Risk-Based Therapy in Treating Younger Patients With Newly Diagnosed Liver Cancer

PRIMARY OBJECTIVES:

I. To estimate the event-free survival (EFS) in children with stage I (non-pure fetal
histology [PFH], non-small cell undifferentiated [SCU]) and stage II (non-SCU) hepatoblastoma
treated with surgical resection followed by 2 cycles of cisplatin, fluorouracil, and
vincristine sulfate (C5V).

II. To determine the feasibility and toxicity of adding doxorubicin (doxorubicin
hydrochloride) to the chemotherapy regimen of C5V for children with intermediate-risk
hepatoblastoma.

III. To estimate the response rate to vincristine (vincristine sulfate), irinotecan
(irinotecan hydrochloride), and temsirolimus in previously untreated children with high-risk,
metastatic hepatoblastoma.

IV. To determine whether timely (between diagnosis and end of second cycle of chemotherapy)
consultation with a treatment center with surgical expertise in major pediatric liver
resection and transplant can be achieved in 70% of patients with potentially unresectable
hepatoblastoma.

V. To foster the collection of tumor tissue and biologic samples to facilitate translational
research and to provide data that may aid in risk-adapted approaches for subsequent clinical
trials.

SECONDARY OBJECTIVES:

I. To estimate the EFS of patients with stage I PFH treated with surgery alone. II. To
determine whether orthotopic liver transplantation (OLT) can be accomplished after successful
referral and completion of 4 cycles of initial chemotherapy.

III. To estimate the 2-year EFS for patients once identified as candidates for possible OLT,
the 2-year EFS for patients referred to a transplant center that are resected without OLT,
and the 2-year EFS for patients referred to a transplant center who receive OLT.

IV. To register children with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver
Unresectable Tumor Observatory), an international cooperative registry for children
transplanted for liver tumors.

V. To determine if pretreatment extent of disease (PRETEXT) grouping can predict tumor
resectability.

VI. To monitor the concordance between institutional assessment of PRETEXT grouping and
PRETEXT grouping as performed by expert panel review.

VII. To estimate the proportion of stage IV patients who have surgical resection of
metastatic pulmonary lesions.

VIII. To determine the proportion and estimate the EFS of patients with potentially poor
prognostic factors including alpha fetoprotein (AFP) < 100 ng/mL at diagnosis, microscopic
positive surgical margins, surgical complications, multifocal tumors, microscopic vascular
invasion, macrotrabecular histologic subtype, and SCU histologic subtype.

OUTLINE: Patients are assigned to 1 of 4 treatment groups according to risk group.

VERY LOW-RISK GROUP: Patients undergo surgery and receive no further treatment.

LOW-RISK GROUP: (regimen T) Patients undergo surgery and then receive adjuvant cisplatin
intravenously (IV) over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and
vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days
for 2 courses in the absence of disease progression or unacceptable toxicity.

INTERMEDIATE-RISK GROUP: (regimen F) (closed to accrual as of 3/12/2012) Patients receive
C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4
minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin
hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses
in the absence of disease progression or unacceptable toxicity. Patients also undergo
surgical resection after course 2 OR surgical resection or liver transplantation after course
4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses
5 and 6.

HIGH-RISK GROUP: (regimen H) Patients receive up front VIT chemotherapy comprising
vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90
minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT
repeats every 21 days for 2 courses in the absence of disease progression or unacceptable
toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT
in between each 2-course block. Patients with no disease response receive 6 courses of C5VD
in the absence of disease progression or unacceptable toxicity. Patients undergo tumor
resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD.
Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6.

After completion of study therapy, patients who receive chemotherapy are followed up
periodically for at least 4 years.

Inclusion Criteria:

- Patients must be newly diagnosed with histologically-proven hepatoblastoma

- 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 on AHEP0731 without a biopsy

- Clinical situations in which such 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 AHEP0731 when emergent treatment is
given, the following must occur:

- The patient must have a clinical diagnosis of hepatoblastoma, including an
elevated alpha fetoprotein, and must meet all AHEP0731 eligibility criteria
at the time of emergent treatment

- Patient must be enrolled on AHEP0731 prior to initiating protocol therapy; a
patient will be ineligible if any chemotherapy is administered prior to
AHEP0731 enrollment

- If the patient receives AHEP0731 chemotherapy 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 will be staged for risk classification and treatment at diagnosis using
Children's Oncology Group (COG) staging guidelines

- At the time of study enrollment, the patient's treatment regimen must be identified;
if the patient's primary tumor was resected prior to the day of enrollment and a blood
specimen for the determination of serum alpha fetoprotein was not obtained prior to
that surgery, the patient will be considered to have alpha fetoprotein of greater than
100 ng/mL for the purpose of treatment assignment; if tumor samples obtained prior to
the date of enrollment were not sufficient to determine whether small cell
undifferentiated (SCU) histology was present, treatment assignment will be made
assuming SCU is not present in the tumor

- For patients with stage I or II disease, specimens for rapid central review have been
submitted and the rapid central review diagnosis and staging must be available to be
provided on the AHEP0731 eligibility case report form (CRF)

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores 0, 1, or 2; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age

- Patients may have had surgical resection of some or all sites of hepatoblastoma prior
to enrollment

- Organ function requirements are not required for enrolled patients who are stage I,
PFH and will not be receiving chemotherapy

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR serum creatinine based on age/gender as follows:

- 1 month to < 6 months: 0.4 mg/dL

- 6 months to < 1 year: 0.5 mg/dL

- 1 to < 2 years: 0.6 mg/dL

- 2 to < 6 years: 0.8 mg/dL

- 6 to < 10 years: 1 mg/dL

- 10 to < 13 years: 1.2 mg/dL

- 13 to < 16 years: 1.5 mg/dL (male) or 1.4 mg/dL (female)

- >= 16 years: 1.7 mg/dL (male) or 1.4 mg/dL (female)

- Total bilirubin < 1.5 x upper limit of normal (ULN) for age

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
ULN for age

- Absolute neutrophil count (ANC) > 750/uL

- Platelet count > 75,000/uL

- Shortening fraction >= 27% by echocardiogram

- Ejection fraction >= 47% by radionuclide angiogram (multi gated acquisition scan
[MUGA]); Note: the echocardiogram (or MUGA) may be done within 28 days prior to
enrollment

- Serum triglyceride level =< 300 mg/dL (=< 3.42 mmol/L)

- Serum cholesterol level =< 300 mg/dL (7.75 mmol/L)

- Random or fasting blood glucose within the upper normal limits for age; if the initial
blood glucose is a random sample that is outside of the normal limits, then a
follow-up fasting blood glucose can be obtained and must be within the upper normal
limits for age

- Normal pulmonary function tests (including diffusing capacity of the lungs for carbon
monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at
rest, known requirement for supplemental oxygen); Note: for patients who do not have
respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests
(PFTs) are NOT required

- Patients with seizure disorder may be enrolled if on non-enzyme inducing
anticonvulsants and if seizures are well controlled

- Prothrombin time (PT) < 1.2 x ULN

- 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:

- Patients with stage I or II disease who do not have specimens submitted for rapid
central pathology review by day 14 after initial surgical resection

- Patients that have been previously treated with chemotherapy for hepatoblastoma or
other hepatoblastoma-directed therapy (e.g., radiation therapy, biologic agents, local
therapy [embolization, radiofrequency ablation, laser]) are not eligible

- Patients who have received any prior chemotherapy are not eligible

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anticancer agents are not eligible

- Patients who have previously received a solid organ transplant are not eligible

- Patients who have an uncontrolled infection are not eligible

- Females who are pregnant or breast feeding are not eligible for this study

- Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained

- Males and females of reproductive potential are not eligible unless they have agreed
to use an effective contraceptive method

- Patients receiving corticosteroids are not eligible; patients must have been off
corticosteroids for 7 days prior to start of chemotherapy

- Patients who are currently receiving enzyme inducing anticonvulsants are not eligible

- Patients must not be receiving any of the following potent cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors: erythromycin,
clarithromycin, azithromycin, ketoconazole, itraconazole, voriconazole, posaconazole,
grapefruit juice or St. John's wort

- Patients who are currently receiving therapeutic anticoagulants (including aspirin,
low molecular weight heparin, warfarin and others) are not eligible

- Patients who are currently receiving angiotensin-converting enzymes (ACE) inhibitors
are not eligible

- Patients must not have had major surgery within 6 weeks prior to enrollment on the
high risk stratum; patients with history of recent minor surgical procedures (vascular
catheter placement, bone marrow evaluation, laparoscopic surgery, liver tumor biopsy)
will be eligible