Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Liver Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Children's Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00980460
First received: September 18, 2009
Last updated: February 5, 2014
Last verified: February 2014
  Purpose

This phase III trial is studying the side effects of giving doxorubicin hydrochloride together with combination chemotherapy and to compare different chemotherapy regimens to see how well they work in treating young patients with newly diagnosed liver cancer. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether surgery is more effective with or without chemotherapy or which chemotherapy regimen may be more effective in treating young patients with liver cancer.


Condition Intervention Phase
Childhood Hepatoblastoma
Stage I Childhood Liver Cancer
Stage II Childhood Liver Cancer
Stage III Childhood Liver Cancer
Stage IV Childhood Liver Cancer
Procedure: therapeutic conventional surgery
Drug: cisplatin
Drug: fluorouracil
Drug: vincristine sulfate
Drug: doxorubicin hydrochloride
Drug: irinotecan hydrochloride
Procedure: liver transplantation
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment of Children With All Stages of Hepatoblastoma

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Event-free survival [ Time Frame: Time from patient enrollment to progression, treatment failure, death from any cause, diagnosis of a second malignant neoplasm, or last follow-up, assessed up to 5 years ] [ Designated as safety issue: No ]
    Estimated by the method of Kaplan and Meier.

  • Incidence of adverse events graded according to CTCAE version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    All Grade 3 or 4 or greater non-hematological toxicities as well as any toxicity that requires submission of an AdEERs report will be reported while the patient is on protocol therapy. The frequency of each toxicity type will be quantified as the percent of reporting periods on which the toxicity of the relevant grade is reported.

  • Disease status at the end of 2 courses of therapy [ Time Frame: Up to 42 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Feasibility of referral for liver transplantation [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    A patient for whom referral is considered appropriate who receives a consultation after enrollment will be considered a success with respect to feasibility.


Estimated Enrollment: 216
Study Start Date: September 2009
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Very low-risk group
Patients undergo therapeutic conventional surgery and then receive no further treatment.
Procedure: therapeutic conventional surgery
Undergo surgery
Other: laboratory biomarker analysis
Correlative studies
Experimental: Low-risk group (regimen T)
Patients undergo surgery and then receive adjuvant cisplatin IV over 6 hours on day 1, fluorouracil IV on day 2, and vincristine sulfate IV on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.
Procedure: therapeutic conventional surgery
Undergo surgery
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Other: laboratory biomarker analysis
Correlative studies
Experimental: Intermediate-risk group (regimen F)
Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV on day 2, vincristine sulfate IV 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.
Procedure: therapeutic conventional surgery
Undergo surgery
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Procedure: liver transplantation
Undergo liver transplant
Other: laboratory biomarker analysis
Correlative studies
Experimental: High-risk group (regimen W)
Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Responding patients then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block and non-responding patients receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplantation after course 4 of C5VD followed by 2 courses of adjuvant C5VD.
Procedure: therapeutic conventional surgery
Undergo surgery
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Procedure: liver transplantation
Undergo liver transplant
Other: laboratory biomarker analysis
Correlative studies

  Hide Detailed Description

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the event-free survival (EFS) in pediatric patients with stage I (non-PFH, non-SCU) and stage II (non-SCU) hepatoblastoma treated with surgical resection followed by 2 courses of cisplatin, fluorouracil, and vincristine (C5V).

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

III. To estimate the response rate to vincristine and irinotecan hydrochloride in previously untreated pediatric patients with high-risk, metastatic hepatoblastoma.

IV. To determine whether timely (between diagnosis and end of second course 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 liver transplantation (OLT) can be accomplished after successful referral and completion of 4 courses 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 pediatric patients with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver Unresectable Tumor Observatory), an international cooperative registry for pediatric patients transplanted for liver tumors.

V. To determine if 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 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: This is a multicenter study. Patients are stratified according to risk (very low vs low vs intermediate vs high). 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 IV over 6 hours on day 1, fluorouracil IV on day 2, and vincristine sulfate IV 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) Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV on day 2, vincristine sulfate IV 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.

HIGH-RISK GROUP: (regimen W) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI 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 1 courses of VI 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 transplantation after course 4 of C5VD followed by 2 courses of adjuvant C5VD.

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

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed newly diagnosed hepatoblastoma

    • All stages* and all histologic variants allowed
  • Patients are assigned to the following risk groups:

    • Very low-risk: grossly resected tumors (stage I) with PFH AND an elevated AFP level > 100 ng/mL
    • Low-risk: grossly resected tumors (stage I-II) AND lacking any unfavorable biologic feature (i.e., any SCU elements or a low diagnostic AFP level < 100 ng/mL)
    • Intermediate-risk: gross residual disease/unresectable disease OR grossly resected disease with any SCU elements but no metastatic disease and no low diagnostic AFP level < 100 ng/mL
    • High-risk: metastatic disease OR low diagnostic AFP level < 100 ng/mL regardless of stage
  • ECOG performance status 0-2
  • ANC* > 750/μL
  • Platelet count* > 75,000/μL
  • Creatinine clearance* or radioisotope glomerular filtration rate* ≥ 70 mL/min 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) 1.4 mg/dL (female)
  • Total bilirubin* < 1.5 times upper limit of normal (ULN) for age
  • SGOT (AST)* or SGPT (ALT)* < 10 times ULN for age
  • Shortening fraction** ≥ 27% by echocardiogram
  • Ejection fraction** ≥ 47% by radionuclide angiogram (MUGA)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Prior surgical resection of some or all sites of hepatoblastoma allowed
  • No prior chemotherapy for hepatoblastoma or other hepatoblastoma-directed therapy (e.g., radiation therapy, biologic agents, local therapy [embolization, radiofrequency ablation, laser])
  • No other prior chemotherapy
  • No concurrent radiotherapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00980460

  Show 171 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Principal Investigator: Howard Katzenstein Children's Oncology Group
  More Information

No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00980460     History of Changes
Other Study ID Numbers: AHEP0731, NCI-2011-01975, CDR0000654889, COG-AHEP0731, U10CA098543
Study First Received: September 18, 2009
Last Updated: February 5, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatoblastoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Liver Diseases
Neoplasms, Complex and Mixed
Neoplasms by Histologic Type
Irinotecan
Cisplatin
Doxorubicin
Fluorouracil
Vincristine
Camptothecin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on July 23, 2014