medical Center
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MorristownUnited StatesUnknown status
Vanderbilt University/Ingram Cancer Center
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NashvilleUnited StatesUnknown status
The Children's Hospital at TriStar Centennial
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NashvilleUnited StatesUnknown status
Newark Beth Israel Medical Center
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NewarkUnited StatesUnknown status
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
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New BrunswickUnited StatesUnknown status
Yale University
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New HavenUnited StatesUnknown status
The Steven and Alexandra Cohen Children's Medical Center of New York
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New Hyde ParkUnited StatesUnknown status
Children's Hospital New Orleans
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New OrleansUnited StatesUnknown status
Ochsner Medical Center Jefferson
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New OrleansUnited StatesUnknown status
Memorial Sloan-Kettering Cancer Center
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New YorkUnited StatesUnknown status
NYP/Weill Cornell Medical Center
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New YorkUnited StatesUnknown status
Mount Sinai Hospital
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New YorkUnited StatesUnknown status
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
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New YorkUnited StatesUnknown status
Laura and Isaac Perlmutter Cancer Center at NYU Langone
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New YorkUnited StatesUnknown status
Children's Hospital of The King's Daughters
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NorfolkUnited StatesUnknown status
UCSF Benioff Children's Hospital Oakland
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OaklandUnited StatesUnknown status
Kaiser Permanente-Oakland
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OaklandUnited StatesUnknown status
Advocate Children's Hospital-Oak Lawn
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Oak LawnUnited StatesUnknown status
University of Oklahoma Health Sciences Center
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Oklahoma CityUnited StatesUnknown status
Children's Hospital and Medical Center of Omaha
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OmahaUnited StatesUnknown status
University of Nebraska Medical Center
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OmahaUnited StatesUnknown status
Children's Hospital of Orange County
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OrangeUnited StatesUnknown status
AdventHealth Orlando
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OrlandoUnited StatesUnknown status
Arnold Palmer Hospital for Children
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OrlandoUnited StatesUnknown status
Nemours Children's Hospital
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OrlandoUnited StatesUnknown status
Lucile Packard Children's Hospital Stanford University
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Palo AltoUnited StatesUnknown status
Advocate Children's Hospital-Park Ridge
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Park RidgeUnited StatesUnknown status
Saint Joseph's Regional Medical Center
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PatersonUnited StatesUnknown status
Sacred Heart Hospital
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PensacolaUnited StatesUnknown status
OSF Children's Hospital of Illinois
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PeoriaUnited StatesUnknown status
Children's Hospital of Philadelphia
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PhiladelphiaUnited StatesUnknown status
Saint Christopher's Hospital for Children
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PhiladelphiaUnited StatesUnknown status
Phoenix Childrens Hospital
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PhoenixUnited StatesUnknown status
Children's Hospital of Pittsburgh of UPMC
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PittsburghUnited StatesUnknown status
Legacy Emanuel Children's Hospital
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PortlandUnited StatesUnknown status
Oregon Health and Science University
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PortlandUnited StatesUnknown status
Naval Medical Center - Portsmouth
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PortsmouthUnited StatesUnknown status
Rhode Island Hospital
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ProvidenceUnited StatesUnknown status
Renown Regional Medical Center
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RenoUnited StatesUnknown status
VCU Massey Comprehensive Cancer Center
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RichmondUnited StatesUnknown status
Mayo Clinic in Rochester
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RochesterUnited StatesUnknown status
Corewell Health Children's
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Royal OakUnited StatesUnknown status
Sutter Medical Center Sacramento
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SacramentoUnited StatesUnknown status
University of California Davis Comprehensive Cancer Center
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SacramentoUnited StatesUnknown status
Primary Children's Hospital
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Salt Lake CityUnited StatesUnknown status
University of Texas Health Science Center at San Antonio
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San AntonioUnited StatesUnknown status
Children's Hospital of San Antonio
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San AntonioUnited StatesUnknown status
Methodist Children's Hospital of South Texas
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San AntonioUnited StatesUnknown status
Rady Children's Hospital - San Diego
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San DiegoUnited StatesUnknown status
Naval Medical Center -San Diego
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San DiegoUnited StatesUnknown status
UCSF Medical Center-Mission Bay
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San FranciscoUnited StatesUnknown status
Memorial Health University Medical Center
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SavannahUnited StatesUnknown status
Maine Children's Cancer Program
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ScarboroughUnited StatesUnknown status
Seattle Children's Hospital
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SeattleUnited StatesUnknown status
Sanford USD Medical Center - Sioux Falls
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Sioux FallsUnited StatesUnknown status
Providence Sacred Heart Medical Center and Children's Hospital
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SpokaneUnited StatesUnknown status
Baystate Medical Center
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SpringfieldUnited StatesUnknown status
Southern Illinois University School of Medicine
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SpringfieldUnited StatesUnknown status
Cardinal Glennon Children's Medical Center
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St LouisUnited StatesUnknown status
Washington University School of Medicine
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St LouisUnited StatesUnknown status
Mercy Hospital Saint Louis
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St LouisUnited StatesUnknown status
Stony Brook University Medical Center
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Stony BrookUnited StatesUnknown status
Johns Hopkins All Children's Hospital
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St. PetersburgUnited StatesUnknown status
State University of New York Upstate Medical University
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SyracuseUnited StatesUnknown status
Mary Bridge Children's Hospital and Health Center
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TacomaUnited StatesUnknown status
Madigan Army Medical Center
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TacomaUnited StatesUnknown status
Tampa General Hospital
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TampaUnited StatesUnknown status
Saint Joseph's Hospital/Children's Hospital-Tampa
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TampaUnited StatesUnknown status
Scott and White Memorial Hospital
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TempleUnited StatesUnknown status
Montefiore Medical Center - Moses Campus
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The BronxUnited StatesUnknown status
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
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ToledoUnited StatesUnknown status
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
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TorranceUnited StatesUnknown status
New York Medical College
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ValhallaUnited StatesUnknown status
MedStar Georgetown University Hospital
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Washington D.C.United StatesUnknown status
Children's National Medical Center
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Washington D.C.United StatesUnknown status
Saint Mary's Medical Center
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West Palm BeachUnited StatesUnknown status
Alfred I duPont Hospital for Children
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WilmingtonUnited StatesUnknown status
Wake Forest University Health Sciences
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Winston-SalemUnited StatesUnknown status

This page is information, not medical advice. Discuss any trial with your doctor.