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