The PHITT trial is an over-arching study for patients with Hepatoblastoma (HB) and Hepatocellular Carcinoma (HCC). This trial will use a risk-adapted approach to the treatment of children diagnosed with HB. Children with HCC will be included as a separate cohort.
The trial will evaluate whether reducing treatment for low risk HB patients maintains their excellent event free survival (EFS) and decreases acute and long-term toxicity. Intensification of therapy with the use of novel agents will be evaluated in the high risk group. The trial will also compare three different regimens in intermediate risk HB. Patients with HCC will be divided into groups based on whether the tumour is resectable or unresectable and/or metastatic. Evaluation of the biology of HB and HCC, using the identification/validation of novel and already reported prognostic biomarkers as well as toxicity biomarkers is a key strand of this trial, so patients in all risk groups can be registered. The trial is also designed to optimise the collection of clinically annotated biologic specimens and establish the world's largest repository of blood and tissue samples from paediatric patients with HB and HCC. The trial includes 4 randomised comparisons addressing therapeutic questions. For low risk HB patients, outcome with a total of 4 cycles of treatment is not inferior to those receiving a total of 6 cycles of treatment. For intermediate risk patients, 3 regimens will be compared for outcome and toxicity. For high risk patients, 2 post induction regimens will be compared for outcome. For resected HCC patients, the addition of GEMOX to PLADO regimen will be compared. In addition the following will be assessed: * To validate a new global risk stratification, defined by Children's Hepatic Tumours International Collaboration (CHIC) * To evaluate clinically relevant factors, including the following: * Provide a comprehensive and highly-validated panel of diagnostic and prognostic biomarkers * Determine if paediatric HCC is a biologically different entity to adult HCC * Develop genomic and/or biomarker analysis to predict children who may have an increased risk of developing toxicity with chemotherapy. * To establish a collection of clinically and pathologically-annotated biological samples. * Evaluate a surgical planning tool for an impact on decision making processes in POST-TEXT III and IV HB
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
450
Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination
Arms C, D and E used in combination
Arms C and D used in combination
Event-free survival (EFS)
Event-free survival (EFS) is defined as the time from randomisation (or registration into the trial for non-randomised patients) to first failure event. Patients who have not had an event will be censored at their last follow-up date. 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.
Time frame: From date of randomisation (or registration into the trial for non-randomised patients), until date of first failure event, assessed up to 6 years.
Response in HCC is defined as complete (CR) or partial (PR) response according to RECIST version 1.1 criteria
Response in HCC is defined as complete (CR) or partial (PR) response according to RECIST version 1.1 criteria. The assessment will be performed after 3 cycles of PLADO, or 4 cycles of PLADO+S/GEMOX+S in Group F. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be assumed to be non-responders.
Time frame: From date of screening assessment until date of first response assessment, up to 63 days in Group F
Failure-free survival (FFS)
Failure-free survival (FFS) is defined as the time from randomisation (or registration into the trial for non-randomised patients) to first failure event. Patients who have not had an event will be censored at their last follow-up date. 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. failure to go to resection.
Time frame: From date of randomisation (or registration into the trial for non-randomised patients) until date of first failure event, or date of last follow up assessment, assessed up to 6 years.
Overall survival (OS)
Overall survival (OS) is defined as the time from randomisation (or registration for non-randomised patients) to death from any cause. Patients who have not died will be censored at their last follow-up date.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Arm C used alone
Arms C and D used in combination
Arm D used in combination
Arm D used in combination
Arm F used in combination
Arm F used in combination
Arm used in combination
St. Anna Kinderspital
Vienna, Austria
Cliniques Universitaires Saint-Luc
Brussels, Woluwe-Saint-Lambert, Belgium
University Hospital Motol
Prague, Czechia
Kuopio University Hospital
Kuopio, Finland
CHU de Rennes
Rennes, France
Ludwig-Maximillians-University Munich
Munich, Germany
Children's Health Ireland Crumlin
Dublin, Ireland
Schneider Children's Medical Center
Petah Tikva, Israel
Prinses Maxima Center
Utrecht, Netherlands
Oslo University Hospital
Nydalen, Norway
...and 22 more locations
Time frame: From date of randomisation (or registration for non-randomised patients) until date of death from any cause, or date of last follow up assessment, assessed up to 6 years.
Toxicity categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE)
Toxicity will be recorded in relation to each cycle of randomised treatment and will be categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE)
Time frame: From date of start of randomised treatment until date 30 days after last treatment.
Chemotherapy-related cardiac, nephro- and oto-toxicity using Common Terminology Criteria for Adverse Events (CTCAE)
Chemotherapy-related cardiac, nephro- and oto-toxicity will be recorded in relation to each cycle of treatment and will be categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE)
Time frame: From date of start of randomised treatment until date 30 days after last treatment.
Hearing loss according to the SIOP Boston Scale
Hearing loss will be measured according to the SIOP Boston Scale for oto-toxicity. The assessment will be performed at end of treatment (EOT) and follow up
Time frame: From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.
Best Response
Best Response is defined as CR or PR and is based on radiological response (RECIST v1.1) and Alpha Fetoprotein (AFP) decline. Best Response will be measured throughout treatment period. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be assumed to be non-responders.
Time frame: From date of first treatment until the date of last treatment, or until the date of first documented progression or date of death, assessed up to 6 months.
Surgical resectability defined as complete resection, partial resection or transplant
Surgical resectability is defined as complete resection, partial resection or transplant
Time frame: From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.
Adherence to surgical guidelines
Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.
Time frame: From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.