Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Fundació Institut Germans Trias i Pujol | OTHER |
| University Hospital Munich | OTHER |
| University Hospital, Bonn | OTHER |
| University of Kiel |
Not provided
Not provided
Not provided
Not provided
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:
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
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A Very Low Risk HB | Other | 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 B Low Risk HB | Active Comparator | 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 | Active Comparator | 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 | Active Comparator | 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). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cisplatin | Drug | Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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:
| 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. | From date of screening assessment until date of first response assessment, up to 63 days in Group F |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
|
Not provided
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:
Age ≤30 years
Written informed consent for trial entry
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Madhumita Dandapani, MD PhD | University of Nottingham | Principal Investigator |
| Marc Ansari, MD | University of Geneva, Switzerland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St. Anna Kinderspital | Vienna | 1090 | Austria | |||
| Cliniques Universitaires Saint-Luc |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| OTHER |
| University Hospital Tuebingen | OTHER |
| University of Padova | OTHER |
| Ludwig-Maximilians - University of Munich | OTHER |
| Medical University of Gdansk | OTHER |
| Cliniques universitaires Saint-Luc- Université Catholique de Louvain | OTHER |
| Motol University Hospital | OTHER |
| Rennes University Hospital | OTHER |
| Children's University Hospital, Ireland | OTHER |
| University of Oslo | OTHER |
| Princess Maxima Center for Pediatric Oncology | OTHER |
| Andaluz Health Service | OTHER_GOV |
| Swiss Pediatric Oncology Group | OTHER |
| Gothia Forum - Center for Clinical Trial | OTHER |
| The Leeds Teaching Hospitals NHS Trust | OTHER |
| Bambino Gesù Hospital and Research Institute | OTHER |
| Newcastle University | OTHER |
| Experimental Cancer Medicine Centres | OTHER |
| XenTech, Evry | UNKNOWN |
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Group E Resected HCC | Other | 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 | Active Comparator | 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) |
|
| Doxorubicin | Drug | Arms C, D and E used in combination |
|
| Carboplatin | Drug | Arms C and D used in combination |
|
| 5Fluorouracil | Drug | Arm C used alone |
|
| Vincristine | Drug | Arms C and D used in combination |
|
| Etoposide | Drug | Arm D used in combination |
|
| Irinotecan | Drug | Arm D used in combination |
|
| Gemcitabine | Drug | Arm F used in combination |
|
| Oxaliplatin | Drug | Arm F used in combination |
|
| Sorafenib | Drug | Arm used in combination |
|
| 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. | 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) | 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) | 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 | 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. | 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 | 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. | From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years. |
| Brussels |
| Woluwe-Saint-Lambert |
| 1200 |
| Belgium |
| University Hospital Motol | Prague | 150 06 Prague 5 | Czechia |
| Kuopio University Hospital | Kuopio | FI20029 KYS | Finland |
| CHU de Rennes | Rennes | 35033 | France |
| Ludwig-Maximillians-University Munich | Munich | 80337 Munich | Germany |
| Children's Health Ireland Crumlin | Dublin | 12 N512 | Ireland |
| Schneider Children's Medical Center | Petah Tikva | 4920235 | Israel |
| Prinses Maxima Center | Utrecht | 3584 CS | Netherlands |
| Oslo University Hospital | Nydalen | 0424 Oslo | Norway |
| Medical University of Gdansk | Gdansk | 80-803 | Poland |
| University Hospital Reina Sofia | Córdoba | 14004 | Spain |
| Hopitaux Universitaires de Geneve | Geneva | CH 1211 | Switzerland |
| Royal Aberdeen Children's Hospital | Aberdeen | AB25 2ZG | United Kingdom |
| Royal Belfast Hospital for Sick Children | Belfast | BT12 6BE | United Kingdom |
| Birmingham Children's Hospital | Birmingham | B4 6NH | United Kingdom |
| Bristol Royal Hospital for Children | Bristol | BS2 8BJ | United Kingdom |
| Addenbrooke's Hospital | Cambridge | CB2 0QQ | United Kingdom |
| Noah's Ark Children's Hospital for Wales | Cardiff | CF14 4XW | United Kingdom |
| Royal Hospital for Children | Edinburgh | EH9 1LW | United Kingdom |
| Royal Hospital for Children | Glasgow | G51 4TF | United Kingdom |
| Leeds General Infirmary | Leeds | LS1 3EX | United Kingdom |
| Leicester Royal Infirmary | Leicester | LE1 5WW | United Kingdom |
| Alder Hey Children's Hospital | Liverpool | L12 2AP | United Kingdom |
| Great Ormond Street Hospital | London | WC1N 3JH | United Kingdom |
| Royal Manchester Children's Hospital | Manchester | M13 9WL | United Kingdom |
| Great North Children's Hospital | Newcastle upon Tyne | NE1 4LP | United Kingdom |
| Nottingham Children's Hospital | Nottingham | NG7 2UH | United Kingdom |
| Oxford Children's Hospital | Oxford | OX3 9DU | United Kingdom |
| Sheffield Children's Hospital | Sheffield | S10 2TH | United Kingdom |
| University Hospital Southampton | Southampton | SO16 6YD | United Kingdom |
| The Royal Marsden Hospital | Sutton | SM2 5PT | United Kingdom |
| ID | Term |
|---|---|
| D018197 | Hepatoblastoma |
| D006528 | Carcinoma, Hepatocellular |
| ID | Term |
|---|---|
| D018193 | Neoplasms, Complex and Mixed |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D008113 | Liver Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D002945 | Cisplatin |
| D004317 | Doxorubicin |
| D016190 | Carboplatin |
| D005472 | Fluorouracil |
| D014750 | Vincristine |
| D005047 | Etoposide |
| D000077146 | Irinotecan |
| D000093542 | Gemcitabine |
| D000077150 | Oxaliplatin |
| D000077157 | Sorafenib |
| ID | Term |
|---|---|
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017672 | Nitrogen Compounds |
| D017671 | Platinum Compounds |
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D056831 | Coordination Complexes |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D014748 | Vinca Alkaloids |
| D046948 | Secologanin Tryptamine Alkaloids |
| D026121 | Indole Alkaloids |
| D000470 | Alkaloids |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D054836 | Indolizidines |
| D007212 | Indolizines |
| D011034 | Podophyllotoxin |
| D013764 | Tetrahydronaphthalenes |
| D009281 | Naphthalenes |
| D005960 | Glucosides |
| D002166 | Camptothecin |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D010671 | Phenylurea Compounds |
| D014508 | Urea |
| D000577 | Amides |
| D001555 | Benzene Derivatives |
| D009536 | Niacinamide |
| D009539 | Nicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D011725 | Pyridines |
Not provided
Not provided