Clinical Trials /

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

NCT03533582

Description:

This partially randomized phase II/III trial studies how well cisplatin and combination chemotherapy works in treating children and young adults with hepatoblastoma or liver cancer after surgery. 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 after surgery may kill more tumor cells.

Related Conditions:
  • Hepatoblastoma
  • Hepatocellular Carcinoma
  • Small Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
  • Official Title: Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)

Clinical Trial IDs

  • ORG STUDY ID: AHEP1531
  • SECONDARY ID: NCI-2017-01910
  • SECONDARY ID: AHEP1531
  • SECONDARY ID: AHEP1531
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03533582

Conditions

  • Childhood Hepatocellular Carcinoma
  • Childhood Malignant Liver Neoplasm
  • Elevated Alpha-Fetoprotein
  • Hepatoblastoma
  • SMARCB1 Gene Mutation

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboGROUP D1
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinGROUP A2 (NON-WDF)
DoxorubicinAdriablastin, Hydroxyl Daunorubicin, HydroxyldaunorubicinGROUP C ARM C5VD
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213GROUP D2 ARM CE
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757GROUP C ARM C5VD
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineGROUP F ARM 2 (P/GEMOX)
IrinotecanGROUP D2 ARM VI
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669GROUP F ARM 2 (P/GEMOX)
SorafenibBAY 43-9006GROUP F ARM 1 (PLADO)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateGROUP C ARM C5VD

Purpose

This partially randomized phase II/III trial studies how well cisplatin and combination chemotherapy works in treating children and young adults with hepatoblastoma or liver cancer after surgery. 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 after surgery may kill more tumor cells.

Detailed 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 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) IV. 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) V. 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) VI. 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) VII. 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) VIII. 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) IX. 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) X. 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) XI. 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)

      SECONDARY OBJECTIVES:

      I. Molecular characterization of HB tumors to validate newly identified molecular and
      immunohistochemical biomarkers correlating with known clinical prognostic factors and
      outcome. (Group A-D) II. To determine whether the molecular profile of pediatric HCC overlaps
      with HB or adult-type HCC while correlating biologic features with treatment response and
      survival. (Group E and F) III. To define the prognostic relevance in HB of a ?small cell
      undifferentiated? tumor component and percentage of tumor necrosis in post chemotherapy
      specimens.

      IV. 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.

      V. 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.

      VI. To determine the concordance between institutional and expert panel review assessment of
      PRETEXT and POSTTEXT stage in an international cooperative group setting.

      VII. To assess clinical characteristics, basic chemotherapy and surgical treatment details,
      biological characteristics at baseline and recurrence (when available) and outcome of
      patients with refractory or relapsed hepatoblastoma after initial treatment.

      VIII. To identify novel biomarkers of renal toxicity (urine NGAL, cystatin C and Kim1) from
      cisplatin therapy when given according to the regimens used on this study, and to correlate
      such biomarkers with pharmacogenomics, other associated toxicities, and outcomes.

      TERTIARY 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 determine the prognostic impact on EFS and overall survival (OS) of biopsy technique
      in liver tumors unresectable at diagnosis.

      V. To determine the frequency of intraoperative complications from surgery for local control
      (conventional resection or liver transplantation) and its impact on EFS.

      VI. To determine the 3-year EFS and OS of HB patients who undergo liver transplantation
      versus (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
      metastatectomy.

      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 assess the pharmacogenomics (PG) related to cisplatin therapy in pediatric and
      adolescent liver tumor patients and correlate PG with Boston Grading Scale for ototoxicity.

      OUTLINE:

      GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups.

      GROUP A1 (WELL-DIFFERENTIATED FETAL [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 courses 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 courses in the absence of disease progression or unacceptable
      toxicity. Patients are then assigned to 1 of 2 groups

      GROUP B1 (RESECTABLE): Patients undergo surgery, then are randomized to 1 of 2 arms.

      GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats
      every 14 days for up to 2 courses 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 4 courses in the absence of disease progression or unacceptable
      toxicity.

      GROUP B2 (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment
      repeats every 14 days for up to 2 courses. Patients with resectable tumors undergo surgery,
      then all patients continue with 2 additional courses of cisplatin.

      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 courses in the absence of disease progression or unacceptable
      toxicity. Patients undergo surgery after course 2.

      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 courses in the
      absence of disease progression or unacceptable toxicity. Patients undergo surgery after
      course 2.

      GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on
      days 1, 8, and 15 (for courses 1 and 2) and days 1 and 8 (for course 3) and doxorubicin IV
      over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 courses in the
      absence of disease progression or unacceptable toxicity. 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 up to 3 courses in the
      absence of disease progression or unacceptable toxicity.

      GROUP D2: Patients with residual metastatic disease are randomized to 1of 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 courses 1, 3 and 5, and etoposide IV over 2 hours on
      day 1 and 2 of courses 2, 4 and 6. Treatments repeat every 21 days for up to 6 courses 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 courses 1, 3 and 5. Patients also receive
      vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 90 minutes once
      daily (QD) on days 1 to 5 of courses 2, 4 and 6. Treatments repeat every 21 days for up to 6
      courses 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 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 up to 4 courses 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 courses in the absence of disease progression or
      unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an
      additional 3 courses 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 courses 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 courses 2 and 4. Patients may undergo surgery, if
      tumors are resectable, or receive an additional 4 courses of the treatment.

      After completion of study treatment, patients are followed up for a minimum of 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Group A1 (WDF)Active ComparatorPatients undergo observation.
    GROUP A2 (NON-WDF)ExperimentalPatients receive cisplatin IV over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
    • Cisplatin
    GROUP B1 ARM 4-CDDPExperimentalPatients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
    • Cisplatin
    GROUP B1 ARM 6-CDDPExperimentalPatients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
    • Cisplatin
    GROUP B2 (UNRESECTABLE)ExperimentalPatients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 courses. Patients with resectable tumors undergo surgery, then all patients continue with 2 additional courses of cisplatin.
    • Cisplatin
    GROUP C ARM C5VDExperimentalPatients 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 courses in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after course 2.
    • Cisplatin
    • Doxorubicin
    • Fluorouracil
    • Vincristine Sulfate
    GROUP C ARM CDDPExperimentalPatients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after course 2.
    • Cisplatin
    GROUP D1ExperimentalSIOPEL-4 INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for courses 1 and 2) and days 1 and 8 (for course 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: 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 up to 3 courses in the absence of disease progression or unacceptable toxicity.
    • Carboplatin
    • Cisplatin
    • Doxorubicin
    GROUP D2 ARM CEExperimentalSIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for courses 1 and 2) and days 1 and 8 (for course 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during courses 1, 3 and 5, and etoposide IV over 2 hours on day 1 and 2 of courses 2, 4 and 6. Treatments repeat every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
    • Carboplatin
    • Cisplatin
    • Doxorubicin
    • Etoposide
    GROUP D2 ARM VIExperimentalSIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for courses 1 and 2) and days 1 and 8 (for course 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. 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 courses 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 90 minutes QD on days 1 to 5 of courses 2, 4 and 6. Treatments repeat every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
    • Carboplatin
    • Cisplatin
    • Doxorubicin
    • Irinotecan
    • Vincristine Sulfate
    GROUP E1Active ComparatorPatients undergo observation only.
      GROUP E2 (PLADO)ExperimentalPatients 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 up to 4 courses in the absence of disease progression or unacceptable toxicity.
      • Cisplatin
      • Doxorubicin
      GROUP F ARM 1 (PLADO)ExperimentalPatients 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 3-21. Treatments repeat every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 courses of the treatment.
      • Cisplatin
      • Doxorubicin
      • Sorafenib
      GROUP F ARM 2 (P/GEMOX)ExperimentalPatients 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 courses 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 courses 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 courses of the treatment.
      • Cisplatin
      • Doxorubicin
      • Gemcitabine
      • Oxaliplatin
      • Sorafenib

      Eligibility Criteria

              Inclusion Criteria:
      
                -  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; 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
      
                -  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) >= 70
                   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])
                   < 10x upper limit of normal (ULN) for age
      
                -  Shortening fraction of >= 27% by echocardiogram (for patients on
                   doxorubicin-containing regimens [Groups C, D, E, and F]), or
      
                -  Ejection fraction of >= 50% by radionuclide angiogram (for patients on
                   doxorubicin-containing regimens (Groups C, D, E, and F)
      
                -  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 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
      
                -  This criteria apply ONLY to patients who will receive chemotherapy (all groups other
                   than Group E1):
      
                     -  Female patients who are pregnant; 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
            
      Maximum Eligible Age:30 Years
      Minimum Eligible Age:N/A
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Event-free survival (EFS)
      Time Frame:From date of randomization until 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, assessed up to 5 years
      Safety Issue:
      Description:Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of each failure event and in total, survival curves will be estimated by the method of Kaplan-Meier, EFS estimates at 3 and 5 years with 95% confidence intervals (CI), median EFS with CI will be reported if appropriate. A Cox proportional hazards model with EFS as an outcome measure and treatment and stratification factors as covariates will be constructed. This model will be used in the context of a Bayesian analysis and a log Hazard Ratio (HR) will be derived. Bayesian Normal-Normal conjugate analysis of the data will be used to compare treatments. The analysis will use non-informative prior to represent no information about prior beliefs regarding relative treatment difference.

      Secondary Outcome Measures

      Measure:Failure free survival
      Time Frame:From date of randomization until the date of first documented progression, date of death from any cause, diagnosis of a second malignant neoplasm or failure to go to resection, whichever came first, assessed up to 5 years
      Safety Issue:
      Description:Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of each failure event and in total, survival curves will be estimated by the method of Kaplan-Meier. Bayesian Normal-Normal conjugate analysis of the data will be used to compare treatments. The analysis will use non-informative prior to represent no information about prior beliefs regarding relative treatment difference.
      Measure:Overall survival
      Time Frame:From date of randomization (or registration for non-randomized patients) until the date of death from any cause, assessed up to 5 years
      Safety Issue:
      Description:
      Measure:Incidence of adverse events
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Will be categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE).
      Measure:Chemotherapy-related cardiac, nephro- and oto-toxicity
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Will be recorded in relation to each cycle of treatment and will be categorized and graded using Common Terminology Criteria for Adverse Events.
      Measure:Hearing loss measured according to the SIOP Boston Scale for oto-toxicity
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of patients at each the SIOP Boston Scale for oto-toxicity category (i.e. grade 0 to grade 4) and the number (and proportion) of patients who are not assessable for this outcome, (i.e. because of early stopping of treatment, additional treatments to protocol treatment, progression prior to the response assessment or death). The number (and proportion) of patients experiencing any grade hearing loss. Grades 1 to grade 4 will be combined in this analysis. The above will be presented for each assessment time point (EOT and at least 1 year and 2 years of follow up).
      Measure:Best response defined as compete response (CR) or partial response (PR) based on radiological response (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and AFP decline
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: best response will be calculated by taking best RECIST category (i.e. CR, PR, stable disease [SD], progressive disease [PD]) for each patient. CR and PR patients will then be grouped into responders. The number (and proportion) of patients at each best response RECIST category (i.e. CR, PR, SD, PD) and the number (and proportion) of patients who are not assessable for response, e.g. because of early stopping of treatment, progression prior to the response assessment or death. The number (and proportion) of responders (CR and PR) and non-responders.
      Measure:Surgical resectability defined as complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients)
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: The number (and proportion) of patients undergoing complete resection, partial resection or transplant. Time to complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients) will be analyzed using the Kaplan-Meier method.
      Measure:Adherence to surgical guidelines defined as the local clinician?s surgical decision to resect or not compared to the current SIOPEL surgical guidelines
      Time Frame:Up to 5 years
      Safety Issue:
      Description:Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: The number (and proportion) of patients at each combination of SIOPEL surgical guideline (to resect or not) and local clinician?s surgical decision. The degree of agreement will be measured by Cohen?s kappa with CI.

      Details

      Phase:Phase 2/Phase 3
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Children's Oncology Group

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