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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00980460




Registration number
NCT00980460
Ethics application status
Date submitted
18/09/2009
Date registered
21/09/2009
Date last updated
21/06/2019

Titles & IDs
Public title
Risk-Based Therapy in Treating Younger Patients With Newly Diagnosed Liver Cancer
Scientific title
Treatment of Children With All Stages of Hepatoblastoma With Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment
Secondary ID [1] 0 0
NCI-2011-01975
Secondary ID [2] 0 0
NCI-2011-01975
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alpha Fetoprotein Increased 0 0
PRETEXT Stage 1 Hepatoblastoma 0 0
PRETEXT Stage 2 Hepatoblastoma 0 0
PRETEXT Stage 3 Hepatoblastoma 0 0
PRETEXT Stage 4 Hepatoblastoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Cisplatin
Treatment: Drugs - Dexrazoxane
Treatment: Drugs - Doxorubicin Hydrochloride
Treatment: Drugs - Fluorouracil
Treatment: Drugs - Irinotecan Hydrochloride
Other interventions - Laboratory Biomarker Analysis
Treatment: Surgery - Liver Transplantation
Treatment: Drugs - Temsirolimus
Treatment: Surgery - Therapeutic Conventional Surgery
Treatment: Drugs - Vincristine Sulfate

Experimental: 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. Responding patients then receive 6 courses of C5VD with 4 courses of VIT 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 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.

Experimental: Intermediate-risk group (regimen F) - 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. (Closed to accrual as of 3/12/2012)

Experimental: Low-risk group (regimen T) - Patients undergo surgery and then receive adjuvant cisplatin 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.

Experimental: Very low-risk group - Patients undergo surgery and then receive no further treatment.


Treatment: Drugs: Cisplatin
Given IV

Treatment: Drugs: Dexrazoxane
Given IV

Treatment: Drugs: Doxorubicin Hydrochloride
Given IV

Treatment: Drugs: Fluorouracil
Given IV

Treatment: Drugs: Irinotecan Hydrochloride
Given IV

Other interventions: Laboratory Biomarker Analysis
Correlative studies

Treatment: Surgery: Liver Transplantation
Undergo liver transplant

Treatment: Drugs: Temsirolimus
Given IV

Treatment: Surgery: Therapeutic Conventional Surgery
Undergo surgery

Treatment: Drugs: Vincristine Sulfate
Given IV

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Intervention code [3] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free survival - Estimated by the method of Kaplan and Meier.
Timepoint [1] 0 0
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 7 years
Primary outcome [2] 0 0
Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events version 5.0 - All grade 3 or 4 or greater non-hematological toxicities as well as any toxicity that requires submission of an Cancer Therapy Evaluation Program Adverse Event Reporting System 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.
Timepoint [2] 0 0
Up to 7 years
Primary outcome [3] 0 0
Rate of death - The estimated on-protocol-therapy death rate and its 95% confidence interval will be reported as the cumulative incidence of on-treatment death and the 95% confidence intervals at four and six month.
Timepoint [3] 0 0
Possibly, probably or likely related to systemic chemotherapy, assessed up to 7 years
Primary outcome [4] 0 0
Disease status at the end of 2 courses of therapy
Timepoint [4] 0 0
Up to 42 days
Secondary outcome [1] 0 0
Feasibility of referral for liver transplantation - A patient for whom referral is considered appropriate who receives a consultation after enrollment will be considered a success with respect to feasibility.
Timepoint [1] 0 0
Up to 7 years

Eligibility
Key inclusion criteria
- Patients must be newly diagnosed with histologically-proven hepatoblastoma

- 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 on AHEP0731 without a biopsy

- Clinical situations in which such 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 AHEP0731 when emergent treatment is
given, the following must occur:

- The patient must have a clinical diagnosis of hepatoblastoma, including an
elevated alpha fetoprotein, and must meet all AHEP0731 eligibility criteria
at the time of emergent treatment

- Patient must be enrolled on AHEP0731 prior to initiating protocol therapy; a
patient will be ineligible if any chemotherapy is administered prior to
AHEP0731 enrollment

- If the patient receives AHEP0731 chemotherapy 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 will be staged for risk classification and treatment at diagnosis using
Children's Oncology Group (COG) staging guidelines

- At the time of study enrollment, the patient's treatment regimen must be identified;
if the patient's primary tumor was resected prior to the day of enrollment and a blood
specimen for the determination of serum alpha fetoprotein was not obtained prior to
that surgery, the patient will be considered to have alpha fetoprotein of greater than
100 ng/mL for the purpose of treatment assignment; if tumor samples obtained prior to
the date of enrollment were not sufficient to determine whether small cell
undifferentiated (SCU) histology was present, treatment assignment will be made
assuming SCU is not present in the tumor

- For patients with stage I or II disease, specimens for rapid central review have been
submitted and the rapid central review diagnosis and staging must be available to be
provided on the AHEP0731 eligibility case report form (CRF)

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores 0, 1, or 2; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age

- Patients may have had surgical resection of some or all sites of hepatoblastoma prior
to enrollment

- Organ function requirements are not required for enrolled patients who are stage I,
PFH and will not be receiving chemotherapy

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 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) or 1.4 mg/dL (female)

- Total bilirubin < 1.5 x upper limit of normal (ULN) for age

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
ULN for age

- Absolute neutrophil count (ANC) > 750/uL

- Platelet count > 75,000/uL

- Shortening fraction >= 27% by echocardiogram

- Ejection fraction >= 47% by radionuclide angiogram (multi gated acquisition scan
[MUGA]); Note: the echocardiogram (or MUGA) may be done within 28 days prior to
enrollment

- Serum triglyceride level =< 300 mg/dL (=< 3.42 mmol/L)

- Serum cholesterol level =< 300 mg/dL (7.75 mmol/L)

- Random or fasting blood glucose within the upper normal limits for age; if the initial
blood glucose is a random sample that is outside of the normal limits, then a
follow-up fasting blood glucose can be obtained and must be within the upper normal
limits for age

- Normal pulmonary function tests (including diffusing capacity of the lungs for carbon
monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at
rest, known requirement for supplemental oxygen); Note: for patients who do not have
respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests
(PFTs) are NOT required

- Patients with seizure disorder may be enrolled if on non-enzyme inducing
anticonvulsants and if seizures are well controlled

- Prothrombin time (PT) < 1.2 x ULN

- 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
Minimum age
No limit
Maximum age
21 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patients with stage I or II disease who do not have specimens submitted for rapid
central pathology review by day 14 after initial surgical resection

- Patients that have been previously treated with chemotherapy for hepatoblastoma or
other hepatoblastoma-directed therapy (e.g., radiation therapy, biologic agents, local
therapy [embolization, radiofrequency ablation, laser]) are not eligible

- Patients who have received any prior chemotherapy are not eligible

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anticancer agents are not eligible

- Patients who have previously received a solid organ transplant are not eligible

- Patients who have an uncontrolled infection are not eligible

- Females who are pregnant or breast feeding are not eligible for this study

- Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained

- Males and females of reproductive potential are not eligible unless they have agreed
to use an effective contraceptive method

- Patients receiving corticosteroids are not eligible; patients must have been off
corticosteroids for 7 days prior to start of chemotherapy

- Patients who are currently receiving enzyme inducing anticonvulsants are not eligible

- Patients must not be receiving any of the following potent cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors: erythromycin,
clarithromycin, azithromycin, ketoconazole, itraconazole, voriconazole, posaconazole,
grapefruit juice or St. John's wort

- Patients who are currently receiving therapeutic anticoagulants (including aspirin,
low molecular weight heparin, warfarin and others) are not eligible

- Patients who are currently receiving angiotensin-converting enzymes (ACE) inhibitors
are not eligible

- Patients must not have had major surgery within 6 weeks prior to enrollment on the
high risk stratum; patients with history of recent minor surgical procedures (vascular
catheter placement, bone marrow evaluation, laparoscopic surgery, liver tumor biopsy)
will be eligible

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA
Recruitment hospital [1] 0 0
John Hunter Children's Hospital - Hunter Regional Mail Centre
Recruitment hospital [2] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 0 0
Women's and Children's Hospital-Adelaide - North Adelaide
Recruitment hospital [4] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
2310 - Hunter Regional Mail Centre
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
5006 - North Adelaide
Recruitment postcode(s) [4] 0 0
6008 - Perth
Recruitment outside Australia
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United States of America
State/province [1] 0 0
Alabama
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United States of America
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Arizona
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Arkansas
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California
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Colorado
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Connecticut
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Delaware
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District of Columbia
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Florida
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Georgia
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Hawaii
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Idaho
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Illinois
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Indiana
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Iowa
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Kentucky
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Louisiana
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Maine
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Massachusetts
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Michigan
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Minnesota
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Mississippi
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Missouri
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Nebraska
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Nevada
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New Hampshire
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New Jersey
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New Mexico
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New York
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North Carolina
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Oregon
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Pennsylvania
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Rhode Island
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South Carolina
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South Dakota
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Tennessee
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Wisconsin
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Brazil
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Sao Paulo
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Alberta
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British Columbia
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Canada
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Manitoba
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Nova Scotia
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Ontario
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Quebec
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Canada
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Saskatchewan
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Japan
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Fukushima Prefecture
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Japan
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Kagoshima
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Japan
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Suntou
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Japan
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Tokyo
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Japan
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Hiroshima City
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Puerto Rico
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San Juan

Funding & Sponsors
Primary sponsor type
Government body
Name
National Cancer Institute (NCI)
Address
Country

Ethics approval
Ethics application status

Summary
Brief 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 website
https://clinicaltrials.gov/show/NCT00980460
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Howard M Katzenstein
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications