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Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03533582
Recruitment Status : Recruiting
First Posted : May 23, 2018
Last Update Posted : November 5, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE May 11, 2018
First Posted Date  ICMJE May 23, 2018
Last Update Posted Date November 5, 2020
Actual Study Start Date  ICMJE May 23, 2018
Estimated Primary Completion Date June 30, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2019)
  • Event-free survival (EFS) [ Time Frame: 3 years ]
    EFS is defined as the time from randomization (or registration into the trial for non-randomized patients) to the first failure event where the failure events are defined as: progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, or diagnosis of a second malignant neoplasm. Patients who have not had an event will be censored at their last follow-up date. EFS for group A, group B1, group C, group D1, group D2 and E will be presented.
  • Percentage of Group B2 participants with resectable tumors [ Time Frame: 6 months ]
    Group B patients who are unresectable after cycles 1 & 2 of cisplatin treatment will be assigned to Group B2. These patients will receive cycles 3-6 of cisplatin treatment.
  • Response rate for Group F patients [ Time Frame: Up to 5 years ]
    Response is defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be classified as non-responders.
Original Primary Outcome Measures  ICMJE
 (submitted: May 22, 2018)
  • Event-free survival (EFS) [ Time Frame: From date of randomization until progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, or diagnosis of a second malignant neoplasm, assessed up to 5 years ]
    Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of each failure event and in total, survival curves will be estimated by the method of Kaplan-Meier, EFS estimates at 3 and 5 years with 95% confidence intervals (CI), median EFS with CI will be reported if appropriate. A Cox proportional hazards model with EFS as an outcome measure and treatment and stratification factors as covariates will be constructed. This model will be used in the context of a Bayesian analysis and a log Hazard Ratio (HR) will be derived. Bayesian Normal-Normal conjugate analysis of the data will be used to compare treatments. The analysis will use non-informative prior to represent no information about prior beliefs regarding relative treatment difference.
  • Response in hepatocellular carcinoma (HCC), defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria [ Time Frame: Up to 5 years ]
    The main analysis will be based on a log-binomial model for a Bernoulli response variable. This model will be used in the context of a Bayesian analysis. A non-informative null centered proper prior distributions for the parameters will be used. Response rate (RR) and 95% credible interval (CrI) will be presented. Posterior probabilities for the pre-specified values of interest will be provided. Additionally, the posterior probabilities of RR being larger than 0.7, 0.8, 0.9, 1, 1.1, 1.2 and 1.3 will be also provided.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2018)
  • Failure free survival [ Time Frame: From date of randomization until the date of first documented progression, date of death from any cause, diagnosis of a second malignant neoplasm or failure to go to resection, whichever came first, assessed up to 5 years ]
    Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of each failure event and in total, survival curves will be estimated by the method of Kaplan-Meier. Bayesian Normal-Normal conjugate analysis of the data will be used to compare treatments. The analysis will use non-informative prior to represent no information about prior beliefs regarding relative treatment difference.
  • Overall survival [ Time Frame: From date of randomization (or registration for non-randomized patients) until the date of death from any cause, assessed up to 5 years ]
  • Incidence of adverse events [ Time Frame: Up to 5 years ]
    Will be categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE).
  • Chemotherapy-related cardiac, nephro- and oto-toxicity [ Time Frame: Up to 5 years ]
    Will be recorded in relation to each cycle of treatment and will be categorized and graded using Common Terminology Criteria for Adverse Events.
  • Hearing loss measured according to the SIOP Boston Scale for oto-toxicity [ Time Frame: Up to 5 years ]
    Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of patients at each the SIOP Boston Scale for oto-toxicity category (i.e. grade 0 to grade 4) and the number (and proportion) of patients who are not assessable for this outcome, (i.e. because of early stopping of treatment, additional treatments to protocol treatment, progression prior to the response assessment or death). The number (and proportion) of patients experiencing any grade hearing loss. Grades 1 to grade 4 will be combined in this analysis. The above will be presented for each assessment time point (EOT and at least 1 year and 2 years of follow up).
  • Best response defined as compete response (CR) or partial response (PR) based on radiological response (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and AFP decline [ Time Frame: Up to 5 years ]
    Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: best response will be calculated by taking best RECIST category (i.e. CR, PR, stable disease [SD], progressive disease [PD]) for each patient. CR and PR patients will then be grouped into responders. The number (and proportion) of patients at each best response RECIST category (i.e. CR, PR, SD, PD) and the number (and proportion) of patients who are not assessable for response, e.g. because of early stopping of treatment, progression prior to the response assessment or death. The number (and proportion) of responders (CR and PR) and non-responders.
  • Surgical resectability defined as complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients) [ Time Frame: Up to 5 years ]
    Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: The number (and proportion) of patients undergoing complete resection, partial resection or transplant. Time to complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients) will be analyzed using the Kaplan-Meier method.
  • Adherence to surgical guidelines defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines [ Time Frame: Up to 5 years ]
    Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: The number (and proportion) of patients at each combination of SIOPEL surgical guideline (to resect or not) and local clinician?s surgical decision. The degree of agreement will be measured by Cohen?s kappa with CI.
Current Other Pre-specified Outcome Measures
 (submitted: November 13, 2019)
  • Failure free survival [ Time Frame: 3 years ]
    Failure free survival is defined as the time from randomization (or registration into the trial for non-randomized patients) to first failure event. Failure events are: progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, diagnosis of a second malignant neoplasm, or failure to go to resection.
  • Overall survival [ Time Frame: 3 years ]
    Overall survival is defined as the time from randomization (or registration for non-randomized patients) to death from any cause.
  • Percentage of patients experiencing grade 3 or higher adverse events [ Time Frame: 8 months ]
    The percentage of patients experiencing grade 3 or higher toxicity will be reported, where adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
  • Percentage of patients with chemotherapy-related cardiac, nephro- and oto-toxicity [ Time Frame: Up to 5 years ]
    Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
  • Percentage of patients with hearing loss [ Time Frame: Up to 5 years ]
    Hearing loss will be measured according to the SIOP Boston Scale for ototoxicity.
  • Best response [ Time Frame: Up to 5 years ]
    Response in hepatocellular carcinoma (HCC) will be defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Response in HB will be defined as CR or PR based on radiological response (RECIST v1.1) and AFP decline.
  • Percentage of participants who are surgically resectable [ Time Frame: Up to 5 years ]
    Surgical resectability is defined as complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients).
  • Percentage of participants with adherence to surgical guidelines [ Time Frame: Up to 5 years ]
    Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
Official Title  ICMJE Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)
Brief Summary This partially randomized phase II/III trial studies how well, in combination with surgery, cisplatin and combination chemotherapy works in treating children and young adults with hepatoblastoma or hepatocellular carcinoma. Drugs used in chemotherapy, such as cisplatin, doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan, sorafenib, gemcitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving combination chemotherapy may kill more tumor cells than one type of chemotherapy alone.
Detailed Description

PRIMARY OBJECTIVES:

I. To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB) and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes.

II. To determine the event-free survival (EFS) in patients with HB whose tumor is completely resected at diagnosis and either receive no adjuvant chemotherapy (completely resected well differentiated fetal [WDF] histology HB) or 2 cycles of standard dose cisplatin monotherapy (completely resected non-well differentiated fetal histology HB - 100 mg/m^2/cycle given 3 weeks apart). (Group A) III. To demonstrate that 4 to 6 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m^2/cycle; 320-480 mg/m^2 total) is adequate for low risk HB. (Group B) IIIa. In patients who are resected after 2 cycles of cisplatin monotherapy, to compare EFS following a randomized comparison of 2 versus 4 post-operative cycles of cisplatin monotherapy. (Group B) IIIb. In patients whose tumors are deemed unresectable after 2 cycles of cisplatin monotherapy, to determine the proportion of tumors rendered completely resectable by an additional 2 or 4 cycles of chemotherapy. (Group B) IV. To compare in a randomized fashion, EFS in patients with intermediate risk HB treated with 6 cycles of cisplatin/5-fluorouracil/vincristine/doxorubicin (C5VD) chemotherapy versus 6 cycles of interval compressed cisplatin monotherapy (100 mg/m^2/dose). (Group C) V. To determine the EFS in patients with HCC whose tumor is completely resected at diagnosis who receive no adjuvant chemotherapy (completely resected HCC arising in the context of underlying liver disease) or 4 cycles of cisplatin/doxorubicin (PLADO) (completely resected de novo HCC). (Group E) VI. To improve the EFS of patients with high risk HB by treating them with interval compressed cisplatin and doxorubicin based induction regimen followed by response-adapted consolidation therapy. (Group D) VIa. In patients whose metastatic disease resolves with the administration of Societe Internationale d'Oncologie Pediatrique (SIOPEL) 4 Induction therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in a large international study. (Group D1) VIb. In patients whose metastatic disease does not resolve with the administration of SIOPEL 4 Induction therapy, to determine in a randomized comparison which post induction treatment (irinotecan and vincristine sulfate [vincristine] alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with carboplatin and doxorubicin) results in superior outcomes. (Group D Arm CE & Arm VI) VII. In patients with unresectable/metastatic HCC at diagnosis, to determine whether the addition of gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib backbone improves chemotherapy response, resectability and survival. (Group F)

EXPLORATORY OBJECTIVES:

I. To determine if the Childhood Hepatic tumor International Consortium (CHIC) hepatoblastoma risk stratification analysis of very low risk (Group A), low risk (Group B), intermediate risk (Group C) and high risk (Group D) groups stratifies patients allowing appropriate utilization of varying intensity chemotherapy regimens and surgical resection strategies.

II. To define the prognostic relevance of a positive microscopic margin in Group A-D resected HB specimens.

III. To define the frequency of histologically detectable multifocal lesions in liver explants and resected specimens in which multifocal disease was detected at diagnosis and disappeared on cross sectional imaging following treatment with chemotherapy.

IV. To define the prognostic relevance in HB of a 'small cell undifferentiated' tumor component and percentage of tumor necrosis in post chemotherapy specimens.

V. To determine the prognostic impact on EFS and overall survival (OS) of biopsy technique in liver tumors unresectable at diagnosis.

VI. To determine the 3-year EFS and OS of HB patients who undergo liver transplantation vs extreme resection in Group C and D patients.

VII. To determine the 3-year EFS and OS of Group D patients who undergo pulmonary metastasectomy.

VIII. To determine the 3-year EFS and OS of patients who undergo liver transplantation for HCC.

IX. To determine the frequency of relapse in non-metastatic HCC in children treated by liver transplantation versus conventional resection.

X. To determine the concordance of Pretreatment Extent of Disease (PRETEXT) and Post-treatment Extent of disease (POSTTEXT) based surgical guidelines and the surgical intervention performed.

XI. To collect for future analysis, HB and HCC tumor specimens that can be molecularly characterized to validate newly identified molecular and immunohistochemical biomarkers correlating with known clinical prognostic factors and outcome.

XII. To collect for future analysis samples to assess the pharmacogenomics (PG) related to cisplatin therapy in pediatric and adolescent liver tumor patients and correlate PG with Boston Grading Scale for ototoxicity.

XIII. To collect for future analysis samples such that novel biomarkers of renal toxicity (urine neutrophil gelatinase-associated lipocalin [NGAL], cystatin C and Kim1) from cisplatin therapy can be correlated with pharmacogenomics, other associated toxicities, and outcomes.

XIV. To determine which system (Children's Oncology Group [COG] PRETEXT, SIOPEL PRETEXT, or a new hybrid definition of PRETEXT) of the annotation factors for V, P, E, F and R provides the best prognostic information for determining response to chemotherapy, guiding risk based therapy, predicting surgical resectability, and EFS.

XV. To determine the concordance between institutional and expert panel review assessment of PRETEXT and POSTTEXT stage in an international cooperative group setting.

OUTLINE:

GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups.

GROUP A1 (WDF): Patients undergo observation.

GROUP A2 (NON-WDF): Patients receive cisplatin (CDDP) intravenously (IV) over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

GROUP B (LOW RISK HB): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 2 groups

GROUP B1 (RESECTABLE): Patients receive 2 cycles of cisplatin, undergo surgery, then are randomized to 1 of 2 arms (2 vs 4 additional cycles of cisplatin).

GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 4 total cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity.

GROUP B1 ARM 6-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles(2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity.

GROUP B2 (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). Patients with resectable tumors undergo surgery, then all patients continue with 2 additional cycles of cisplatin.

GROUP C (INTERMEDIATE RISK HB): Patients are randomized to 1 of 2 arms.

GROUP C ARM CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

GROUP C ARM C5VD: Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 (for cycles 1 and 2) and days 1 and 2 (for cycle 3). Cycles 1 and 2 are 28 days; cycle 3 is 21 days. Patients are then assigned to 1 of 2 arms.

GROUP D1: CONSOLIDATION THERAPY: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

GROUP D2: Patients with residual metastatic disease are randomized to 1 of 2 arms.

GROUP D2 ARM CE: Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin IV over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP D2 ARM VI: Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 60-90 minutes once daily (QD) on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP E (RESECTED HCC): Patients are assigned to 1 of 2 groups.

GROUP E1: Patients with HCC secondary to underlying hepatic disease undergo observation only.

GROUP E2 (PLADO): Patients with de novo HCC receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

GROUP F (UNRESECTED AND/OR METASTATIC HCC): Patients are randomized to 1 of 2 arms.

GROUP F ARM 1 (PLADO): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib orally (PO) twice daily (BID) on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment.

GROUP F ARM 2 (P/GEMOX): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment.

After completion of study treatment, patients are followed up for a minimum of 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Childhood Hepatocellular Carcinoma
  • Childhood Malignant Liver Neoplasm
  • Fibrolamellar Carcinoma
  • Hepatoblastoma
  • Hepatocellular Malignant Neoplasm, Not Otherwise Specified
Intervention  ICMJE
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Cisplatin
    Given IV
    Other Names:
    • Abiplatin
    • 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
    • Platosin
  • Drug: Doxorubicin
    Given IV
    Other Names:
    • Adriablastin
    • Hydroxydaunomycin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16
    • VP 16-213
    • VP-16
    • VP-16-213
    • VP16
  • Drug: Fluorouracil
    Given IV
    Other Names:
    • 5 Fluorouracil
    • 5 Fluorouracilum
    • 5 FU
    • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
    • 5-Fluorouracil
    • 5-Fluracil
    • 5-Fu
    • 5FU
    • AccuSite
    • Carac
    • Fluoro Uracil
    • Fluouracil
    • Flurablastin
    • Fluracedyl
    • Fluracil
    • Fluril
    • Fluroblastin
    • Ribofluor
    • Ro 2-9757
    • Ro-2-9757
  • Drug: Gemcitabine
    Given IV
    Other Names:
    • dFdC
    • dFdCyd
    • Difluorodeoxycytidine
  • Drug: Irinotecan
    Given IV
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Oxaliplatin
    Given IV
    Other Names:
    • 1-OHP
    • Ai Heng
    • Aiheng
    • Dacotin
    • Dacplat
    • Diaminocyclohexane Oxalatoplatinum
    • Eloxatin
    • Eloxatine
    • JM-83
    • Oxalatoplatin
    • Oxalatoplatinum
    • RP 54780
    • RP-54780
    • SR-96669
  • Other: Patient Observation
    Undergo watchful waiting
    Other Names:
    • Active Surveillance
    • deferred therapy
    • expectant management
    • Observation
    • Watchful Waiting
  • Drug: Sorafenib
    Given PO
    Other Names:
    • BA4 43 9006
    • BAY 43-9006
    • Bay-439006
  • Drug: Vincristine Sulfate
    Given IV
    Other Names:
    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate
Study Arms  ICMJE
  • Active Comparator: Group A1 (WDF)
    Patients undergo observation.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Patient Observation
  • Experimental: GROUP A2 (NON-WDF)
    Patients receive cisplatin IV over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP B1 ARM 4-CDDP
    Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 4 cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP B1 ARM 6-CDDP
    Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 6 cycles (2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP B2 (UNRESECTABLE)
    Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 6 cycles (4 pre-surgery, 2 post-surgery).
    Interventions:
    • Drug: Cisplatin
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP C ARM C5VD
    Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Drug: Fluorouracil
    • Other: Laboratory Biomarker Analysis
    • Drug: Vincristine Sulfate
  • Experimental: GROUP C ARM CDDP
    Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.
    Interventions:
    • Drug: Cisplatin
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP D1

    SIOPEL-4 INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 during cycles 1 and 2 and days 1 and 2 during cycle 3. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

    CONSOLIDATION: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

    Interventions:
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP D2 ARM CE

    SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

    Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

    Interventions:
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP D2 ARM VI

    SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

    Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 90 minutes QD on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

    Interventions:
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Drug: Irinotecan
    • Other: Laboratory Biomarker Analysis
    • Drug: Vincristine Sulfate
  • Active Comparator: GROUP E1
    Patients undergo observation only.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Patient Observation
  • Experimental: GROUP E2 (PLADO)
    Patients receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Other: Laboratory Biomarker Analysis
  • Experimental: GROUP F ARM 1 (PLADO)
    Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Other: Laboratory Biomarker Analysis
    • Drug: Sorafenib
  • Experimental: GROUP F ARM 2 (P/GEMOX)
    Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Drug: Gemcitabine
    • Other: Laboratory Biomarker Analysis
    • Drug: Oxaliplatin
    • Drug: Sorafenib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 22, 2018)
1220
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2025
Estimated Primary Completion Date June 30, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients in Group F must have a body surface area (BSA) >= 0.6 m^2
  • Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified, should be classified and treated per hepatoblastoma treatment arms; note that rapid central pathology review is required in some cases; please note: all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by immunohistochemistry (IHC) according to the practices at the institution
  • Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining
  • For all Group A patients, WDF status as determined by rapid review will be used to further stratify patients to Group A1 or A2

    • For Groups B, C and D, rapid review is required if patients are either >= 8 years of age or have an alphafetoprotein (AFP) =< 100 at diagnosis
    • For all Groups E and F patients, rapid central pathology review is required
  • 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 without a biopsy

    • Clinical situations in which 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 AHEP1531 when emergent treatment is given, the following must occur:

      • The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment
      • Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment
    • Note: If the patient receives AHEP1531 chemotherapy emergently 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 may have had surgical resection of the hepatic malignancy prior to enrollment; all other anti-cancer therapy for the current liver lesion is prohibited
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 or

    • A serum creatinine based on age/gender as follows:

      • Age: maximum serum creatinine (mg/dL)
      • 1 month to < 6 months: 0.4 (male and female)
      • 6 months to < 1 year: 0.5 (male and female)
      • 1 to < 2 years: 06 (male and female)
      • 2 to < 6 years: 0.8 (male and female)
      • 6 to < 10 years: 1 (male and female)
      • 10 to < 13 years: 1.2 (male and female)
      • 13 to < 16 years: 1.5 (male), 1.4 (female)
      • >= 16 years: 1.7 (male), 1.4 (female)
  • Total bilirubin =< 5 x upper limit of normal (ULN) for age
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 10 x upper limit of normal (ULN) for age
  • Shortening fraction of >= 28% by echocardiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment) or
  • Ejection fraction of >= 47% by echocardiogram or radionuclide angiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment)
  • Group F patients only: QT/corrected QT (QTc) interval =< 450 milliseconds for males and =< 470 milliseconds for females (assessed within 8 weeks prior to study enrollment)
  • Normal pulmonary function tests (including diffusion capacity of the lung for carbon monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy [Groups A2, B, C, D, E2, F]); for patients who do not have respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
  • 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:

  • Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible
  • Patients who are currently receiving another investigational drug
  • Patients who are currently receiving other anticancer agents
  • Patients with uncontrolled infection
  • Patients who previously received a solid organ transplant, other than those who previously received an orthotopic liver transplantation (OLT) as primary treatment of their hepatocellular carcinoma
  • Patients with hypersensitivity to any drugs on their expected treatment arm
  • Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)
  • Group D:

    • Patients with chronic inflammatory bowel disease and/or bowel obstruction
    • Patients with concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment
  • Group F:

    • Patients with peripheral sensitive neuropathy with functional impairment
    • Patients with a personal or family history of congenital long QT syndrome
  • This criteria apply ONLY to patients who will receive chemotherapy (all groups other than Groups A1 and E1):

    • Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
    • Lactating females who plan to breastfeed their infants
    • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

      • Note for Group F: patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 30 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   Saudi Arabia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03533582
Other Study ID Numbers  ICMJE AHEP1531
NCI-2017-01910 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AHEP1531 ( Other Identifier: Children's Oncology Group )
AHEP1531 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Gregory M Tiao Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP