Paediatric Hepatic International Tumour Trial
- Conditions
- Carcinoma, HepatocellularHepatoblastoma
- Interventions
- Registration Number
- NCT03017326
- Lead Sponsor
- University of Birmingham
- 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
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 450
-
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Group C Intermediate Risk HB 5Fluorouracil Patients will be randomised to receive Cisplatin (80mg/m2), Carboplatin (500mg/m2) and Doxorubicin (60mg/m2) as SIOPEL-3HR (5 cycles), Cisplatin (100mg/m2), Doxorubicin (60mg/m2) 5-Fluorouracil (600mg/m2) and Vincristine (4.5mg/m2) as C5VD (6 cycles), or 6 cycles of high dose Cisplatin (100mg/m2) Group B Low Risk HB Cisplatin Patients who are resected after 2 cycles of Cisplatin will be randomised to receive 4 or 6 cycles of Cisplatin overall (80mg/m2). Patients who are not resected will continue to receive up to 6 cycles of Cisplatin (80mg/m2) until resection. Group C Intermediate Risk HB Cisplatin Patients will be randomised to receive Cisplatin (80mg/m2), Carboplatin (500mg/m2) and Doxorubicin (60mg/m2) as SIOPEL-3HR (5 cycles), Cisplatin (100mg/m2), Doxorubicin (60mg/m2) 5-Fluorouracil (600mg/m2) and Vincristine (4.5mg/m2) as C5VD (6 cycles), or 6 cycles of high dose Cisplatin (100mg/m2) Group A Very Low Risk HB Cisplatin Patients with well differentiated foetal histology will receive 2 cycles of Cisplatin (2x 100mg/m2). Patients will non-well differentiated histology will be followed up only (no intervention). Group C Intermediate Risk HB Carboplatin Patients will be randomised to receive Cisplatin (80mg/m2), Carboplatin (500mg/m2) and Doxorubicin (60mg/m2) as SIOPEL-3HR (5 cycles), Cisplatin (100mg/m2), Doxorubicin (60mg/m2) 5-Fluorouracil (600mg/m2) and Vincristine (4.5mg/m2) as C5VD (6 cycles), or 6 cycles of high dose Cisplatin (100mg/m2) Group C Intermediate Risk HB Doxorubicin Patients will be randomised to receive Cisplatin (80mg/m2), Carboplatin (500mg/m2) and Doxorubicin (60mg/m2) as SIOPEL-3HR (5 cycles), Cisplatin (100mg/m2), Doxorubicin (60mg/m2) 5-Fluorouracil (600mg/m2) and Vincristine (4.5mg/m2) as C5VD (6 cycles), or 6 cycles of high dose Cisplatin (100mg/m2) Group C Intermediate Risk HB Vincristine Patients will be randomised to receive Cisplatin (80mg/m2), Carboplatin (500mg/m2) and Doxorubicin (60mg/m2) as SIOPEL-3HR (5 cycles), Cisplatin (100mg/m2), Doxorubicin (60mg/m2) 5-Fluorouracil (600mg/m2) and Vincristine (4.5mg/m2) as C5VD (6 cycles), or 6 cycles of high dose Cisplatin (100mg/m2) Group D High Risk HB Cisplatin Patients will receive SIOPEL-4 regimen (Cisplatin 70mg/m2, Doxorubicin 30mg/m2) then have surgery. Post surgery, patients with remaining metastases will be randomised to receive 6 cycles of either Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Carboplatin (800mg/m2) and Etoposide (400mg/m2), or Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Vincristine (3mg/m2) and Irinotecan (250mg/m2). Patients with no metastases will receive the standard treatment of 3 cycles of Carboplatin (500mg/m2) and Doxorubicin (40mg/m2). Group D High Risk HB Doxorubicin Patients will receive SIOPEL-4 regimen (Cisplatin 70mg/m2, Doxorubicin 30mg/m2) then have surgery. Post surgery, patients with remaining metastases will be randomised to receive 6 cycles of either Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Carboplatin (800mg/m2) and Etoposide (400mg/m2), or Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Vincristine (3mg/m2) and Irinotecan (250mg/m2). Patients with no metastases will receive the standard treatment of 3 cycles of Carboplatin (500mg/m2) and Doxorubicin (40mg/m2). Group D High Risk HB Carboplatin Patients will receive SIOPEL-4 regimen (Cisplatin 70mg/m2, Doxorubicin 30mg/m2) then have surgery. Post surgery, patients with remaining metastases will be randomised to receive 6 cycles of either Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Carboplatin (800mg/m2) and Etoposide (400mg/m2), or Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Vincristine (3mg/m2) and Irinotecan (250mg/m2). Patients with no metastases will receive the standard treatment of 3 cycles of Carboplatin (500mg/m2) and Doxorubicin (40mg/m2). Group D High Risk HB Vincristine Patients will receive SIOPEL-4 regimen (Cisplatin 70mg/m2, Doxorubicin 30mg/m2) then have surgery. Post surgery, patients with remaining metastases will be randomised to receive 6 cycles of either Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Carboplatin (800mg/m2) and Etoposide (400mg/m2), or Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Vincristine (3mg/m2) and Irinotecan (250mg/m2). Patients with no metastases will receive the standard treatment of 3 cycles of Carboplatin (500mg/m2) and Doxorubicin (40mg/m2). Group D High Risk HB Etoposide Patients will receive SIOPEL-4 regimen (Cisplatin 70mg/m2, Doxorubicin 30mg/m2) then have surgery. Post surgery, patients with remaining metastases will be randomised to receive 6 cycles of either Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Carboplatin (800mg/m2) and Etoposide (400mg/m2), or Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Vincristine (3mg/m2) and Irinotecan (250mg/m2). Patients with no metastases will receive the standard treatment of 3 cycles of Carboplatin (500mg/m2) and Doxorubicin (40mg/m2). Group D High Risk HB Irinotecan Patients will receive SIOPEL-4 regimen (Cisplatin 70mg/m2, Doxorubicin 30mg/m2) then have surgery. Post surgery, patients with remaining metastases will be randomised to receive 6 cycles of either Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Carboplatin (800mg/m2) and Etoposide (400mg/m2), or Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Vincristine (3mg/m2) and Irinotecan (250mg/m2). Patients with no metastases will receive the standard treatment of 3 cycles of Carboplatin (500mg/m2) and Doxorubicin (40mg/m2). Group E Resected HCC Cisplatin Patients with an underlying predisposition to HCC through genetic, viral or metabolic conditions will be followed up (no intervention). De novo or fibrolamellar HCC patients will receive 4 cycles of PLADO regimen (Cisplatin (80mg/m2) and Doxorubicin (60mg/m2)) over 4 cycles. Group E Resected HCC Doxorubicin Patients with an underlying predisposition to HCC through genetic, viral or metabolic conditions will be followed up (no intervention). De novo or fibrolamellar HCC patients will receive 4 cycles of PLADO regimen (Cisplatin (80mg/m2) and Doxorubicin (60mg/m2)) over 4 cycles. Group F Unresected HCC Gemcitabine Patients will be randomised to receive up to 6 cycles of PLADO (Cisplatin 80mg/m2, Doxorubicin 60mg/m2) with Sorafenib (300mg/m2) or up to 8 cycles of PLADO with Sorafenib and GEMOX (Gemcitabine 1000mg/m2, Oxaliplatin 100mg/m2) with Sorafenib (300mg/m2) Group F Unresected HCC Cisplatin Patients will be randomised to receive up to 6 cycles of PLADO (Cisplatin 80mg/m2, Doxorubicin 60mg/m2) with Sorafenib (300mg/m2) or up to 8 cycles of PLADO with Sorafenib and GEMOX (Gemcitabine 1000mg/m2, Oxaliplatin 100mg/m2) with Sorafenib (300mg/m2) Group F Unresected HCC Doxorubicin Patients will be randomised to receive up to 6 cycles of PLADO (Cisplatin 80mg/m2, Doxorubicin 60mg/m2) with Sorafenib (300mg/m2) or up to 8 cycles of PLADO with Sorafenib and GEMOX (Gemcitabine 1000mg/m2, Oxaliplatin 100mg/m2) with Sorafenib (300mg/m2) Group F Unresected HCC Oxaliplatin Patients will be randomised to receive up to 6 cycles of PLADO (Cisplatin 80mg/m2, Doxorubicin 60mg/m2) with Sorafenib (300mg/m2) or up to 8 cycles of PLADO with Sorafenib and GEMOX (Gemcitabine 1000mg/m2, Oxaliplatin 100mg/m2) with Sorafenib (300mg/m2) Group F Unresected HCC Sorafenib Patients will be randomised to receive up to 6 cycles of PLADO (Cisplatin 80mg/m2, Doxorubicin 60mg/m2) with Sorafenib (300mg/m2) or up to 8 cycles of PLADO with Sorafenib and GEMOX (Gemcitabine 1000mg/m2, Oxaliplatin 100mg/m2) with Sorafenib (300mg/m2)
- Primary Outcome Measures
Name Time Method 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.
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.
- Secondary Outcome Measures
Name Time Method 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.
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
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.
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.
Trial Locations
- Locations (31)
Cliniques Universitaires Saint-Luc
🇧🇪Brussels, Woluwe-Saint-Lambert, Belgium
Children's Health Ireland Crumlin
🇮🇪Dublin, Ireland
Schneider Children's Medical Center
🇮🇱Petach Tikva, Israel
University Hospital Southampton
🇬🇧Southampton, United Kingdom
The Royal Marsden Hospital
🇬🇧Sutton, United Kingdom
Royal Hospital for Children
🇬🇧Glasgow, United Kingdom
Leicester Royal Infirmary
🇬🇧Leicester, United Kingdom
Leeds General Infirmary
🇬🇧Leeds, United Kingdom
University Hospital Motol
🇨🇿Prague, Czechia
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
Alder Hey Children's Hospital
🇬🇧Liverpool, United Kingdom
University Hospital Reina Sofia
🇪🇸Córdoba, Spain
Birmingham Children's Hospital
🇬🇧Birmingham, United Kingdom
Great Ormond Street Hospital
🇬🇧London, United Kingdom
Great North Children's Hospital
🇬🇧Newcastle Upon Tyne, United Kingdom
Nottingham Children's Hospital
🇬🇧Nottingham, United Kingdom
Oxford Children's Hospital
🇬🇧Oxford, United Kingdom
Sheffield Children's Hospital
🇬🇧Sheffield, United Kingdom
CHU de Rennes
🇫🇷Rennes, France
St. Anna Kinderspital
🇦🇹Vienna, Austria
Kuopio University Hospital
🇫🇮Kuopio, Finland
Prinses Maxima Center
🇳🇱Utrecht, Netherlands
Oslo University Hospital
🇳🇴Nydalen, Norway
Ludwig-Maximillians-University Munich
🇩🇪Munich, Germany
Royal Belfast Hospital for Sick Children
🇬🇧Belfast, United Kingdom
Medical University of Gdansk
🇵🇱Gdańsk, Poland
Royal Aberdeen Children's Hospital
🇬🇧Aberdeen, United Kingdom
Hopitaux Universitaires de Geneve
🇨🇭Geneva, Switzerland
Bristol Royal Hospital for Children
🇬🇧Bristol, United Kingdom
Addenbrooke's Hospital
🇬🇧Cambridge, United Kingdom
Noah's Ark Children's Hospital for Wales
🇬🇧Cardiff, United Kingdom