Find-A-Study

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

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.

Study Contact

Principal Investigator
Anne-Marie Langevin

Virginia Diaz
210-562-9149
diazvr@uthscsa.edu

Jaclyn Hung
210-450-5358
hungj@uthscsa.edu

Eligibility

Eligible Ages: Under30 Years
Eligible Genders: All
Accepts Healthy Volunteers: No

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

Study Design

Phase: Phase 2/Phase 3
Study Type: Interventional
Allocation: Randomized
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
Masking: None (Open Label)
Condition: Childhood Hepatocellular Carcinoma
Childhood Malignant Liver Neoplasm
Fibrolamellar Carcinoma
Hepatoblastoma
Hepatocellular Malignant Neoplasm, Not Otherwise Specified

Arm Groups

Arm	Description	Intervention
Experimental GROUP A2 (NON-WDF)	Patients 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies
Experimental GROUP B1 ARM 6-CDDP	Patients 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies
Experimental 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies Drug: Vincristine Sulfate Given IV Other names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate Drug: Doxorubicin Given IV Other names: Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin Drug: Fluorouracil Given IV Other names: 5 Fluorouracil 5 Fluorouracilum 5 FU 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-Fu 5FU AccuSite Carac Fluoro Uracil Flu
Experimental GROUP D1	SIOPEL-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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies Drug: Carboplatin Given IV Other names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Nov Drug: Doxorubicin Given IV Other names: Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin
Experimental GROUP D2 ARM VI	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. 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies Drug: Vincristine Sulfate Given IV Other names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate Drug: Carboplatin Given IV Other names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Nov Drug: Doxorubicin Given IV Other names: Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin Drug: Irinotecan Given IV
Experimental GROUP E2 (PLADO)	Patients 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies Drug: Doxorubicin Given IV Other names: Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin
Experimental 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Drug: Gemcitabine Given IV Other names: dFdC dFdCyd Difluorodeoxycytidine Other: Laboratory Biomarker Analysis Correlative studies Drug: Doxorubicin Given IV Other names: Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin Drug: Oxaliplatin Given IV Other names: 1-OHP Ai Heng Aiheng Dacotin Dacplat Diaminocyclohexane Oxalatoplatinum Eloxatin Eloxatine JM-83 Oxalatoplatin Oxalatoplatinum RP 54780 Drug: Sorafenib Given PO Other names: BA4 43 9006 BAY 43-9006 Bay-439006
Active Comparator Group A1 (WDF)	Patients undergo observation.	Other: Laboratory Biomarker Analysis Correlative studies Other: Patient Observation Undergo watchful waiting Other names: Active Surveillance deferred therapy expectant management Observation Watchful Waiting
Experimental GROUP B1 ARM 4-CDDP	Patients 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies
Experimental GROUP B2 (UNRESECTABLE)	Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 6 cycles (4 pre-surgery, 2 post-surgery).	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies
Experimental 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies
Experimental GROUP D2 ARM CE	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. 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Drug: Etoposide Given IV Other names: Demethyl Epipodophyllotoxin Ethylidine Glucoside EPEG Lastet Toposar Vepesid VP 16 VP 16-213 VP-16 VP-16-213 VP16 Other: Laboratory Biomarker Analysis Correlative studies Drug: Carboplatin Given IV Other names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Nov Drug: Doxorubicin Given IV Other names: Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin
Active Comparator GROUP E1	Patients undergo observation only.	Other: Laboratory Biomarker Analysis Correlative studies Other: Patient Observation Undergo watchful waiting Other names: Active Surveillance deferred therapy expectant management Observation Watchful Waiting
Experimental 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 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.	Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Other: Laboratory Biomarker Analysis Correlative studies Drug: Doxorubicin Given IV Other names: Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin Drug: Sorafenib Given PO Other names: BA4 43 9006 BAY 43-9006 Bay-439006