Paediatric Hepatic International Tumour Trial (PHITT)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Hepatocellular; Hepatoblastoma
• Intervention / Treatment: Drug: Cisplatin; Drug: Doxorubicin; Drug: Carboplatin; Drug: 5Fluorouracil; Drug: Vincristine; Drug: Etoposide; Drug: Irinotecan; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: Sorafenib

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

• Study Type: Interventional
• Enrollment (Estimated): 450
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • St. Anna Kinderspital
• Belgium
  • Woluwe-Saint-Lambert
    • Brussels, Woluwe-Saint-Lambert, Belgium, 1200
      • Cliniques Universitaires Saint-luc
• Czechia
  • Prague, Czechia, 150 06 Prague 5
    • University Hospital Motol
• Finland
  • Kuopio, Finland, FI20029 KYS
    • Kuopio University Hospital
• France
  • Rennes, France, 35033
    • CHU de Rennes
• Germany
  • Munich, Germany, 80337 Munich
    • Ludwig-Maximillians-University Munich
• Ireland
  • Dublin, Ireland, 12 N512
    • Children's Health Ireland Crumlin
• Israel
  • Petah Tikva, Israel, 4920235
    • Schneider Children's Medical Center
• Netherlands
  • Utrecht, Netherlands, 3584 CS
    • Prinses Maxima Center
• Norway
  • Nydalen, Norway, 0424 Oslo
    • Oslo University Hospital
• Poland
  • Gdansk, Poland, 80-803
    • Medical University of Gdansk
• Spain
  • Córdoba, Spain, 14004
    • University Hospital Reina Sofía
• Switzerland
  • Geneva, Switzerland, CH 1211
    • Hôpitaux Universitaires de Genève
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZG
    • Royal Aberdeen Children's Hospital
  • Belfast, United Kingdom, BT12 6BE
    • Royal Belfast Hospital for Sick Children
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
  • Bristol, United Kingdom, BS2 8BJ
    • Bristol Royal Hospital for Children
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • Noah's Ark Children's Hospital for Wales
  • Edinburgh, United Kingdom, EH9 1LW
    • Royal Hospital For Children
  • Glasgow, United Kingdom, G51 4TF
    • Royal Hospital For Children
  • Leeds, United Kingdom, LS1 3EX
    • Leeds General Infirmary
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
  • Liverpool, United Kingdom, L12 2AP
    • Alder Hey Children's Hospital
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Great North Children's Hospital
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham Children's Hospital
  • Oxford, United Kingdom, OX3 9DU
    • Oxford Children's Hospital
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's Hospital
  • Southampton, United Kingdom, SO16 6YD
    • University Hospital Southampton
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group A Very Low Risk HB; 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).	Drug: Cisplatin; Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination
Active Comparator: Group B Low Risk HB; 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.	Drug: Cisplatin; Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination
Active Comparator: Group C Intermediate Risk HB; 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)	Drug: Cisplatin; Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination; Drug: Doxorubicin; Arms C, D and E used in combination; Drug: Carboplatin; Arms C and D used in combination; Drug: 5Fluorouracil; Arm C used alone; Drug: Vincristine; Arms C and D used in combination
Active Comparator: Group D High Risk HB; 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).	Drug: Cisplatin; Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination; Drug: Doxorubicin; Arms C, D and E used in combination; Drug: Carboplatin; Arms C and D used in combination; Drug: Vincristine; Arms C and D used in combination; Drug: Etoposide; Arm D used in combination; Drug: Irinotecan; Arm D used in combination
Other: Group E Resected HCC; 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.	Drug: Cisplatin; Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination; Drug: Doxorubicin; Arms C, D and E used in combination
Active Comparator: Group F Unresected HCC; 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)	Drug: Cisplatin; Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination; Drug: Doxorubicin; Arms C, D and E used in combination; Drug: Gemcitabine; Arm F used in combination; Drug: Oxaliplatin; Arm F used in combination; Drug: Sorafenib; Arm used in combination

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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: 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.	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

Secondary Outcome Measures

Outcome Measure	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: 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.	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.

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: University of Oslo; The Leeds Teaching Hospitals NHS Trust; University of Padova; Bambino Gesù Hospital and Research Institute; University of Kiel; Ludwig-Maximilians - University of Munich; University Hospital, Bonn; Cliniques universitaires Saint-Luc- Université Catholique de Louvain; Rennes University Hospital; Newcastle University; University Hospital Tuebingen; Andaluz Health Service; Fundació Institut Germans Trias i Pujol; Princess Maxima Center for Pediatric Oncology; Motol University Hospital; Medical University of Gdansk; University Hospital Munich; Children's University Hospital, Ireland; Gothia Forum - Center for Clinical Trial; Swiss Pediatric Oncology Group; Experimental Cancer Medicine Centres; XenTech, Evry
• Investigators: Principal Investigator: Madhumita Dandapani, MD PhD, University of Nottingham; Principal Investigator: Marc Ansari, MD, University of Geneva, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2017
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: December 14, 2016
• First Submitted That Met QC Criteria: January 10, 2017
• First Posted (Estimated): January 11, 2017

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Neoplasms, Complex and Mixed; Carcinoma, Hepatocellular; Hepatoblastoma; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Camptothecin; Alkaloids; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Amides; Indoles; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Benzene Derivatives; Uracil; Pyrimidinones; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Anthracyclines; Naphthacenes; Aminoglycosides; Platinum Compounds; Daunorubicin; Urea; Acids, Heterocyclic; Phenylurea Compounds; Niacinamide; Nicotinic Acids; Sorafenib; Oxaliplatin; Irinotecan; Gemcitabine; Fluorouracil; Etoposide; Carboplatin; Doxorubicin; Vincristine; Cisplatin
• Other Study ID Numbers: RG_15-114

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No