Risk-Based Therapy in Treating Younger Patients With Newly Diagnosed Liver Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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 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 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 center that are resected without OLT, and the 2-year EFS for patients referred to a transplant center who receive OLT. IV. To register children with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver Unresectable Tumor Observatory), an international cooperative registry for children transplanted for liver tumors. V. To determine if pretreatment extent of disease (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 alpha fetoprotein (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: 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 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. After completion of study therapy, patients who receive chemotherapy are followed up periodically for at least 4 years.

Official Title
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Treatment of Children With All Stages of Hepatoblastoma With Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment

Conditions
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PRETEXT I Hepatoblastoma, PRETEXT II Hepatoblastoma, PRETEXT III Hepatoblastoma, PRETEXT IV Hepatoblastoma

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Dexrazoxane
* Drug: Doxorubicin Hydrochloride
* Drug: Fluorouracil
* Drug: Irinotecan Hydrochloride
* Other: Laboratory Biomarker Analysis
* Procedure: Liver Transplantation
* Drug: Temsirolimus
* Procedure: Therapeutic Conventional Surgery
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-risk group (regimen H)<br>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 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. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Liver Transplantation<br>* Undergo liver transplant<br>* Other names: Transplantation of Liver;Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: High-risk group (regimen W)<br>(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. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Intermediate-risk group (regimen F)<br>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) | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Dexrazoxane<br>* Given IV<br>* Other names: Soluble ICRF (L-isomer);Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Liver Transplantation<br>* Undergo liver transplant<br>* Other names: Transplantation of Liver;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Low-risk group (regimen T)<br>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. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Very low-risk group<br>Patients undergo surgery and then receive no further treatment. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact. | 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 | 
| Number of Cycles on Which Grade 3 or Higher Adverse Events Coded According to CTC AE Version 5 Were Observed | All grade 3 or 4 or greater non-hematological toxicities. The frequency of each toxicity type will be quantified as the number of reporting periods on which the toxicity of the relevant grade is reported. This measure does not apply to patients enrolled in the VERY LOW RISK group. | During protocol therapy up to 1 year after enrollment | 
| Number of Deaths | Number of patients who experience on-protocol-therapy death possibly, probably or likely related to systemic chemotherapy. This outcome measure applies to INTERMEDIATE RISK patients only. | During protocol therapy or within 30 days of the termination of protocol therapy up to 1 year after enrollment | 
| Disease Status at the End of 2 Courses of Therapy | RECIST v 1.1 and serum alphafetoprotein responses are evaluated separately. RECIST v 1.1 complete response (CR) is defined as disappearance of all target lesions and partial response (PR) is defined as reduction of at last 30% in the sum of the longest dimension of all target lesions (CR and PR measured by CT or MRI) between enrollment. Serum alphafetoprotein response is a decrease of at least 90% from the last serum alphafetoprotein measurement from the baseline prior to the start of chemotherapy to the end of cycle 2. This is calculated for HIGH RISK regimen W and HIGH RISK regimen H only. | First two cycles of therapy- up to 42 days after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 cycles of therapy - up to 3 months after enrollment |