Official Title
Treatment of Children With All Stages of Hepatoblastoma With Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment
Summary:
This phase III trial studies the side effects and how well risk-based therapy works in
treating younger patients with newly diagnosed liver cancer. Surgery, chemotherapy drugs
(cancer fighting medicines), and when necessary, liver transplant, are the main current
treatments for hepatoblastoma. The stage of the cancer is one factor used to decide the best
treatment. Treating patients according to the risk group they are in may help get rid of the
cancer, keep it from coming back, and decrease the side effects of chemotherapy.
Trial Description
Primary Outcome:
- Event-free survival
- Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events version 5.0
- Rate of death
- Disease status at the end of 2 courses of therapy
Secondary Outcome:
- Feasibility of referral for liver transplantation
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 centre 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 tumour 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 centre that are resected without OLT,
and the 2-year EFS for patients referred to a transplant centre who receive OLT.
IV. To register children with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver
Unresectable Tumour Observatory), an international cooperative registry for children
transplanted for liver tumours.
V. To determine if pretreatment extent of disease (PRETEXT) grouping can predict tumour
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 tumours, 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 W) (regimen W replaced by regimen H as of Amendment 3B) 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.
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 tumour
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.
View this trial on ClinicalTrials.gov
