Carcinoma, Hepatocellular, Hepatoblastoma
Conditions
Brief summary
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.
Detailed description
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
Interventions
DRUGCisplatin
Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination
DRUGDoxorubicin
Arms C, D and E used in combination
DRUGCarboplatin
Arms C and D used in combination
DRUG5Fluorouracil
Arm C used alone
DRUGVincristine
Arms C and D used in combination
DRUGEtoposide
Arm D used in combination
DRUGIrinotecan
Arm D used in combination
DRUGGemcitabine
Arm F used in combination
DRUGOxaliplatin
Arm F used in combination
DRUGSorafenib
Arm used in combination
Sponsors
University of Birmingham
Fundació Institut Germans Trias i Pujol
University Hospital Munich
University Hospital, Bonn
University of Kiel
University Hospital Tuebingen
University of Padova
Ludwig-Maximilians - University of Munich
Medical University of Gdansk
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Motol University Hospital
Rennes University Hospital
Children's University Hospital, Ireland
University of Oslo
Princess Maxima Center for Pediatric Oncology
Andaluz Health Service
Swiss Pediatric Oncology Group
Gothia Forum - Center for Clinical Trial
The Leeds Teaching Hospitals NHS Trust
Bambino Gesù Hospital and Research Institute
Newcastle University
Experimental Cancer Medicine Centres
XenTech, Evry
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of HB\* and histologically defined diagnosis of HB or HCC. \*Histological confirmation of HB is required except in emergency situations where: * a) the patient meets all other eligibility criteria, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy. * b) there is anatomic or mechanical compromise of critical organ function by tumour (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.) * c) Uncorrectable coagulopathy * Age ≤30 years * Written informed consent for trial entry
Exclusion criteria
* Any previous chemotherapy or currently receiving anti-cancer agents * Recurrent disease * Previously received a solid organ transplant; other than orthotopic liver transplantation (OLT). * Uncontrolled infection * Unable to follow or comply with the protocol for any reason * Second malignancy * Pregnant or breastfeeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) | From date of randomisation (or registration into the trial for non-randomised patients), until date of first failure event, assessed up to 6 years. | 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. |
| Response in HCC is defined as complete (CR) or partial (PR) response according to RECIST version 1.1 criteria | From date of screening assessment until date of first response assessment, up to 63 days in Group F | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Failure-free survival (FFS) | 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. | 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. |
| Overall survival (OS) | 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. | 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. |
| Toxicity categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE) | From date of start of randomised treatment until date 30 days after last treatment. | 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) |
| Chemotherapy-related cardiac, nephro- and oto-toxicity using Common Terminology Criteria for Adverse Events (CTCAE) | From date of start of randomised treatment until date 30 days after last treatment. | 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) |
| Hearing loss according to the SIOP Boston Scale | From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years. | 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 |
| Best Response | 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. | 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. |
| Surgical resectability defined as complete resection, partial resection or transplant | From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years. | Surgical resectability is defined as complete resection, partial resection or transplant |
| Adherence to surgical guidelines | From date of registration until date of last follow up assessment, or date of death, assessed up to 6 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. |
Countries
Austria, Belgium, Czechia, Finland, France, Germany, Ireland, Israel, Netherlands, Norway, Poland, Spain, Switzerland, United Kingdom
Contacts
PRINCIPAL_INVESTIGATORMadhumita Dandapani, MD PhD
University of Nottingham
PRINCIPAL_INVESTIGATORMarc Ansari, MD
University of Geneva, Switzerland
Outcome results
None listed