Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)

Primary Outcome Measures  :

1. 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 ]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.
   
2. Response in hepatocellular carcinoma (HCC), defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria [ Time Frame: Up to 5 years ]The main analysis will be based on a log-binomial model for a Bernoulli response variable. This model will be used in the context of a Bayesian analysis. A non-informative null centered proper prior distributions for the parameters will be used. Response rate (RR) and 95% credible interval (CrI) will be presented. Posterior probabilities for the pre-specified values of interest will be provided. Additionally, the posterior probabilities of RR being larger than 0.7, 0.8, 0.9, 1, 1.1, 1.2 and 1.3 will be also provided.
   

Secondary Outcome Measures  :

1. 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 ]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.

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