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

Hepatoblastoma Clinical Trial

Official title:

Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03533582
• Other study ID #: AHEP1531
• Secondary ID: NCI-2017-01910AH
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: May 24, 2018
• Est. completion date: June 30, 2026

Study information

• Verified date: April 2024
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

PRIMARY OBJECTIVES: I. To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB) and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes. II. To determine the event-free survival (EFS) in patients with HB whose tumor is completely resected at diagnosis and either receive no adjuvant chemotherapy (completely resected well differentiated fetal [WDF] histology HB) or 2 cycles of standard dose cisplatin monotherapy (completely resected non-well differentiated fetal histology HB - 100 mg/m^2/cycle given 3 weeks apart). (Group A) III. To demonstrate that 4 to 6 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m^2/cycle; 320-480 mg/m^2 total) is adequate for low risk HB. (Group B) IIIa. In patients who are resected after 2 cycles of cisplatin monotherapy, to compare EFS following a randomized comparison of 2 versus 4 post-operative cycles of cisplatin monotherapy. (Group B) IIIb. In patients whose tumors are deemed unresectable after 2 cycles of cisplatin monotherapy, to determine the proportion of tumors rendered completely resectable by an additional 2 or 4 cycles of chemotherapy. (Group B) IV. To compare in a randomized fashion, EFS in patients with intermediate risk HB treated with 6 cycles of cisplatin/5-fluorouracil/vincristine/doxorubicin (C5VD) chemotherapy versus 6 cycles of interval compressed cisplatin monotherapy (100 mg/m^2/dose). (Group C) V. To determine the EFS in patients with HCC whose tumor is completely resected at diagnosis who receive no adjuvant chemotherapy (completely resected HCC arising in the context of underlying liver disease) or 4 cycles of cisplatin/doxorubicin (PLADO) (completely resected de novo HCC). (Group E) VI. To improve the EFS of patients with high risk HB by treating them with interval compressed cisplatin and doxorubicin based induction regimen followed by response-adapted consolidation therapy. (Group D) VIa. In patients whose metastatic disease resolves with the administration of Societe Internationale d'Oncologie Pediatrique (SIOPEL) 4 Induction therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in a large international study. (Group D1) VIb. In patients whose metastatic disease does not resolve with the administration of SIOPEL 4 Induction therapy, to determine in a randomized comparison which post induction treatment (irinotecan and vincristine sulfate [vincristine] alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with carboplatin and doxorubicin) results in superior outcomes. (Group D Arm CE & Arm VI) VII. In patients with unresectable/metastatic HCC at diagnosis, to determine whether the addition of gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib backbone improves chemotherapy response, resectability and survival. (Group F) EXPLORATORY OBJECTIVES: I. To determine if the Childhood Hepatic tumor International Consortium (CHIC) hepatoblastoma risk stratification analysis of very low risk (Group A), low risk (Group B), intermediate risk (Group C) and high risk (Group D) groups stratifies patients allowing appropriate utilization of varying intensity chemotherapy regimens and surgical resection strategies. II. To define the prognostic relevance of a positive microscopic margin in Group A-D resected HB specimens. III. To define the frequency of histologically detectable multifocal lesions in liver explants and resected specimens in which multifocal disease was detected at diagnosis and disappeared on cross sectional imaging following treatment with chemotherapy. IV. To define the prognostic relevance in HB of a 'small cell undifferentiated' tumor component and percentage of tumor necrosis in post chemotherapy specimens. V. To determine the prognostic impact on EFS and overall survival (OS) of biopsy technique in liver tumors unresectable at diagnosis. VI. To determine the 3-year EFS and OS of HB patients who undergo liver transplantation vs extreme resection in Group C and D patients. VII. To determine the 3-year EFS and OS of Group D patients who undergo pulmonary metastasectomy. VIII. To determine the 3-year EFS and OS of patients who undergo liver transplantation for HCC. IX. To determine the frequency of relapse in non-metastatic HCC in children treated by liver transplantation versus conventional resection. X. To determine the concordance of Pretreatment Extent of Disease (PRETEXT) and Post-treatment Extent of disease (POSTTEXT) based surgical guidelines and the surgical intervention performed. XI. To collect for future analysis, HB and HCC tumor specimens that can be molecularly characterized to validate newly identified molecular and immunohistochemical biomarkers correlating with known clinical prognostic factors and outcome. XII. To evaluate the hepatoblastoma molecular risk-predictive model (HB-MRP) to risk stratify hepatoblastoma patients in the context of the current AHEP1531 trial. XIII. To collect for future analysis samples to assess the pharmacogenomics (PG) related to cisplatin therapy in pediatric and adolescent liver tumor patients and correlate PG with Boston Grading Scale for ototoxicity. XIV. To collect for future analysis samples such that novel biomarkers of renal toxicity (urine neutrophil gelatinase-associated lipocalin [NGAL], cystatin C and Kim1) from cisplatin therapy can be correlated with pharmacogenomics, other associated toxicities, and outcomes. XV. To determine which system (Children's Oncology Group [COG] PRETEXT, SIOPEL PRETEXT, or a new hybrid definition of PRETEXT) of the annotation factors for V, P, E, F and R provides the best prognostic information for determining response to chemotherapy, guiding risk based therapy, predicting surgical resectability, and EFS. XVI. To determine the concordance between institutional and expert panel review assessment of PRETEXT and POSTTEXT stage in an international cooperative group setting. OUTLINE: GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups. GROUP A1 (WDF): Patients undergo observation. GROUP A2 (NON-WDF): Patients receive cisplatin (CDDP) intravenously (IV) over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. GROUP B (LOW RISK HB): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 2 groups. GROUP B1 (RESECTABLE): Patients receive 2 cycles of cisplatin, undergo surgery, then are randomized to 1 of 2 arms (2 vs 4 additional cycles of cisplatin). GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 4 total cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity. GROUP B1 ARM 6-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity. GROUP B2 (UNRESECTABLE): Patients receive 2 cycles of cisplatin, then are assigned to 1 of 2 arms (resectable vs unresectable). GROUP B2 ARM I (RESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). After cycle 4, patients undergo surgery, then continue with 2 additional cycles of cisplatin. GROUP B2 ARM II (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles. GROUP C (INTERMEDIATE RISK HB): Patients are randomized to 1 of 2 arms. GROUP C ARM CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4. GROUP C ARM C5VD: Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4. GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 (for cycles 1 and 2) and days 1 and 2 (for cycle 3). Cycles 1 and 2 are 28 days; cycle 3 is 21 days. Patients are then assigned to 1 of 2 arms. GROUP D1: CONSOLIDATION THERAPY: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. GROUP D2: Patients with residual metastatic disease are randomized to 1 of 2 arms. GROUP D2 ARM CE: Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin IV over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP D2 ARM VI: Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 60-90 minutes once daily (QD) on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP E (RESECTED HCC): Patients are assigned to 1 of 2 groups. GROUP E1: Patients with HCC secondary to underlying hepatic disease undergo observation only. GROUP E2 (PLADO): Patients with de novo HCC receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. GROUP F (UNRESECTED AND/OR METASTATIC HCC): Patients are randomized to 1 of 2 arms. GROUP F ARM 1 (PLADO): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib orally (PO) twice daily (BID) on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment. GROUP F ARM 2 (P/GEMOX): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment. After completion of study treatment, patients are followed up for a minimum of 2 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 537
• Est. completion date: June 30, 2026
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 who are currently receiving another investigational drug
• Patients who are currently receiving other anticancer agents
• Patients with uncontrolled infection
• 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
• Patients with hypersensitivity to any drugs on their expected treatment arm
• Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)
• 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
• Group F:
• Patients with peripheral sensitive neuropathy with functional impairment
• Patients with a personal or family history of congenital long QT syndrome
• 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

Related Conditions & MeSH terms

• Carcinoma
• Childhood Hepatocellular Carcinoma
• Childhood Malignant Liver Neoplasm
• Fibrolamellar Carcinoma
• Hepatoblastoma
• Hepatocellular Malignant Neoplasm, Not Otherwise Specified
• Liver Neoplasms
• Neoplasms

Intervention

Drug:
• Carboplatin
Given IV
• Cisplatin
Given IV
• Doxorubicin
Given IV
• Etoposide
Given IV
• Fluorouracil
Given IV
• Gemcitabine
Given IV
• Irinotecan
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Oxaliplatin
Given IV

Other:
• Patient Observation
Undergo watchful waiting

Procedure:
• Resection
Undergo surgical resection

Drug:
• Sorafenib
Given PO
• Vincristine Sulfate
Given IV

Locations

Country	Name	City	State
Australia	John Hunter Children's Hospital	Hunter Regional Mail Centre	New South Wales
Australia	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Perth Children's Hospital	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Children's Hospital	London	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)	Quebec
Canada	Jim Pattison Children's Hospital	Saskatoon	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
Puerto Rico	San Jorge Children's Hospital	San Juan
Puerto Rico	University Pediatric Hospital	San Juan
Saudi Arabia	King Faisal Specialist Hospital and Research Centre	Riyadh
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Tufts Children's Hospital	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	T C Thompson Children's Hospital	Chattanooga	Tennessee
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Columbia Regional	Columbia	Missouri
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
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	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	El Paso Children's Hospital	El Paso	Texas
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
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	Mattel Children's Hospital UCLA	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	UMC Cancer Center / UMC Health System	Lubbock	Texas
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Sacred Heart Hospital	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Renown Regional Medical Center	Reno	Nevada
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Naval Medical Center -San Diego	San Diego	California
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Tampa General Hospital	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Puerto Rico,  Saudi Arabia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Failure free survival	Failure free survival is defined as the time from randomization (or registration into the trial for non-randomized patients) to first failure event. Failure events are: progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, diagnosis of a second malignant neoplasm, or failure to go to resection.	3 years
Other	Overall survival	Overall survival is defined as the time from randomization (or registration for non-randomized patients) to death from any cause.	3 years
Other	Percentage of patients experiencing grade 3 or higher adverse events	The percentage of patients experiencing grade 3 or higher toxicity will be reported, where adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.	8 months
Other	Percentage of patients with chemotherapy-related cardiac, nephro- and oto-toxicity	Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.	Up to 5 years
Other	Percentage of patients with hearing loss	Hearing loss will be measured according to the SIOP Boston Scale for ototoxicity.	Up to 5 years
Other	Best response	Response in hepatocellular carcinoma (HCC) will be defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Response in HB will be defined as CR or PR based on radiological response (RECIST v1.1) and AFP decline.	Up to 5 years
Other	Percentage of participants who are surgically resectable	Surgical resectability is defined as complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients).	Up to 5 years
Other	Percentage of participants with adherence to surgical guidelines	Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.	Up to 5 years
Primary	Event-free survival (EFS)	EFS is defined as the time from randomization (or registration into the trial for non-randomized patients) to the first failure event where the failure events are defined as: progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, or diagnosis of a second malignant neoplasm. Patients who have not had an event will be censored at their last follow-up date. EFS for group A, group B1, group C, group D1, group D2 and E will be presented.	3 years
Primary	Percentage of Group B2 participants with resectable tumors	Group B patients who are unresectable after cycles 1 & 2 of cisplatin treatment will be assigned to Group B2. These patients will receive cycles 3-6 of cisplatin treatment.	6 months
Primary	Response rate for Group F patients	Response is defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be classified as non-responders.	Up to 5 years