Paediatric Hepatic International Tumour Trial (PHITT)

September 5, 2022 updated by: University of Birmingham

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

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 (Anticipated)

450

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

      • Vienna, Austria, 1090
        • Recruiting
        • St. Anna Kinderspital
        • Contact:
        • Principal Investigator:
          • Heidrun Boztug
    • Woluwe-Saint-Lambert
      • Brussels, Woluwe-Saint-Lambert, Belgium, 1200
        • Recruiting
        • Cliniques Universitaires Saint-Luc
        • Contact:
        • Principal Investigator:
          • Benedicte Brichard
      • Prague, Czechia, 150 06 Prague 5
        • Recruiting
        • University Hospital Motol
        • Contact:
        • Principal Investigator:
          • Josef Malis, MD
      • Rennes, France, 35033
      • Munich, Germany, 80337 Munich
        • Recruiting
        • Ludwig-Maximillians-University Munich
        • Contact:
        • Principal Investigator:
          • Irene Schmid
      • Dublin, Ireland, 12 N512
        • Recruiting
        • Children's Health Ireland Crumlin
        • Contact:
        • Principal Investigator:
          • Michael Capra
      • Petach Tikva, Israel, 4920235
        • Recruiting
        • Schneider Children's Medical Center
        • Contact:
        • Principal Investigator:
          • Helen Toledano
      • Utrecht, Netherlands, 3584 CS
        • Recruiting
        • Prinses Maxima Center
        • Contact:
        • Principal Investigator:
          • Jozef Zsiros
      • Nydalen, Norway, 0424 Oslo
        • Recruiting
        • Oslo University Hospital
        • Contact:
        • Principal Investigator:
          • Anne Gro Wesenberg Rognlien
      • Gdańsk, Poland, 80-803
        • Recruiting
        • Medical University of Gdansk
        • Contact:
        • Principal Investigator:
          • Piotr Czauderna
      • Córdoba, Spain, 14004
        • Recruiting
        • University Hospital Reina Sofia
        • Contact:
        • Principal Investigator:
          • Maria Mateos
      • Geneva, Switzerland, CH 1211
        • Recruiting
        • Hôpitaux Universitaires de Genève
        • Contact:
        • Principal Investigator:
          • Marc Ansari
      • Aberdeen, United Kingdom, AB25 2ZG
        • Recruiting
        • Royal Aberdeen Children's Hospital
        • Principal Investigator:
          • Courtney Willis, MD PhD
      • Belfast, United Kingdom, BT12 6BE
        • Recruiting
        • Royal Belfast Hospital for Sick Children
        • Principal Investigator:
          • Anthony McCarthy, MD PhD
      • Birmingham, United Kingdom, B4 6NH
        • Recruiting
        • Birmingham Children's Hospital
        • Principal Investigator:
          • Dave Hobin, MB ChB
      • Bristol, United Kingdom, BS2 8BJ
        • Recruiting
        • Bristol Royal Hospital for Children
        • Principal Investigator:
          • Antony Ng, MBBS PhD
      • Cambridge, United Kingdom, CB2 0QQ
        • Recruiting
        • Addenbrooke's Hospital
        • Principal Investigator:
          • Amos Burke, MB ChB
      • Cardiff, United Kingdom, CF14 4XW
        • Recruiting
        • Noah's Ark Children's Hospital for Wales
        • Principal Investigator:
          • Catherine Morley-Jacob, MD MBBS
      • Edinburgh, United Kingdom, EH9 1LW
        • Recruiting
        • Royal Hospital for Children
        • Principal Investigator:
          • Mark Broughman, MD MBChB
      • Glasgow, United Kingdom, G51 4TF
        • Recruiting
        • Royal Hospital for Children
        • Principal Investigator:
          • Jairam Sastry, MD FRSM
      • Leeds, United Kingdom, LS1 3EX
        • Recruiting
        • Leeds General Infirmary
        • Principal Investigator:
          • Danielle Ingham, PhD MRCPCH
      • Leicester, United Kingdom, LE1 5WW
        • Recruiting
        • Leicester Royal Infirmary
        • Principal Investigator:
          • Emma Ross, MBBS MRCPCH
      • Liverpool, United Kingdom, L12 2AP
        • Recruiting
        • Alder Hey Children's Hospital
        • Principal Investigator:
          • Barry Pizer, MD ChB FRCPCH
      • London, United Kingdom, WC1N 3JH
        • Recruiting
        • Great Ormond Street Hospital
        • Principal Investigator:
          • Catriona Duncan, MBBS MRCP
      • Manchester, United Kingdom, M13 9WL
        • Recruiting
        • Royal Manchester Children's Hospital
        • Principal Investigator:
          • Bernadette Brennan, MBChB FRCPCH
      • Newcastle Upon Tyne, United Kingdom, NE1 4LP
        • Recruiting
        • Great North Children's Hospital
        • Principal Investigator:
          • Gail Halliday, BSc MRCPCH
      • Nottingham, United Kingdom, NG7 2UH
        • Recruiting
        • Nottingham Children's Hospital
        • Principal Investigator:
          • Madhumita Dandapani, MBBS MRCPCH
      • Oxford, United Kingdom, OX3 9DU
        • Recruiting
        • Oxford Children's Hospital
        • Principal Investigator:
          • Esther Blanco, BSc MRCPCH
      • Sheffield, United Kingdom, S10 2TH
        • Recruiting
        • Sheffield Children's Hospital
        • Principal Investigator:
          • Anna Jenkins, MBBS MRCPCH
      • Southampton, United Kingdom, SO16 6YD
        • Recruiting
        • University Hospital Southampton
        • Principal Investigator:
          • Jessica Bate, MBBS MRCPCH
      • Sutton, United Kingdom, SM2 5PT
        • Recruiting
        • The Royal Marsden Hospital
        • Principal Investigator:
          • Paola Angelini, MD PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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).
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.
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)
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
Arm C used alone
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).
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
Arms C and D used in combination
Arm D used in combination
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.
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
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)
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
Arm F used in combination
Arm F used in combination
Arm used in combination

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event-free survival (EFS)
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.

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
Time Frame: 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.
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)
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.

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)
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.
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)
Time Frame: 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)
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)
Time Frame: 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)
From date of start of randomised treatment until date 30 days after last treatment.
Hearing loss according to the SIOP Boston Scale
Time Frame: 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
From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.
Best Response
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.
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
Time Frame: 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
From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.
Adherence to surgical guidelines
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 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

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 24, 2017

Primary Completion (Anticipated)

December 1, 2024

Study Completion (Anticipated)

December 1, 2025

Study Registration Dates

First Submitted

December 14, 2016

First Submitted That Met QC Criteria

January 10, 2017

First Posted (Estimate)

January 11, 2017

Study Record Updates

Last Update Posted (Actual)

September 9, 2022

Last Update Submitted That Met QC Criteria

September 5, 2022

Last Verified

September 1, 2022

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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