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, 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.

Related Conditions:
  • Hepatoblastoma
  • Hepatocellular Carcinoma
  • Small Cell Undifferentiated Hepatoblastoma
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
  • Fibrolamellar Carcinoma
  • Hepatoblastoma
  • Hepatocellular Malignant Neoplasm, Not Otherwise Specified

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, 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, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinGROUP C ARM C5VD
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16GROUP D2 ARM CE
Fluorouracil5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-Fu, 5FU, 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)
SorafenibBA4 43 9006, BAY 43-9006, Bay-439006GROUP 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, 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.

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 [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 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.

      XIII. 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.

      XIV. 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.

      XV. 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 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). Patients with
      resectable tumors undergo surgery, then all patients continue with 2 additional cycles 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 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.
    

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 cycles 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 4 cycles (2 pre-surgery, 2 post-surgery) 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 6 cycles (2 pre-surgery, 4 post-surgery) 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 6 cycles (4 pre-surgery, 2 post-surgery).
    • 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 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.
    • 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 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.
    • Cisplatin
    GROUP D1ExperimentalSIOPEL-4 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 during cycles 1 and 2 and days 1 and 2 during cycle 3. Treatment repeats every 28 days for up to 3 cycles 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 cycles 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 cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 cycles 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 cycles 1, 3 and 5, and carboplatin 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 up to 6 cycles 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 cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 cycles 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 cycles 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 cycles 2, 4 and 6. Treatments repeat every 21 days for up to 6 cycles 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 4 cycles 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 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.
      • 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 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.
      • Cisplatin
      • Doxorubicin
      • Gemcitabine
      • Oxaliplatin
      • Sorafenib

      Eligibility Criteria

              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 A2, 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
      
                -  This criteria apply ONLY to patients who will receive chemotherapy (all groups other
                   than Groups A1 and 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
            
      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:3 years
      Safety Issue:
      Description: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.

      Details

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

      Last Updated

      March 19, 2021