Clinical Trials /

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

NCT00980460

Description:

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.

Related Conditions:
  • Hepatoblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Risk-Based Therapy in Treating Younger Patients With Newly Diagnosed Liver Cancer
  • Official Title: Treatment of Children With All Stages of Hepatoblastoma With Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment

Clinical Trial IDs

  • ORG STUDY ID: NCI-2011-01975
  • SECONDARY ID: NCI-2011-01975
  • SECONDARY ID: CDR0000654889
  • SECONDARY ID: 10-00098
  • SECONDARY ID: AHEP0731
  • SECONDARY ID: COG-AHEP0731
  • SECONDARY ID: AHEP0731
  • SECONDARY ID: AHEP0731
  • SECONDARY ID: U10CA180886
  • SECONDARY ID: U10CA098543
  • SECONDARY ID: UG1CA189958
  • NCT ID: NCT00980460
  • NCT ALIAS: NCT02265692

Conditions

  • PRETEXT Stage 1 Hepatoblastoma
  • PRETEXT Stage 2 Hepatoblastoma
  • PRETEXT Stage 3 Hepatoblastoma
  • PRETEXT Stage 4 Hepatoblastoma

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinLow-risk group (regimen T)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexIntermediate-risk group (regimen F)
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Low-risk group (regimen T)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440EHigh-risk group (regimen H)
TemsirolimusCCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog, Rapamycin Analog CCI-779, ToriselHigh-risk group (regimen H)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateLow-risk group (regimen T)

Purpose

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

      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 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) (closed to accrual as of 3/12/2012) 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 H) Patients receive up front VIT chemotherapy comprising
      vincristine sulfate IV 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.

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

Trial Arms

NameTypeDescriptionInterventions
High-risk group (regimen H)ExperimentalPatients receive up front VIT chemotherapy comprising vincristine sulfate IV 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.
  • Cisplatin
  • Doxorubicin Hydrochloride
  • Fluorouracil
  • Irinotecan Hydrochloride
  • Temsirolimus
  • Vincristine Sulfate
Intermediate-risk group (regimen F)ExperimentalPatients 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. (closed to accrual as of 3/12/2012)
  • Cisplatin
  • Doxorubicin Hydrochloride
  • Fluorouracil
  • Vincristine Sulfate
Low-risk group (regimen T)ExperimentalPatients 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.
  • Cisplatin
  • Fluorouracil
  • Vincristine Sulfate
Very low-risk groupExperimentalPatients undergo surgery and then receive no further treatment.

    Eligibility Criteria

            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 (eg,
                           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 (eg, 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
                 text 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
          
    Maximum Eligible Age:21 Years
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure: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 7 years
    Safety Issue:
    Description:Estimated by the method of Kaplan and Meier.

    Secondary Outcome Measures

    Measure:Feasibility of referral for liver transplantation
    Time Frame:Up to 7 years
    Safety Issue:
    Description:A patient for whom referral is considered appropriate who receives a consultation after enrollment will be considered a success with respect to feasibility.

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    March 5, 2018