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

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.

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